@article{zahid_waguespack_harman_kercher_nath_hasan_rizvi_spring_enderling_2024, title={Fractionated photoimmunotherapy stimulates an anti-tumour immune response: an integrated mathematical and in vitro study}, volume={9}, ISSN={["1532-1827"]}, DOI={10.1038/s41416-024-02844-y}, abstractNote={Abstract Background Advanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery. Methods We use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control. Results In vitro measurements of PIT dose responses revealed that although low light doses (<10 J/cm 2 ) lead to limited tumour cell killing they also increased proliferation of anti-tumour immune effector cells. Model simulations demonstrated that breaking up a larger light dose into multiple lower dose fractions (vis-à-vis fractionated radiotherapy) could be utilised to effect tumour control via stimulation of an anti-tumour immune response. Conclusions There is promise for applying fractionated PIT in the setting of EOC. However, recommending specific fractionated PIT dosimetry and timing will require appropriate model calibration on tumour-immune interaction data in human patients and subsequent validation of model predictions in prospective clinical trials.}, journal={BRITISH JOURNAL OF CANCER}, author={Zahid, Mohammad U. and Waguespack, Matthew and Harman, Rebecca C. and Kercher, Eric M. and Nath, Shubhankar and Hasan, Tayyaba and Rizvi, Imran and Spring, Bryan Q. and Enderling, Heiko}, year={2024}, month={Sep} }
 @article{overchuk_rickard_tulino_tan_ligler_huang_rizvi_2024, title={Overcoming the effects of fluid shear stress in ovarian cancer cell lines: Doxorubicin alone or photodynamic priming to target platinum resistance}, volume={6}, ISSN={["1751-1097"]}, url={https://doi.org/10.1111/php.13967}, DOI={10.1111/php.13967}, abstractNote={Abstract Resistance to platinum‐based chemotherapies remains a significant challenge in advanced‐stage high‐grade serous ovarian carcinoma, and patients with malignant ascites face the poorest outcomes. It is, therefore, important to understand the effects of ascites, including the associated fluid shear stress (FSS), on phenotypic changes and therapy response, specifically FSS‐induced chemotherapy resistance and the underlying mechanisms in ovarian cancer. This study investigated the effects of FSS on response to cisplatin, a platinum‐based chemotherapy, and doxorubicin, an anthracycline, both of which are commonly used to manage advanced‐stage ovarian cancer. Consistent with prior research, OVCAR‐3 and Caov‐3 cells cultivated under FSS demonstrated significant resistance to cisplatin. Examination of the role of mitochondria revealed an increase in mitochondrial DNA copy number and intracellular ATP content in cultures grown under FSS, suggesting that changes in mitochondria number and metabolic activity may contribute to platinum resistance. Interestingly, no resistance to doxorubicin was observed under FSS, the first such observation of a lack of resistance under these conditions. Finally, this study demonstrated the potential of photodynamic priming using benzoporphyrin derivative, a clinically approved photosensitizer that localizes in part to mitochondria and endoplasmic reticula, to enhance the efficacy of cisplatin, but not doxorubicin, thereby overcoming FSS‐induced platinum resistance.}, journal={PHOTOCHEMISTRY AND PHOTOBIOLOGY}, author={Overchuk, Marta and Rickard, Brittany P. and Tulino, Justin and Tan, Xianming and Ligler, Frances S. and Huang, Huang-Chiao and Rizvi, Imran}, year={2024}, month={Jun} }
 @article{ruhi_rickard_overchuk_sinawang_stanley_mansi_sierra_hayes_tan_akin_et al._2024, title={PpIX-enabled fluorescence-based detection and photodynamic priming of platinum-resistant ovarian cancer cells under fluid shear stress}, volume={8}, ISSN={["1751-1097"]}, DOI={10.1111/php.14014}, abstractNote={Abstract Over 75% percent of ovarian cancer patients are diagnosed with advanced‐stage disease characterized by unresectable intraperitoneal dissemination and the presence of ascites, or excessive fluid build‐up within the abdomen. Conventional treatments include cytoreductive surgery followed by multi‐line platinum and taxane chemotherapy regimens. Despite an initial response to treatment, over 75% of patients with advanced‐stage ovarian cancer will relapse and succumb to platinum‐resistant disease. Recent evidence suggests that fluid shear stress (FSS), which results from the movement of fluid such as ascites, induces epithelial‐to‐mesenchymal transition and confers resistance to carboplatin in ovarian cancer cells. This study demonstrates, for the first time, that FSS‐induced platinum resistance correlates with increased cellular protoporphyrin IX (PpIX), the penultimate downstream product of heme biosynthesis, the production of which can be enhanced using the clinically approved pro‐drug aminolevulinic acid (ALA). These data suggest that, with further investigation, PpIX could serve as a fluorescence‐based biomarker of FSS‐induced platinum resistance. Additionally, this study investigates the efficacy of PpIX‐enabled photodynamic therapy (PDT) and the secretion of extracellular vesicles under static and FSS conditions in Caov‐3 and NIH:OVCAR‐3 cells, two representative cell lines for high‐grade serous ovarian carcinoma (HGSOC), the most lethal form of the disease. FSS induces resistance to ALA‐PpIX‐mediated PDT, along with a significant increase in the number of EVs. Finally, the ability of PpIX‐mediated photodynamic priming (PDP) to enhance carboplatin efficacy under FSS conditions is quantified. These preliminary findings in monolayer cultures necessitate additional studies to determine the feasibility of PpIX as a fluorescence‐based indicator, and mediator of PDP, to target chemoresistance in the context of FSS.}, journal={PHOTOCHEMISTRY AND PHOTOBIOLOGY}, author={Ruhi, Mustafa Kemal and Rickard, Brittany P. and Overchuk, Marta and Sinawang, Prima Dewi and Stanley, Elizabeth and Mansi, Matthew and Sierra, Raymond G. and Hayes, Brandon and Tan, Xianming and Akin, Demir and et al.}, year={2024}, month={Aug} }
 @article{overchuk_ruhi_rickard_ligler_rizvi_2023, title={Development of a light emitting device for the treatment of peritoneal car- cinomatosis of ovarian origin by intracavitary photodynamic therapy}, volume={41}, ISSN={["1873-1597"]}, DOI={10.1016/j.pdpdt.2023.103406}, abstractNote={Peritoneal carcinomatosis of ovarian origin (PCO) is an evolution of ovarian cancer, which is the fourth leading cause of death by cancer in women in France. PCO is defined by dissemination of cancerous cells from ovarian cancer to the peritoneal cavity. Photodynamic therapy (PDT) has been proposed in complement to the standard of care, consisting of surgery and chemotherapy. However, litterature has highlighted the lack of selectivity of available photosensitizers (PS) leading to inconclusive results [1, 2]. In this context, PRODYNOV project, initiated by our research team INSERM U1189 ONCOTHAI, has enabled the development of a patented PS. The high selectivity of this PS makes possible to carry out relevant PDT for PCO provided that an adequate illumination device would exist. In this study, we developed and assessed such a device. First, a test bench aiming to evaluate quantity and homogeneity of the delivered illumination has been developed. It is composed of a fantom of peritoneal cavity in which seven optical probes connected to a power-meter were placed in strategic zones characterised by high recurrence risk. Then, three illumination devices were implemented and assessed. The first one consisted of six fixed light emitting fabrics (LEF), the second one was a moving luminous wand, and the last one, a hybrid one, combined a fixed luminous wand and six fixed LEF. Light doses received by the probes have been calculated by integrating measured powers over illumination time. Each of the seven optical probes received a mean light dose of 0.68 mJ with the first illumination device (minimum: 18.37 10−3 mJ, maximum: 2.66 mJ), 0.11 mJ with the second one (minimum: 5.25 10−3 mJ, maximum: 0.35 mJ) and 0.65 mJ with the third one (minimum: 48.19 10−3 mJ, maximum: 1.27 mJ). With a variation coefficient of 77.1% (versus 93.1% for the first device and 119.5% for the second one), the hybrid device enabled to homogeneously illuminate the largest part of the cavity. For these reasons, the hybrid method has been selected as illumination process for PDT of PCO. Illumination solutions for PDT of PCO have been proposed and tested. One of these solutions has been approved. The light dose necessary for an effective treatment remains to be determined and first feasability tests will be led on mini-pig by the end of the year.}, journal={PHOTODIAGNOSIS AND PHOTODYNAMIC THERAPY}, author={Overchuk, Marta and Ruhi, Mustafa Kemal and Rickard, Brittany and Ligler, Frances and Rizvi, Imran}, year={2023}, month={Mar} }
 @article{rickard_overchuk_tulino_tan_ligler_bae-jump_fenton_rizvi_2023, title={Exposure to select PFAS and PFAS mixtures alters response to platinum-based chemotherapy in endometrial cancer cell lines}, volume={22}, ISSN={1476-069X}, url={http://dx.doi.org/10.1186/s12940-023-01034-2}, DOI={10.1186/s12940-023-01034-2}, abstractNote={Abstract
                Background
                Exposure to per- and poly-fluoroalkyl substances (PFAS) has been associated with significant alterations in female reproductive health. These include changes in menstrual cyclicity, timing of menarche and menopause, and fertility outcomes, as well as increased risk of endometriosis, all of which may contribute to an increased risk of endometrial cancer. The effect of PFAS on endometrial cancer cells, specifically altered treatment response and biology, however, remains poorly studied. Like other gynecologic malignancies, a key contributor to lethality in endometrial cancer is resistance to chemotherapeutics, specifically to platinum-based agents that are used as the standard of care for patients with advanced-stage and/or recurrent disease.
              
                Objectives
                To explore the effect of environmental exposures, specifically PFAS, on platinum-based chemotherapy response and mitochondrial function in endometrial cancer.
              
                Methods
                HEC-1 and Ishikawa endometrial cancer cells were exposed to sub-cytotoxic nanomolar and micromolar concentrations of PFAS/PFAS mixtures and were treated with platinum-based chemotherapy. Survival fraction was measured 48-h post-chemotherapy treatment. Mitochondrial membrane potential was evaluated in both cell lines following exposure to PFAS ± chemotherapy treatment.
              
                Results
                HEC-1 and Ishikawa cells displayed differing outcomes after PFAS exposure and chemotherapy treatment. Cells exposed to PFAS appeared to be less sensitive to carboplatin, with instances of increased survival fraction, indicative of platinum resistance, observed in HEC-1 cells. In Ishikawa cells treated with cisplatin, PFAS mixture exposure significantly decreased survival fraction. In both cell lines, increases in mitochondrial membrane potential were observed post-PFAS exposure ± chemotherapy treatment.
              
                Discussion
                Exposure of endometrial cancer cell lines to PFAS/PFAS mixtures had varying effects on response to platinum-based chemotherapies. Increased survival fraction post-PFAS + carboplatin treatment suggests platinum resistance, while decreased survival fraction post-PFAS mixture + cisplatin exposure suggests enhanced therapeutic efficacy. Regardless of chemotherapy sensitivity status, mitochondrial membrane potential findings suggest that PFAS exposure may affect endometrial cancer cell mitochondrial functioning and should be explored further.
              }, number={1}, journal={Environmental Health}, publisher={Springer Science and Business Media LLC}, author={Rickard, Brittany P. and Overchuk, Marta and Tulino, Justin and Tan, Xianming and Ligler, Frances S. and Bae-Jump, Victoria L. and Fenton, Suzanne E. and Rizvi, Imran}, year={2023}, month={Dec} }
 @article{rickard_overchuk_chappell_kemal ruhi_sinawang_nguyen hoang_akin_demirci_franco_fenton_et al._2023, title={Methods to Evaluate Changes in Mitochondrial Structure and Function in Cancer}, volume={15}, ISSN={2072-6694}, url={http://dx.doi.org/10.3390/cancers15092564}, DOI={10.3390/cancers15092564}, abstractNote={Mitochondria are regulators of key cellular processes, including energy production and redox homeostasis. Mitochondrial dysfunction is associated with various human diseases, including cancer. Importantly, both structural and functional changes can alter mitochondrial function. Morphologic and quantifiable changes in mitochondria can affect their function and contribute to disease. Structural mitochondrial changes include alterations in cristae morphology, mitochondrial DNA integrity and quantity, and dynamics, such as fission and fusion. Functional parameters related to mitochondrial biology include the production of reactive oxygen species, bioenergetic capacity, calcium retention, and membrane potential. Although these parameters can occur independently of one another, changes in mitochondrial structure and function are often interrelated. Thus, evaluating changes in both mitochondrial structure and function is crucial to understanding the molecular events involved in disease onset and progression. This review focuses on the relationship between alterations in mitochondrial structure and function and cancer, with a particular emphasis on gynecologic malignancies. Selecting methods with tractable parameters may be critical to identifying and targeting mitochondria-related therapeutic options. Methods to measure changes in mitochondrial structure and function, with the associated benefits and limitations, are summarized.}, number={9}, journal={Cancers}, publisher={MDPI AG}, author={Rickard, Brittany P. and Overchuk, Marta and Chappell, Vesna A. and Kemal Ruhi, Mustafa and Sinawang, Prima Dewi and Nguyen Hoang, Tina Thuy and Akin, Demir and Demirci, Utkan and Franco, Walfre and Fenton, Suzanne E. and et al.}, year={2023}, month={Apr}, pages={2564} }
 @article{overchuk_ruhi_rickard_ligler_rizvi_2023, title={Targeted PDT Combinations to Overcome Fluid Shear Stress-induced Plat- inum Resistance in Ovarian Cancer}, volume={41}, ISSN={["1873-1597"]}, DOI={10.1016/j.pdpdt.2023.103405}, abstractNote={Ovarian cancer is the deadliest gynecologic malignancy — in 2020 alone, ovarian cancer claimed lives of 13,940 patients in the United States and 29,000 in Europe [1]. Such high ovarian cancer mortality can be explained by the fact that most patients are diagnosed with advanced-stage disease and 70% of them develop resistance to platinum-based therapies within the first 5 years [1]. One of the potential contributing factors to treatment failure in ovarian cancer is malignant ascites, or excessive fluid buildup in the peritoneal cavity. Ascites creates a unique molecular and biophysical environment, providing cancer cells with a nutrient- and growth factor-rich media and exposing them to abnormal physical stress. Our research group has been studying the effects of fluid shear stress (FSS) on ovarian cancer cell phenotypes and treatment responsiveness [2]. It was found that FSS confers resistance to carboplatin, activates the epidermal growth factor receptor (EGFR) as well as the downstream signaling cascades, and promotes epithelial-mesenchymal transition. These findings revealed the need for strategies that would remain effective under flow conditions and aid the effectiveness of standard of care treatments. Photodynamic therapy (PDT), which utilizes photosensitizers and light to generate cytotoxic reactive molecular species, provides a mechanistically distinct way of targeting chemoresistant cell populations. It was demonstrated that low-dose PDT with EGFR-targeted benzoporphyrin derivative photoimmunoconjugates remains effective in a 3D perfusion model for ovarian cancer, under conditions that induce resistance to carboplatin and EGFR overexpression and activation [2]. Encouraged by these findings, we continue exploring benzoporphyrin derivative-enabled PDT as a stand-alone therapy or in combination with cisplatin under static and flow conditions. Overall, we believe that photodynamic therapy has a potential to become an indispensable tool in late-stage ovarian cancer treatment, effectively destroying and/or sensitizing chemoresistant cell populations, decreasing the required chemotherapy dose and expanding the therapeutic window.}, journal={PHOTODIAGNOSIS AND PHOTODYNAMIC THERAPY}, author={Overchuk, Marta and Ruhi, Mustafa Kemal and Rickard, Brittany and Ligler, Frances and Rizvi, Imran}, year={2023}, month={Mar} }
 @article{sorrin_zhou_may_liu_mcnaughton_rahman_liang_rizvi_roque_huang_2023, title={Transient fluid flow improves photoimmunoconjugate delivery and photoimmunotherapy efficacy}, volume={26}, ISSN={["2589-0042"]}, url={https://europepmc.org/articles/PMC10372742}, DOI={10.1016/j.isci.2023.107221}, abstractNote={Circulating drugs in the peritoneal cavity is an effective strategy for advanced ovarian cancer treatment. Photoimmunotherapy, an emerging modality with potential for the treatment of ovarian cancer, involves near-infrared light activation of antibody-photosensitizer conjugates (photoimmunoconjugates) to generate cytotoxic reactive oxygen species. Here, a microfluidic cell culture model is used to study how fluid flow-induced shear stress affects photoimmunoconjugate delivery to ovarian cancer cells. Photoimmunoconjugates are composed of the antibody, cetuximab, conjugated to the photosensitizer, and benzoporphyrin derivative. Longitudinal tracking of photoimmunoconjugate treatment under flow conditions reveals enhancements in subcellular photosensitizer accumulation. Compared to static conditions, fluid flow-induced shear stress at 0.5 and 1 dyn/cm2 doubled the cellular delivery of photoimmunoconjugates. Fluid flow-mediated treatment with three different photosensitizer formulations (benzoporphyrin derivative, photoimmunoconjugates, and photoimmunoconjugate-coated liposomes) led to enhanced phototoxicity compared to static conditions. This study confirms the fundamental role of fluid flow-induced shear stress in the anti-cancer effects of photoimmunotherapy.}, number={8}, journal={ISCIENCE}, author={Sorrin, Aaron J. and Zhou, Keri and May, Katherine and Liu, Cindy and McNaughton, Kathryn and Rahman, Idrisa and Liang, Barry J. and Rizvi, Imran and Roque, Dana M. and Huang, Huang-Chiao}, year={2023}, month={Aug} }
 @article{kessel_obaid_rizvi_2022, title={Critical PDT theory II: Current concepts and indications}, volume={39}, ISSN={["1873-1597"]}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458629}, DOI={10.1016/j.pdpdt.2022.102923}, abstractNote={While photodynamic therapy (PDT) is effective for the eradication of select neoplasia and certain other pathologic conditions, it has yet to achieve wide acceptance in clinical medicine. A variety of factors contribute to this situation including relations with the pharmaceutical industry that have often been problematic. Some current studies relating to photodynamic effects are 'phenomenological', i.e., they describe phenomena that only reiterate what is already known. The net result has been a tendency of granting agencies to become disillusioned with support for PDT research. This report is intended to provide some thoughts on current research efforts that improve clinical relevance and those that do not.}, journal={PHOTODIAGNOSIS AND PHOTODYNAMIC THERAPY}, author={Kessel, David and Obaid, Girgis and Rizvi, Imran}, year={2022}, month={Sep} }
 @article{rickard_overchuk_obaid_ruhi_demirci_fenton_santos_kessel_rizvi_2022, title={Photochemical Targeting of Mitochondria to Overcome Chemoresistance in Ovarian Cancer<sup>†}, volume={99}, ISSN={0031-8655 1751-1097}, url={http://dx.doi.org/10.1111/php.13723}, DOI={10.1111/php.13723}, abstractNote={AbstractOvarian cancer is the most lethal gynecologic malignancy with a stubborn mortality rate of ~65%. The persistent failure of multiline chemotherapy, and significant tumor heterogeneity, has made it challenging to improve outcomes. A target of increasing interest is the mitochondrion because of its essential role in critical cellular functions, and the significance of metabolic adaptation in chemoresistance. This review describes mitochondrial processes, including metabolic reprogramming, mitochondrial transfer and mitochondrial dynamics in ovarian cancer progression and chemoresistance. The effect of malignant ascites, or excess peritoneal fluid, on mitochondrial function is discussed. The role of photodynamic therapy (PDT) in overcoming mitochondria‐mediated resistance is presented. PDT, a photochemistry‐based modality, involves the light‐based activation of a photosensitizer leading to the production of short‐lived reactive molecular species and spatiotemporally confined photodamage to nearby organelles and biological targets. The consequential effects range from subcytotoxic priming of target cells for increased sensitivity to subsequent treatments, such as chemotherapy, to direct cell killing. This review discusses how PDT‐based approaches can address key limitations of current treatments. Specifically, an overview of the mechanisms by which PDT alters mitochondrial function, and a summary of preclinical advancements and clinical PDT experience in ovarian cancer are provided.}, number={2}, journal={Photochemistry and Photobiology}, publisher={Wiley}, author={Rickard, Brittany P. and Overchuk, Marta and Obaid, Girgis and Ruhi, Mustafa Kemal and Demirci, Utkan and Fenton, Suzanne E. and Santos, Janine H. and Kessel, David and Rizvi, Imran}, year={2022}, month={Oct}, pages={448–468} }
 @article{rickard_tan_fenton_rizvi_2022, title={Photodynamic Priming Overcomes Per‐ and Polyfluoroalkyl Substance (<scp>PFAS}, volume={99}, ISSN={0031-8655 1751-1097}, url={http://dx.doi.org/10.1111/php.13728}, DOI={10.1111/php.13728}, abstractNote={Abstract Per‐ and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants linked to adverse outcomes, including for female reproductive biology and related cancers. We recently reported, for the first time, that PFAS induce platinum resistance in ovarian cancer, potentially through altered mitochondrial function. Platinum resistance is a major barrier in the management of ovarian cancer, necessitating complementary therapeutic approaches. Photodynamic therapy (PDT) is a light‐based treatment modality that reverses platinum resistance and synergizes with platinum‐based chemotherapy. The present study is the first to demonstrate the ability of photodynamic priming (PDP), a low‐dose, sub‐cytotoxic variant of PDT, to overcome PFAS‐induced platinum resistance. Comparative studies of PDP efficacy using either benzoporphyrin derivative (BPD) or 5‐aminolevulinic acid‐induced protoporphyrin IX (PpIX) were conducted in two human ovarian cancer cell lines (NIH:OVCAR‐3 and Caov‐3). BPD and PpIX are clinically approved photosensitizers that preferentially localize to, or are partly synthesized in, mitochondria. PDP overcomes carboplatin resistance in PFAS‐exposed ovarian cancer cells, demonstrating the feasibility of this approach to target the deleterious effects of environmental contaminants. Decreased survival fraction in PDP + carboplatin treated cells was accompanied by decreased mitochondrial membrane potential, suggesting that PDP modulates the mitochondrial membrane, reducing membrane potential and re‐sensitizing ovarian cancer cells to carboplatin.}, number={2}, journal={Photochemistry and Photobiology}, publisher={Wiley}, author={Rickard, Brittany P. and Tan, Xianming and Fenton, Suzanne E. and Rizvi, Imran}, year={2022}, month={Nov}, pages={793–813} }
 @article{karimnia_stanley_fitzgerald_rizvi_slack_celli_2022, title={Photodynamic Stromal Depletion Enhances Therapeutic Nanoparticle Delivery in 3D Pancreatic Ductal Adenocarcinoma Tumor Models}, volume={8}, ISSN={["1751-1097"]}, url={https://doi.org/10.1111/php.13663}, DOI={10.1111/php.13663}, abstractNote={ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human malignancies. PDAC is characterized by dense fibrous stroma which obstructs drug delivery and plays complex tumor‐promoting roles. Photodynamic therapy (PDT) is a light‐based modality which has been demonstrated to be clinically feasible and effective for tumors of the pancreas. Here, we use in vitro heterocellular 3D co‐culture models in conjunction with imaging, bulk rheology and microrheology to investigate photodegradation of non‐cellular components of PDAC stroma (photodynamic stromal depletion, PSD). By measuring the rheology of extracellular matrix (ECM) before and after PDT we find that softening of ECM is concomitant with increased transport of nanoparticles (NPs). At the same time, as shown by us previously, photodestruction of stromal fibroblasts leads to enhanced tumor response to PDT. Here we specifically evaluate the capability of PSD to enhance RNA nanomedicine delivery, using a NP carrying an inhibitor of miR‐21‐5P, a PDAC oncomiR. We confirm improved delivery of this therapeutic NP after PSD by observation of increased expression of PDCD4, a protein target of miR‐21‐5P. Collectively, these results in 3D tumor models suggest that PSD could be developed to enhance delivery of other cancer therapeutics and improve tumor response to treatment.}, journal={PHOTOCHEMISTRY AND PHOTOBIOLOGY}, author={Karimnia, Vida and Stanley, M. Elizabeth and Fitzgerald, Christian T. and Rizvi, Imran and Slack, Frank J. and Celli, Jonathan P.}, year={2022}, month={Aug} }
 @article{rickard_tan_fenton_rizvi_2022, title={Select Per- and Polyfluoroalkyl Substances (PFAS) Induce Resistance to Carboplatin in Ovarian Cancer Cell Lines}, volume={23}, ISSN={1422-0067}, url={http://dx.doi.org/10.3390/ijms23095176}, DOI={10.3390/ijms23095176}, abstractNote={Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants associated with adverse reproductive outcomes including reproductive cancers in women. PFAS can alter normal ovarian function, but the effects of PFAS on ovarian cancer progression and therapy response remain understudied. Ovarian cancer is the most lethal gynecologic malignancy, and a major barrier to effective treatment is resistance to platinum-based chemotherapy. Platinum resistance may arise from exposure to external stimuli such as environmental contaminants. This study evaluated PFAS and PFAS mixture exposures to two human ovarian cancer cell lines to evaluate the ability of PFAS exposure to affect survival fraction following treatment with carboplatin. This is the first study to demonstrate that, at sub-cytotoxic concentrations, select PFAS and PFAS mixtures increased survival fraction in ovarian cancer cells following carboplatin treatment, indicative of platinum resistance. A concomitant increase in mitochondrial membrane potential, measured by the JC-1 fluorescent probe, was observed in PFAS-exposed and PFAS + carboplatin-treated cells, suggesting a potential role for altered mitochondrial function that requires further investigation.}, number={9}, journal={International Journal of Molecular Sciences}, publisher={MDPI AG}, author={Rickard, Brittany P. and Tan, Xianming and Fenton, Suzanne E. and Rizvi, Imran}, year={2022}, month={May}, pages={5176} }
 @article{conrad_conway_polacheck_rizvi_scarcelli_2022, title={Water transport regulates nucleus volume, cell density, Young's modulus, and E-cadherin expression in tumor spheroids.}, url={https://doi.org/10.1016/j.ejcb.2022.151278}, DOI={10.1016/j.ejcb.2022.151278}, abstractNote={Cell volume is maintained by the balance of water and solutes across the cell membrane and plays an important role in mechanics and biochemical signaling in cells. Here, we assess the relationship between cell volume, mechanical properties, and E-cadherin expression in three-dimensional cultures for ovarian cancer. To determine the effect of water transport in multi-cellular tumors, ovarian cancer spheroids were subjected to hypotonic and hypertonic shock using water and sucrose mixtures, respectively. Increased osmolality resulted in decreased nucleus volume, increased Young’s modulus, and increased tumor cell density in ovarian cancer spheroids. Next, we looked at the reversibility of mechanics and morphology after 5 min of osmotic shock and found that spheroids had a robust ability to return to their original state. Finally, we quantified the size of E-cadherin clusters at cell-cell junctions and observed a significant increase in aggregate size following 30 min of hypertonic and hypotonic osmotic shocks. Yet, these effects were not apparent after 5 min of osmotic shock, illustrating a temporal difference between E-cadherin regulation and the immediate mechanical and morphology changes. Still, the osmotically induced E-cadherin aggregates which formed at the 30-minute timepoint was reversible when spheroids were replenished with isotonic medium. Altogether, this work demonstrated an important role of osmolality in transforming mechanical, morphology, and molecular states.}, journal={European journal of cell biology}, author={Conrad, Christina and Conway, J and Polacheck, WJ and Rizvi, I and Scarcelli, G}, year={2022}, month={Sep} }
 @article{soto_guimaraes_reis_franco_rizvi_demirci_2021, title={Emerging biofabrication approaches for gastrointestinal organoids towards patient specific cancer models}, volume={504}, ISSN={["1872-7980"]}, url={https://doi.org/10.1016/j.canlet.2021.01.023}, DOI={10.1016/j.canlet.2021.01.023}, abstractNote={Tissue engineered organoids are simple biomodels that can emulate the structural and functional complexity of specific organs. Here, we review developments in three-dimensional (3D) artificial cell constructs to model gastrointestinal dynamics towards cancer diagnosis. We describe bottom-up approaches to fabricate close-packed cell aggregates, from the use of biochemical and physical cues to guide the self-assembly of organoids, to the use of engineering approaches, including 3D printing/additive manufacturing and external field-driven protocols. Finally, we outline the main challenges and possible risks regarding the potential translation of gastrointestinal organoids from laboratory settings to patient-specific models in clinical applications.}, journal={CANCER LETTERS}, author={Soto, Fernando and Guimaraes, Carlos F. and Reis, Rui L. and Franco, Walfre and Rizvi, Imran and Demirci, Utkan}, year={2021}, month={Apr}, pages={116–124} }
 @misc{rickard_conrad_sorrin_ruhi_reader_huang_franco_scarcelli_polacheck_roque_et al._2021, title={Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response}, volume={13}, ISSN={["2072-6694"]}, url={https://www.mdpi.com/2072-6694/13/17/4318}, DOI={10.3390/cancers13174318}, abstractNote={Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.}, number={17}, journal={CANCERS}, author={Rickard, Brittany P. and Conrad, Christina and Sorrin, Aaron J. and Ruhi, Mustafa Kemal and Reader, Jocelyn C. and Huang, Stephanie A. and Franco, Walfre and Scarcelli, Giuliano and Polacheck, William J. and Roque, Dana M. and et al.}, year={2021}, month={Sep} }
 @article{conrad_moore_polacheck_rizvi_scarcelli_2022, title={Mechanical Modulation of Ovarian Cancer Tumor Nodules Under Flow}, volume={69}, url={https://doi.org/10.1109/TBME.2021.3092641}, DOI={10.1109/TBME.2021.3092641}, abstractNote={Perfusion models are valuable tools to mimic complex features of the tumor microenvironment and to study cell behavior. In ovarian cancer, mimicking disease pathology of ascites has been achieved by seeding tumor nodules on a basement membrane and subjecting them to long-term continuous flow. In this scenario it is particularly important to study the role of mechanical stress on cancer progression. Mechanical cues are already known to be important in key cancer processes such as survival, proliferation, and migration. However, probing cell mechanical properties within microfluidic platforms has not been achievable with current technologies since samples are not easily accessible within most microfluidic channels.Here, to analyze the mechanical properties of cells within a perfusion chamber, we use Brillouin confocal microscopy, an all-optical technique that requires no contact or perturbation to the sample.Our results indicate that ovarian cancer nodules under long-term continuous flow have a significantly lower longitudinal modulus compared to nodules maintained in a static condition.We further dissect the role of distinct mechanical perturbations (e.g., shear flow, osmolality) on tumor nodule properties.In summary, the unique combination of a long-term microfluidic culture and noninvasive mechanical analysis technique provides insights on the effects of physical forces in ovarian cancer pathology.}, number={1}, journal={IEEE Transactions on Biomedical Engineering}, publisher={Institute of Electrical and Electronics Engineers (IEEE)}, author={Conrad, Christina and Moore, Kaitlin and Polacheck, William and Rizvi, Imran and Scarcelli, Giuliano}, year={2022}, month={Jan}, pages={294–301} }
 @article{rickard_rizvi_fenton_2022, title={Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease}, volume={465}, ISSN={0300-483X}, url={http://dx.doi.org/10.1016/j.tox.2021.153031}, DOI={10.1016/j.tox.2021.153031}, abstractNote={Per- and poly-fluoroalkyl substances (PFAS) are widespread environmental contaminants frequently detected in drinking water supplies worldwide that have been linked to a variety of adverse reproductive health outcomes in women. Compared to men, reproductive health effects in women are generally understudied while global trends in female reproduction rates are declining. Many factors may contribute to the observed decline in female reproduction, one of which is environmental contaminant exposure. PFAS have been used in home, food storage, personal care and industrial products for decades. Despite the phase-out of some legacy PFAS due to their environmental persistence and adverse health effects, alternative, short-chain and legacy PFAS mixtures will continue to pollute water and air and adversely influence women's health. Studies have shown that both long- and short-chain PFAS disrupt normal reproductive function in women through altering hormone secretion, menstrual cyclicity, and fertility. Here, we summarize the role of a variety of PFAS and PFAS mixtures in female reproductive tract dysfunction and disease. Since these chemicals may affect reproductive tissues directly or indirectly through endocrine disruption, the role of PFAS in breast, thyroid, and hypothalamic-pituitary-gonadal axis function are also discussed as the interplay between these tissues may be critical in understanding the long-term reproductive health effects of PFAS in women. A major research gap is the need for mechanism of action data - the targets for PFAS in the female reproductive and endocrine systems are not evident, but the effects are many. Given the global decline in female fecundity and the ability of PFAS to negatively impact female reproductive health, further studies are needed to examine effects on endocrine target tissues involved in the onset of reproductive disorders of women.}, journal={Toxicology}, publisher={Elsevier BV}, author={Rickard, Brittany P. and Rizvi, Imran and Fenton, Suzanne E.}, year={2022}, month={Jan}, pages={153031} }
 @article{broekgaarden_alkhateeb_bano_bulin_obaid_rizvi_hasan_2020, title={Cabozantinib Inhibits Photodynamic Therapy-Induced Auto- and Paracrine MET Signaling in Heterotypic Pancreatic Microtumors}, url={https://doi.org/10.3390/cancers12061401}, DOI={10.3390/cancers12061401}, abstractNote={Extensive desmoplasia is a hallmark of pancreatic ductal adenocarcinoma (PDAC), which frequently associates with treatment resistance. Recent findings indicate that a combination of photodynamic therapy and the multi-kinase inhibitor cabozantinib achieved local tumor control and a significant decrease in tumor metastases in preclinical PDAC models, but the underlying therapeutic mechanisms remain unclear. This study elucidates the molecular basis of this multi-agent regimen, focusing on the role of MET signaling. Since MET activation stems from its interaction with hepatocyte growth factor (HGF), which is typically secreted by fibroblasts, we developed heterotypic PDAC microtumor models that recapitulate these interactions. In these models, MET signaling can be constitutively activated through paracrine and autocrine mechanisms. Photodynamic therapy caused significant elevations in HGF secretion by fibroblasts, suggesting it plays a complex role in the modulation of the paracrine HGF–MET signaling cascade in desmoplastic tumors. Blocking MET phosphorylation with adjuvant cabozantinib caused a significant improvement in photodynamic therapy efficacy, most notably by elevating spheroid necrosis at low radiant exposures. These findings highlight that adjuvant photodynamic therapy can augment chemotherapy efficacies, and potentially achieve improved management of desmoplastic PDAC in a more tolerable manner.}, journal={Cancers}, author={Broekgaarden, Mans and Alkhateeb, Ahmed and Bano, Shazia and Bulin, Anne-Laure and Obaid, Girgis and Rizvi, Imran and Hasan, Tayyaba}, year={2020}, month={May} }
 @article{nath_pigula_khan_hanna_ruhi_dehkordy_pushpavanam_rege_moore_tsujita_et al._2020, title={Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress}, url={https://www.mdpi.com/2077-0383/9/4/924}, DOI={10.3390/jcm9040924}, abstractNote={A key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, as well as stromal and physical cues in the microenvironment. Ovarian cancer commonly disseminates via transcoelomic routes to distant sites, which is associated with the frequent production of malignant ascites, as well as the poorest prognosis. In addition to providing a cell and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress on tumors. An understudied area in ovarian cancer research is the impact of fluid shear stress on treatment failure. Here, we investigate the effect of fluid shear stress on response to platinum-based chemotherapy and the modulation of molecular pathways associated with aggressive disease in a perfusion model for adherent 3D ovarian cancer nodules. Resistance to carboplatin is observed under flow with a concomitant increase in the expression and activation of the epidermal growth factor receptor (EGFR) as well as downstream signaling members mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). The uptake of platinum by the 3D ovarian cancer nodules was significantly higher in flow cultures compared to static cultures. A downregulation of phospho-focal adhesion kinase (p-FAK), vinculin, and phospho-paxillin was observed following carboplatin treatment in both flow and static cultures. Interestingly, low-dose anti-EGFR photoimmunotherapy (PIT), a targeted photochemical modality, was found to be equally effective in ovarian tumors grown under flow and static conditions. These findings highlight the need to further develop PIT-based combinations that target the EGFR, and sensitize ovarian cancers to chemotherapy in the context of flow-induced shear stress.}, journal={Journal of Clinical Medicine}, author={Nath, Shubhankar and Pigula, Michael and Khan, Amjad P. and Hanna, William and Ruhi, Mustafa Kemal and Dehkordy, Farzaneh MahmoodPoor and Pushpavanam, Karthik and Rege, Kaushal and Moore, Kaitlin and Tsujita, Yujiro and et al.}, year={2020}, month={Mar} }
 @article{karimnia_rizvi_slack_celli_2021, title={Photodestruction of Stromal Fibroblasts Enhances Tumor Response to PDT in 3D Pancreatic Cancer Coculture Models}, volume={97}, ISSN={["1751-1097"]}, url={https://doi.org/10.1111/php.13339}, DOI={10.1111/php.13339}, abstractNote={AbstractPancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human cancers. The dismal response of PDAC to virtually all therapeutics is associated, in part, with a characteristically dense fibrotic stroma. This stroma not only acts as a barrier to drug perfusion, but also promotes tumor survival through paracrine crosstalk and biophysical interactions. Photodynamic therapy (PDT) is being explored for PDAC treatment, though the impact of tumor‐promoting stromal crosstalk on PDT response in PDAC is not well‐characterized. The current study assesses the effect of tumor‐stroma interactions on response to PDT or chemotherapy in heterocellular 3D cocultures using PDAC cells and two different fibroblastic cell types (pancreatic stellate cells, PSCs, and a normal human fibroblast cell line, MRC5) embedded in extracellular matrix (ECM). While stromal fibroblasts promote resistance to chemotherapy as expected, PDAC 3D nodules in coculture with fibroblasts exhibit increased response to PDT relative to homotypic cultures. These results point to the potential for PDT to overcome tumor‐promoting stromal interactions associated with poor therapeutic response in PDAC.}, number={2}, journal={PHOTOCHEMISTRY AND PHOTOBIOLOGY}, author={Karimnia, Vida and Rizvi, Imran and Slack, Frank J. and Celli, Jonathan P.}, year={2021}, month={Mar}, pages={416–426} }
 @article{sorrin_ruhi_ferlic_karimnia_polacheck_celli_huang_rizvi_2020, title={Photodynamic Therapy and the Biophysics of the Tumor Microenvironment}, url={https://doi.org/10.1111/php.13209}, DOI={10.1111/php.13209}, abstractNote={Targeting the tumor microenvironment (TME) provides opportunities to modulate tumor physiology, enhance the delivery of therapeutic agents, impact immune response and overcome resistance. Photodynamic therapy (PDT) is a photochemistry-based, nonthermal modality that produces reactive molecular species at the site of light activation and is in the clinic for nononcologic and oncologic applications. The unique mechanisms and exquisite spatiotemporal control inherent to PDT enable selective modulation or destruction of the TME and cancer cells. Mechanical stress plays an important role in tumor growth and survival, with increasing implications for therapy design and drug delivery, but remains understudied in the context of PDT and PDT-based combinations. This review describes pharmacoengineering and bioengineering approaches in PDT to target cellular and noncellular components of the TME, as well as molecular targets on tumor and tumor-associated cells. Particular emphasis is placed on the role of mechanical stress in the context of targeted PDT regimens, and combinations, for primary and metastatic tumors.}, journal={Photochemistry and Photobiology}, author={Sorrin, Aaron J. and Ruhi, Mustafa Kemal and Ferlic, Nathaniel A. and Karimnia, Vida and Polacheck, William J. and Celli, Jonathan P. and Huang, Huang‐Chiao and Rizvi, Imran}, year={2020}, month={Mar} }
 @article{anbil_pigula_huang_mallidi_broekgaarden_baglo_de silva_simeone_mino-kenudson_maytin_et al._2020, title={Vitamin D Receptor Activation and Photodynamic Priming Enables Durable Low-dose Chemotherapy}, volume={19}, ISSN={["1538-8514"]}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272264}, DOI={10.1158/1535-7163.MCT-19-0791}, abstractNote={Abstract
               Patients with cancer often confront the decision of whether to continue high-dose chemotherapy at the expense of cumulative toxicities. Reducing the dose of chemotherapy regimens while preserving efficacy is sorely needed to preserve the performance status of these vulnerable patients, yet has not been prioritized. Here, we introduce a dual pronged approach to modulate the microenvironment of desmoplastic pancreatic tumors and enable significant dose deescalation of the FDA-approved chemotherapeutic nanoliposomal irinotecan (nal-IRI) without compromising tumor control. We demonstrate that light-based photodynamic priming (PDP) coupled with vitamin D3 receptor (VDR) activation within fibroblasts increases intratumoral nal-IRI accumulation and suppresses protumorigenic CXCL12/CXCR7 crosstalk. Combined photodynamic and biochemical modulation of the tumor microenvironment enables a 75% dose reduction of nal-IRI while maintaining treatment efficacy, resulting in improved tolerability. Modifying the disease landscape to increase the susceptibility of cancer, via preferentially modulating fibroblasts, represents a promising and relatively underexplored strategy to enable dose deescalation. The approach presented here, using a combination of three clinically available therapies with nonoverlapping toxicities, can be rapidly translated with minimal modification to treatment workflow, and challenges the notion that significant improvements in chemotherapy efficacy can only be achieved at the expense of increased toxicity.}, number={6}, journal={MOLECULAR CANCER THERAPEUTICS}, author={Anbil, Sriram and Pigula, Michael and Huang, Huang-Chiao and Mallidi, Srivalleesha and Broekgaarden, Mans and Baglo, Yan and De Silva, Pushpamali and Simeone, Diane M. and Mino-Kenudson, Mari and Maytin, Edward V and et al.}, year={2020}, month={Jun}, pages={1308–1319} }
 @article{kercher_nath_rizvi_spring_2020, title={Cancer Cell‐targeted and Activatable Photoimmunotherapy Spares T Cells in a 3D Coculture Model}, url={https://doi.org/10.1111/php.13153}, DOI={10.1111/php.13153}, abstractNote={Abstract Photodynamic therapy ( PDT ) is an established therapeutic modality that uses nonionizing near‐infrared light to activate photocytotoxicity of endogenous or exogenous photosensitizers ( PS s). An ongoing avenue of cancer research involves leveraging PDT to stimulate antitumor immune responses; however, these effects appear to be best elicited in low‐dose regimens that do not provide significant tumor reduction using conventional, nonspecific PS s. The loss of immune enhancement at higher PDT doses may arise in part from indiscriminate damage to local immune cell populations, including tumor‐infiltrating T cells. We previously introduced “tumor‐targeted, activatable photoimmunotherapy” (ta PIT ) using molecular‐targeted and cell‐activatable antibody– PS conjugates to realize precision tumor photodamage with microscale fidelity. Here, we investigate the immune cell sparing effect provided by ta PIT in a 3D model of the tumor immune microenvironment. We report that high‐dose ta PIT spares 25% of the local immune cell population, five times more than the conventional PDT regimen, in a 3D coculture model incorporating epithelial ovarian cancer cells and T cells. These findings suggest that the enhanced selectivity of ta PIT may be utilized to achieve local tumor reduction with sparing of intratumor effector immune cells that would otherwise be lost if treated with conventional PDT .}, journal={Photochemistry and Photobiology}, author={Kercher, Eric M. and Nath, Shubhankar and Rizvi, Imran and Spring, Bryan Q.}, year={2020}, month={Mar} }
 @article{spring_lang_kercher_rizvi_wenham_conejo-garcia_hasan_gatenby_enderling_2019, title={Illuminating the Numbers: Integrating Mathematical Models to Optimize Photomedicine Dosimetry and Combination Therapies}, volume={7}, ISSN={["2296-424X"]}, DOI={10.3389/fphy.2019.00046}, abstractNote={Cancer photomedicine offers unique mechanisms for inducing local tumor damage with the potential to stimulate local and systemic anti-tumor immunity. Optically-active nanomedicine offers these features as well as spatiotemporal control of tumor-focused drug release to realize synergistic combination therapies. Achieving quantitative dosimetry is a major challenge, and dosimetry is fundamental to photomedicine for personalizing and tailoring therapeutic regimens to specific patients and anatomical locations. The challenge of dosimetry is perhaps greater for photomedicine than many standard therapies given the complexity of light delivery and light-tissue interactions as well as the resulting photochemistry responsible for tumor damage and drug-release, in addition to the usual intricacies of therapeutic agent delivery. An emerging multidisciplinary approach in oncology utilizes mathematical and computational models to iteratively and quantitively analyze complex dosimetry, and biological response parameters. These models are parameterized by preclinical and clinical observations and then tested against previously unseen data. Such calibrated and validated models can be deployed to simulate treatment doses, protocols, and combinations that have not yet been experimentally or clinically evaluated and can provide testable optimal treatment outcomes in a practical workflow. Here, we foresee the utility of these computational approaches to guide adaptive therapy, and how mathematical models might be further developed and integrated as a novel methodology to guide precision photomedicine.}, journal={FRONTIERS IN PHYSICS}, author={Spring, Bryan Q. and Lang, Ryan T. and Kercher, Eric M. and Rizvi, Imran and Wenham, Robert M. and Conejo-Garcia, Jose R. and Hasan, Tayyaba and Gatenby, Robert A. and Enderling, Heiko}, year={2019}, month={Apr} }
 @article{conrad_gray_stroka_rizvi_scarcelli_2019, title={Mechanical Characterization of 3D Ovarian Cancer Nodules Using Brillouin Confocal Microscopy}, volume={12}, ISSN={["1865-5033"]}, DOI={10.1007/s12195-019-00570-7}, abstractNote={The mechanical interaction between cells and their microenvironment is emerging as an important determinant of cancer progression and sensitivity to treatment, including in ovarian cancer (OvCa). However, current technologies limit mechanical analysis in 3D culture systems. Brillouin Confocal Microscopy is an optical non-contact method to assess the mechanical properties of biological materials. Here, we validate the ability of this technology to assess the mechanical properties of 3D tumor nodules.OvCa cells were cultured in 3D using two established methods: (1) overlay cultures on Matrigel; (2) spheroids in ultra-low attachment plates. To alter the mechanical state of these tumors, nodules were immersed in PBS with varying levels of sucrose to induce osmotic stress. Next, nodule mechanical properties were measured by Brillouin microscopy and validated with standard stress-strain tests: Atomic Force Microscopy (AFM) and a parallel plate compression device (Microsquisher). Finally, the nodules were treated with a chemotherapeutic commonly used to manage OvCa, carboplatin, to determine treatment-induced effects on tumor mechanical properties.Brillouin microscopy allows mechanical analysis with limited penetration depth (~ 92 µm for Matrigel method; ~ 54 µm for low attachment method). Brillouin microscopy metrics displayed the same trends as the corresponding "gold-standard" Young's moduli measured with stress-strain methods when the osmolality of the medium was increased. Nodules treated with carboplatin showed a decrease in Brillouin frequency shift.This validation study paves the way to evaluate the mechanics of 3D nodules, with micron-scale three-dimensional resolution and without contact, thus extending the experimental possibilities.}, number={3}, journal={CELLULAR AND MOLECULAR BIOENGINEERING}, author={Conrad, Christina and Gray, Kelsey M. and Stroka, Kimberly M. and Rizvi, Imran and Scarcelli, Giuliano}, year={2019}, month={Jun}, pages={215–226} }
 @article{rizvi_nath_obaid_ruhi_moore_bano_kessel_hasan_2019, title={A Combination of Visudyne and a Lipid‐anchored Liposomal Formulation of Benzoporphyrin Derivative Enhances Photodynamic Therapy Efficacy in a 3D Model for Ovarian Cancer}, url={https://doi.org/10.1111/php.13066}, DOI={10.1111/php.13066}, abstractNote={Abstract A major objective in developing new treatment approaches for lethal tumors is to reduce toxicity to normal tissues while maintaining therapeutic efficacy. Photodynamic therapy ( PDT ) provides a mechanistically distinct approach to treat tumors without the systemic toxicity of chemotherapy drugs. PDT involves the light‐based activation of a small molecule, a photosensitizer ( PS ), to generate reactive molecular species ( RMS ) that are toxic to target tissue. Depending on the PS localization, various cellular and subcellular components can be targeted, causing selective photodamage. It has been shown that targeted lysosomal photodamage followed by, or simultaneous with, mitochondrial photodamage using two different PS results in a considerable enhancement in PDT efficacy. Here, two liposomal formulations of benzoporphyrin derivative ( BPD ): (1) Visudyne (clinically approved) and (2) an in‐house formulation entrapping a lipid conjugate of BPD are used in combination with direct PS localization to mitochondria, endoplasmic reticulum and lysosomes, enabling simultaneous photodamage to all three organelles using a single wavelength of light. Building on findings by our group, and others, this study demonstrates, for the first time in a 3D model for ovarian cancer, that BPD ‐mediated photodestruction of lysosomes and mitochondria/ ER significantly enhances PDT efficacy at lower light doses than treatment with either PS formulation alone.}, journal={Photochemistry and Photobiology}, author={Rizvi, Imran and Nath, Shubhankar and Obaid, Girgis and Ruhi, Mustafa Kemal and Moore, Kaitlin and Bano, Shazia and Kessel, David and Hasan, Tayyaba}, year={2019}, month={Jan} }
 @article{broekgaarden_rizvi_bulin_petrovic_goldschmidt_massodi_celli_hasan_2018, title={Neoadjuvant photodynamic therapy augments immediate and prolonged oxaliplatin efficacy in metastatic pancreatic cancer organoids.}, url={https://europepmc.org/articles/PMC5849191}, DOI={10.18632/oncotarget.24425}, abstractNote={// Mans Broekgaarden 1 , Imran Rizvi 1 , Anne-Laure Bulin 1 , Ljubica Petrovic 2 , Ruth Goldschmidt 1 , Iqbal Massodi 1 , Jonathan P. Celli 2 and Tayyaba Hasan 1 1 Wellman Center for Photomedicine, Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA 2 Department of Physics, University of Massachusetts, Boston, MA 02125, USA Correspondence to: Tayyaba Hasan, email: thasan@mgh.harvard.edu Keywords: translational therapies; organoid models; experimental medicine; combination therapy; photochemotherapy Abbreviations: OxPt: oxaliplatin; BPD: benzoporphyrin derivative; PDT: photodynamic therapy; PI: propidium iodide Received: November 19, 2017 Accepted: January 23, 2018 Published: February 06, 2018 ABSTRACT Effective treatment of advanced metastatic disease remains the primary challenge in the management of inoperable pancreatic cancer. Current therapies such as oxaliplatin (OxPt)-based chemotherapy regimens (FOLFIRINOX) provide modest short-term survival improvements, yet with significant toxicity. Photodynamic therapy (PDT), a light-activated cancer therapy, demonstrated clinical promise for pancreatic cancer treatment and enhances conventional chemotherapies with non-overlapping toxicities. This study investigates the capacity of neoadjuvant PDT using a clinically-approved photosensitizer, benzoporphyrin derivative (BPD, verteporfin), to enhance OxPt efficacy in metastatic pancreatic cancer. Treatment effects were evaluated in organotypic three-dimensional (3D) cultures, clinically representative models that bridge the gap between conventional cell cultures and in vivo models. The temporally-spaced, multiparametric analyses demonstrated a superior efficacy for combined PDT+OxPt compared to each monotherapy alone, which was recapitulated on different organotypic pancreatic cancer cultures. The therapeutic benefit of neoadjuvant PDT to OxPt chemotherapy materialized in a time-dependent manner, reducing residual viable tissue and tumor viability in a manner not achievable with OxPt or PDT alone. These findings emphasize the need for intelligent combination therapies and relevant models to evaluate the temporal kinetics of interactions between mechanistically-distinct treatments and highlight the promise of PDT as a neoadjuvant treatment for disseminated pancreatic cancer.}, journal={Oncotarget}, author={Broekgaarden, M and Rizvi, I and Bulin, Anne-Laure and Petrovic, L and Goldschmidt, R and Massodi, I and Celli, JP and Hasan, Tayyaba}, year={2018}, month={Feb} }
 @article{rizvi_obaid_bano_hasan_kessel_2018, title={Photodynamic therapy: Promoting in vitro efficacy of photodynamic therapy by liposomal formulations of a photosensitizing agent.}, url={https://europepmc.org/articles/PMC7449601}, DOI={10.1002/lsm.22813}, abstractNote={Objective A relatively low level of lysosomal photodamage has been shown capable of promoting the efficacy of photodamage simultaneously or subsequently directed to mitochondrial/ER sites. The procedure has hitherto involved the use of two photosensitizing agents that require irradiation at two different wavelengths and different formulation techniques. This, together with different pharmacokinetic profiles of the photosensitizers, adds a layer of complexity to a protocol that we have sought to circumvent. In this study, liposomal formulations were used to direct photodamage created by benzoporphyrin derivative (BPD, Verteporfin) to lysosomes, mitochondria and the ER. This resulted in the development of an optimal targeting profile using a single agent and a single wavelength of activating irradiation. Materials/Methods These studies were carried out in monolayer cultures of OVCAR5 tumor cells. BPD localization was modified by lipid anchoring and formulation in liposomes, and was assessed by fluorescence microscopy. Irradiation was carried out at 690 ± 10 nm with photodamage assessed also using fluorescent probes and microscopy. Results BPD normally localizes in a wide variety of sub‐cellular loci that include both mitochondria and the ER, but lysosomes are spared from photodamage. Using a liposomal formulation containing BPD anchored to a lipid resulted in the targeting of lysosomes. A mixture of liposomes containing “free” and “anchored” BPD was shown to significantly promote photokilling. Eliminating cholesterol from the formulation of the anchored product enhanced lysosomal photodamage; prior studies had revealed that excess cholesterol can have a cytoprotective effect when lysosomes are the PDT target. Discussion The ability of a liposomal formulation to change localization patterns permits directing photodynamic therapy toward specific sub‐cellular loci, thereby promoting photokilling. Incorporating chemotherapeutic agents into such formulations could represent a logical next step in assessing the ability of directed photodamage to enhance tumor eradication. Lasers Surg. Med. 50:499–505, 2018. © 2018 Wiley Periodicals, Inc.}, journal={Lasers in surgery and medicine}, author={Rizvi, I and Obaid, Girgis and Bano, Shazia and Hasan, Tayyaba and Kessel, David}, year={2018}, month={Mar} }
 @article{huang_liu_baglo_rizvi_anbil_pigula_hasan_2017, title={Mechanism-informed Repurposing of Minocycline Overcomes Resistance to Topoisomerase Inhibition for Peritoneal Carcinomatosis.}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805648}, DOI={10.1158/1535-7163.mct-17-0568}, abstractNote={Abstract Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL8, respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations. Mol Cancer Ther; 17(2); 508–20. ©2017 AACR.}, journal={Molecular cancer therapeutics}, author={Huang, HC and Liu, Joyce and Baglo, Y and Rizvi, I and Anbil, S and Pigula, M and Hasan, Tayyaba}, year={2017}, month={Nov} }
 @article{huang_rizvi_liu_anbil_kalra_lee_baglo_paz_hayden_pereira_et al._2017, title={Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery.}, url={https://europepmc.org/articles/PMC5771811}, DOI={10.1158/0008-5472.can-17-1700}, abstractNote={Abstract Physiologic barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduced metastasis, and increased both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (i) increase intratumoral drug accumulation by >10-fold, (ii) increase the duration of drug exposure above a critical therapeutic threshold, and (iii) attenuate surges in CD44 and CXCR4 expression, which mediate chemoresistance often observed after multicycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression, and drug resistance and to extend patient survival. Significance: A biophysical priming approach overcomes key treatment barriers, significantly reduces metastases, and prolongs survival in orthotopic models of human pancreatic cancer. Cancer Res; 78(2); 558–71. ©2017 AACR.}, journal={Cancer research}, author={Huang, HC and Rizvi, I and Liu, Joyce and Anbil, S and Kalra, A and Lee, H and Baglo, Y and Paz, N and Hayden, D and Pereira, Stephen and et al.}, year={2017}, month={Nov} }
 @article{huang_mallidi_liu_chiang_mai_goldschmidt_ebrahim-zadeh_rizvi_hasan_2015, title={Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer.}, url={https://europepmc.org/articles/PMC4775276}, DOI={10.1158/0008-5472.can-15-0391}, abstractNote={Abstract The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple nonoverlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here, we demonstrate that benzoporphyrin derivative-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrate that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment. Cancer Res; 76(5); 1066–77. ©2015 AACR.}, journal={Cancer research}, author={Huang, HC and Mallidi, Srivalleesha and Liu, Joyce and Chiang, Chun-Te and Mai, Z and Goldschmidt, R and Ebrahim-Zadeh, N and Rizvi, I and Hasan, Tayyaba}, year={2015}, month={Dec} }
 @article{mallidi_mai_rizvi_hempstead_arnason_celli_hasan_2015, title={In vivo evaluation of battery-operated light-emitting diode-based photodynamic therapy efficacy using tumor volume and biomarker expression as endpoints.}, url={https://europepmc.org/articles/PMC4408448}, DOI={10.1117/1.jbo.20.4.048003}, abstractNote={In view of the increase in cancer-related mortality rates in low- to middle-income countries (LMIC), there is an urgent need to develop economical therapies that can be utilized at minimal infrastructure institutions. Photodynamic therapy (PDT), a photochemistry-based treatment modality, offers such a possibility provided that low-cost light sources and photosensitizers are available. In this proof-of-principle study, we focus on adapting the PDT light source to a low-resource setting and compare an inexpensive, portable, battery-powered light-emitting diode (LED) light source with a standard, high-cost laser source. The comparison studies were performed in vivo in a xenograft murine model of human squamous cell carcinoma subjected to 5-aminolevulinic acid-induced protoporphyrin IX PDT. We observed virtually identical control of the tumor burden by both the LED source and the standard laser source. Further insights into the biological response were evaluated by biomarker analysis of necrosis, microvessel density, and hypoxia [carbonic anhydrase IX (CAIX) expression] among groups of control, LED-PDT, and laser-PDT treated mice. There is no significant difference in the percent necrotic volume and CAIX expression in tumors that were treated with the two different light sources. These encouraging preliminary results merit further investigations in orthotopic animal models of cancers prevalent in LMICs.}, journal={Journal of biomedical optics}, author={Mallidi, Srivalleesha and Mai, Z and Rizvi, I and Hempstead, J and Arnason, S and Celli, J and Hasan, Tayyaba}, year={2015}, month={Apr} }
 @article{hempstead_jones_ziouche_cramer_rizvi_arnason_hasan_celli_2015, title={Low-cost photodynamic therapy devices for global health settings: Characterization of battery-powered LED performance and smartphone imaging in 3D tumor models.}, url={https://europepmc.org/articles/PMC4428052}, DOI={10.1038/srep10093}, abstractNote={A lack of access to effective cancer therapeutics in resource-limited settings is implicated in global cancer health disparities between developed and developing countries. Photodynamic therapy (PDT) is a light-based treatment modality that has exhibited safety and efficacy in the clinic using wavelengths and irradiances achievable with light-emitting diodes (LEDs) operated on battery power. Here we assess low-cost enabling technology to extend the clinical benefit of PDT to regions with little or no access to electricity or medical infrastructure. We demonstrate the efficacy of a device based on a 635 nm high-output LED powered by three AA disposable alkaline batteries, to achieve strong cytotoxic response in monolayer and 3D cultures of A431 squamous carcinoma cells following photosensitization by administering aminolevulinic acid (ALA) to induce the accumulation of protoporphyrin IX (PpIX). Here we characterize challenges of battery-operated device performance, including battery drain and voltage stability specifically over relevant PDT dose parameters. Further motivated by the well-established capacity of PDT photosensitizers to serve as tumour-selective fluorescence contrast agents, we demonstrate the capability of a consumer smartphone with low-cost add-ons to measure concentration-dependent PpIX fluorescence. This study lays the groundwork for the on-going development of image-guided ALA-PDT treatment technologies for global health applications.}, journal={Scientific reports}, author={Hempstead, J and Jones, DP and Ziouche, A and Cramer, GM and Rizvi, I and Arnason, S and Hasan, Tayyaba and Celli, JP}, year={2015}, month={May} }
 @article{spring_rizvi_xu_hasan_2015, title={The role of photodynamic therapy in overcoming cancer drug resistance.}, url={https://europepmc.org/articles/PMC4520758}, DOI={10.1039/c4pp00495g}, abstractNote={Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation.}, journal={Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology}, author={Spring, BQ and Rizvi, I and Xu, N and Hasan, Tayyaba}, year={2015}, month={Apr} }
 @article{ghogare_rizvi_hasan_greer_2014, title={"Pointsource" delivery of a photosensitizer drug and singlet oxygen: eradication of glioma cells in vitro.}, url={https://europepmc.org/articles/PMC4198175}, DOI={10.1111/php.12274}, abstractNote={Abstract We describe a pointsource sensitizer‐tipped microoptic device for the eradication of glioma U87 cells. The device has a mesoporous fluorinated silica tip which emits singlet oxygen molecules and small quantities of pheophorbide sensitizer for additional production of singlet oxygen in the immediate vicinity. The results show that the device surges in sensitizer release and photokilling with higher rates about midway through the reaction. This was attributed to a self‐amplified autocatalytic reaction where released sensitizer in the extracellular matrix provides positive feedback to assist in the release of additional sensitizer. The photokilling of the glioma cells was analyzed by global toxicity and live/dead assays, where a killing radius around the tip with ~0.3 mm precision was achieved. The implication of these results for a new PDT tool of hard‐to‐resect tumors, e.g . in the brain, is discussed.}, journal={Photochemistry and photobiology}, author={Ghogare, AA and Rizvi, I and Hasan, Tayyaba and Greer, Alexander}, year={2014}, month={Apr} }
 @article{celli_rizvi_blanden_massodi_pogue_hasan_2014, title={An imaging-based platform for high-content, quantitative evaluation of therapeutic response in 3D tumour models.}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24435043/?tool=EBI}, DOI={10.1038/srep03751}, abstractNote={While it is increasingly recognized that three-dimensional (3D) cell culture models recapitulate drug responses of human cancers with more fidelity than monolayer cultures, a lack of quantitative analysis methods limit their implementation for reliable and routine assessment of emerging therapies. Here, we introduce an approach based on computational analysis of fluorescence image data to provide high-content readouts of dose-dependent cytotoxicity, growth inhibition, treatment-induced architectural changes and size-dependent response in 3D tumour models. We demonstrate this approach in adherent 3D ovarian and pancreatic multiwell extracellular matrix tumour overlays subjected to a panel of clinically relevant cytotoxic modalities and appropriately designed controls for reliable quantification of fluorescence signal. This streamlined methodology reads out the high density of information embedded in 3D culture systems, while maintaining a level of speed and efficiency traditionally achieved with global colorimetric reporters in order to facilitate broader implementation of 3D tumour models in therapeutic screening.}, journal={Scientific reports}, author={Celli, JP and Rizvi, I and Blanden, AR and Massodi, I and Pogue, Brian W. and Hasan, Tayyaba}, year={2014}, month={Jan} }
 @article{spring_abu-yousif_palanisami_rizvi_zheng_mai_anbil_sears_mensah_goldschmidt_et al._2014, title={Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates.}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24572574/?tool=EBI}, DOI={10.1073/pnas.1319493111}, abstractNote={Significance Residual micrometastases following standard therapies limit our ability to cure many cancers. This article demonstrates a new therapy and visualization platform that targets residual cancer micrometastases with enhanced sensitivity and selectivity based on “tumor-targeted activation.” This targeted activation feature not only provides a potent therapeutic arm that is effective against chemoresistant disease while minimizing side effects due to nonspecific toxicities but also enables micrometastasis imaging in common sites of disease recurrence to screen patients harboring residual tumor deposits. This approach offers promise for treating and monitoring drug-resistant micrometastases presently “invisible” to clinicians.}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Spring, BQ and Abu-Yousif, AO and Palanisami, A and Rizvi, I and Zheng, X and Mai, Z and Anbil, S and Sears, RB and Mensah, LB and Goldschmidt, R and et al.}, year={2014}, month={Feb} }
 @article{rizvi_gurkan_tasoglu_alagic_celli_mensah_mai_demirci_hasan_2013, title={Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules.}, volume={110}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23645635/?tool=EBI}, DOI={10.1073/pnas.1216989110}, abstractNote={Seventy-five percent of patients with epithelial ovarian cancer present with advanced-stage disease that is extensively disseminated intraperitoneally and prognosticates the poorest outcomes. Primarily metastatic within the abdominal cavity, ovarian carcinomas initially spread to adjacent organs by direct extension and then disseminate via the transcoelomic route to distant sites. Natural fluidic streams of malignant ascites triggered by physiological factors, including gravity and negative subdiaphragmatic pressure, carry metastatic cells throughout the peritoneum. We investigated the role of fluidic forces as modulators of metastatic cancer biology in a customizable microfluidic platform using 3D ovarian cancer nodules. Changes in the morphological, genetic, and protein profiles of biomarkers associated with aggressive disease were evaluated in the 3D cultures grown under controlled and continuous laminar flow. A modulation of biomarker expression and tumor morphology consistent with increased epithelial–mesenchymal transition, a critical step in metastatic progression and an indicator of aggressive disease, is observed because of hydrodynamic forces. The increase in epithelial–mesenchymal transition is driven in part by a posttranslational up-regulation of epidermal growth factor receptor (EGFR) expression and activation, which is associated with the worst prognosis in ovarian cancer. A flow-induced, transcriptionally regulated decrease in E-cadherin protein expression and a simultaneous increase in vimentin is observed, indicating increased metastatic potential. These findings demonstrate that fluidic streams induce a motile and aggressive tumor phenotype. The microfluidic platform developed here potentially provides a flow-informed framework complementary to conventional mechanism-based therapeutic strategies, with broad applicability to other lethal malignancies.}, number={22}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Rizvi, Imran and Gurkan, Umut A. and Tasoglu, Savas and Alagic, N and Celli, JP and Mensah, LB and Mai, Z and Demirci, U and Hasan, Tayyaba}, year={2013}, month={May}, pages={E1974–E1983} }
 @article{anbil_rizvi_celli_alagic_pogue_hasan_2013, title={Impact of treatment response metrics on photodynamic therapy planning and outcomes in a three-dimensional model of ovarian cancer}, volume={18}, DOI={10.1117/1.jbo.18.9.098004}, abstractNote={Common methods to characterize treatment efficacy based on morphological imaging may misrepresent outcomes and exclude effective therapies. Using a three-dimensional model of ovarian cancer, two functional treatment response metrics are used to evaluate photodynamic therapy (PDT) efficacy: total volume, calculated from viable and nonviable cells, and live volume, calculated from viable cells. The utility of these volume-based metrics is corroborated using independent reporters of photodynamic activity: viability, a common fluorescence-based ratiometric analysis, and photosensitizer photobleaching, which is characterized by a loss of fluorescence due in part to the production of reactive species during PDT. Live volume correlated with both photobleaching and viability, suggesting that it was a better reporter of PDT efficacy than total volume, which did not correlate with either metric. Based on these findings, live volume and viability are used to probe the susceptibilities of tumor populations to a range of PDT dose parameters administered using 0.25, 1, and 10 μM benzoporphyrin derivative (BPD). PDT with 0.25 μM BPD produces the most significant reduction in live volume and viability and mediates a substantial shift toward small nodules. Increasingly sophisticated bioengineered models may complement current treatment planning approaches and provide unique opportunities to critically evaluate key parameters including metrics of therapeutic response.}, number={9}, journal={Journal of Biomedical Optics}, publisher={SPIE - International Society for Optical Engineering}, author={Anbil, Sriram and Rizvi, Imran and Celli, Jonathan P. and Alagic, Nermina and Pogue, Brian W. and Hasan, Tayyaba}, year={2013}, pages={098004} }
 @article{rizvi_anbil_alagic_celli_zheng_palanisami_glidden_pogue_hasan_2013, title={PDT dose parameters impact tumoricidal durability and cell death pathways in a 3D ovarian cancer model.}, volume={89}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23442192/?tool=EBI}, DOI={10.1111/php.12065}, abstractNote={The successful implementation of photodynamic therapy (PDT)-based regimens depends on an improved understanding of the dosimetric and biological factors that govern therapeutic variability. Here, the kinetics of tumor destruction and regrowth are characterized by systematically varying benzoporphyrin derivative (BPD)-light combinations to achieve fixed PDT doses (M × J cm(-2)). Three endpoints were used to evaluate treatment response: (1) Viability evaluated every 24 h for 5 days post-PDT; (2) Photobleaching assessed immediately post-PDT; and (3) Caspase-3 activation determined 24 h post-PDT. The specific BPD-light parameters used to construct a given PDT dose significantly impact not only acute cytotoxic efficacy, but also treatment durability. For each dose, PDT with 0.25 μM BPD produces the most significant and sustained reduction in normalized viability compared to 1 and 10 μM BPD. Percent photobleaching correlates with normalized viability for a range of PDT doses achieved within BPD concentrations. To produce a cytotoxic response with 10 μM BPD that is comparable to 0.25 and 1 μM BPD a reduction in irradiance from 150 to 0.5 mW cm(-2) is required. Activated caspase-3 does not correlate with normalized viability. The parameter-dependent durability of outcomes within fixed PDT doses provides opportunities for treatment customization and improved therapeutic planning.}, number={4}, journal={Photochemistry and photobiology}, author={Rizvi, Imran and Anbil, Sriram and Alagic, Nermina and Celli, Jonathan P. and Zheng, Lei Zak and Palanisami, Akilan and Glidden, Michael D. and Pogue, Brian W. and Hasan, Tayyaba}, year={2013}, month={Apr}, pages={942–52} }
 @article{glidden_celli_massodi_rizvi_pogue_hasan_2012, title={Image-Based Quantification of Benzoporphyrin Derivative Uptake, Localization, and Photobleaching in 3D Tumor Models, for Optimization of PDT Parameters}, volume={2}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23082096/?tool=EBI}, DOI={10.7150/thno.4334}, abstractNote={Photodynamic therapy (PDT) is a light-based treatment modality in which wavelength specific activation of a photosensitizer (PS) generates cytotoxic response in the irradiated region.PDT response is critically dependent on several parameters including light dose, PS dose, uptake time, fluence rate, and the mode of light delivery.While the systematic optimization of these treatment parameters can be complex, it also provides multiple avenues for enhancement of PDT efficacy under diverse treatment conditions, provided that a rational framework is established to quantify the impact of parameter selection upon treatment response.Here we present a theranostic technique, combining the inherent ability of the PS to serve simultaneously as a therapeutic and imaging agent, with the use of image-based treatment assessment in three dimensional (3D) in vitro tumor models, to comprise a platform to evaluate the impact of PDT parameters on treatment outcomes.We use this approach to visualize and quantify the uptake, localization, and photobleaching of the PS benzoporphyrin derivative monoacid ring-A (BPD) in a range of treatment conditions with varying uptake times as well as continuous and fractionated light delivery regimens in 3D cultures of AsPC-1 and PANC-1 cells.Informed by photobleaching patterns and correlation with cytotoxic response, asymmetric fractionated light delivery at 4 hours BPD uptake was found to be the most effective regimen assessed.Quantification of the spatial profile of cell killing within multicellular nodules revealed that these conditions also achieve the highest depth of cytotoxicity along the radial axis of 3D nodules.The framework introduced here provides a means for systematic assessment of PDT treatment parameters in biologically relevant 3D tumor models with potential for broader application to other systems.}, number={9}, journal={Theranostics}, author={Glidden, Michael D. and Celli, Jonathan P. and Massodi, Iqbal and Rizvi, Imran and Pogue, Brian W. and Hasan, Tayyaba}, year={2012}, pages={827–839} }
 @article{rizvi_dinh_yu_chang_sherwood_hasan_2012, title={Photoimmunotherapy and Irradiance Modulation Reduce Chemotherapy Cycles and Toxicity in a Murine Model for Ovarian Carcinomatosis: Perspective and Results}, volume={52}, url={https://europepmc.org/articles/PMC3634612}, DOI={10.1002/ijch.201200016}, abstractNote={Significant toxicities from multiple cycles of chemotherapy often cause delays or early termination of treatment, leading to poor outcomes in ovarian cancer patients. Complementary modalities that potentiate the efficacy of traditional agents with fewer cycles and less toxicity are needed. Photodynamic therapy is a mechanistically-distinct modality that synergizes with chemo and biologic agents. A combination regimen with a clinically relevant chemotherapy cocktail (cisplatin + paclitaxel) and anti-EGFR targeted photoimmunotherapy (PIT) is evaluated in a murine model for ovarian carcinomatosis. Mice received either 1 or 2 chemotherapy cycles followed by PIT with a chlorine6-Erbitux photoimmunoconjugate and 25 J/cm2 light. PIT + 1 cycle of chemotherapy significantly reduced tumor burden, comparable to multiple chemotherapy cycles. Relative to 1 cycle of chemotherapy, the addition of PIT did not cause significant mouse weight loss, whereas 2 cycles of chemotherapy led to a significant reduction in weight. Irradiance-dependence on PIT efficacy was a function of the conjugation chemistry, providing an additional variable for optimization of PIT outcome.}, number={8-9}, journal={Israel journal of chemistry}, publisher={Wiley Blackwell (John Wiley & Sons)}, author={Rizvi, Imran and Dinh, TA and Yu, W and Chang, Y and Sherwood, ME and Hasan, Tayyaba}, year={2012}, pages={776–787} }
 @article{xu_celli_rizvi_moon_hasan_demirci_2011, title={A three-dimensional in vitro ovarian cancer coculture model using a high-throughput cell patterning platform.}, volume={6}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21298805/?tool=EBI}, DOI={10.1002/biot.201000340}, abstractNote={In vitro 3D cancer models that provide a more accurate representation of disease in vivo are urgently needed to improve our understanding of cancer pathology and to develop better cancer therapies. However, development of 3D models that are based on manual ejection of cells from micropipettes suffer from inherent limitations such as poor control over cell density, limited repeatability, low throughput, and, in the case of coculture models, lack of reproducible control over spatial distance between cell types (e.g., cancer and stromal cells). In this study, we build on a recently introduced 3D model in which human ovarian cancer (OVCAR-5) cells overlaid on Matrigel™ spontaneously form multicellular acini. We introduce a high-throughput automated cell printing system to bioprint a 3D coculture model using cancer cells and normal fi broblasts micropatterned on Matrigel™ . Two cell types were patterned within a spatially controlled microenvironment (e.g., cell density, cell-cell distance) in a high-throughput and reproducible manner; both cell types remained viable during printing and continued to proliferate following patterning. This approach enables the miniaturization of an established macro-scale 3D culture model and would allow systematic investigation into the multiple unknown regulatory feedback mechanisms between tumor and stromal cells and provide a tool for high-throughput drug screening.}, number={2}, journal={Biotechnology journal}, author={Xu, F and Celli, J and Rizvi, Imran and Moon, S and Hasan, Tayyaba and Demirci, U}, year={2011}, month={Feb}, pages={204–212} }
 @article{evans_abu-yousif_park_klein_celli_rizvi_zheng_hasan_2011, title={Killing hypoxic cell populations in a 3D tumor model with EtNBS-PDT.}, volume={6}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21876751/?tool=EBI}, DOI={10.1371/journal.pone.0023434}, abstractNote={An outstanding problem in cancer therapy is the battle against treatment-resistant disease. This is especially true for ovarian cancer, where the majority of patients eventually succumb to treatment-resistant metastatic carcinomatosis. Limited perfusion and diffusion, acidosis, and hypoxia play major roles in the development of resistance to the majority of front-line therapeutic regimens. To overcome these limitations and eliminate otherwise spared cancer cells, we utilized the cationic photosensitizer EtNBS to treat hypoxic regions deep inside in vitro 3D models of metastatic ovarian cancer. Unlike standard regimens that fail to penetrate beyond ∼150 µm, EtNBS was found to not only penetrate throughout the entirety of large (>200 µm) avascular nodules, but also concentrate into the nodules' acidic and hypoxic cores. Photodynamic therapy with EtNBS was observed to be highly effective against these hypoxic regions even at low therapeutic doses, and was capable of destroying both normoxic and hypoxic regions at higher treatment levels. Imaging studies utilizing multiphoton and confocal microscopies, as well as time-lapse optical coherence tomography (TL-OCT), revealed an inside-out pattern of cell death, with apoptosis being the primary mechanism of cell killing. Critically, EtNBS-based photodynamic therapy was found to be effective against the model tumor nodules even under severe hypoxia. The inherent ability of EtNBS photodynamic therapy to impart cytotoxicity across a wide range of tumoral oxygenation levels indicates its potential to eliminate treatment-resistant cell populations.}, number={8}, journal={PloS one}, author={Evans, CL and Abu-Yousif, AO and Park, YJ and Klein, OJ and Celli, JP and Rizvi, Imran and Zheng, X and Hasan, Tayyaba}, year={2011}, month={Aug} }
 @article{celli_spring_rizvi_evans_samkoe_verma_pogue_hasan_2010, title={Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and Optimization}, volume={110}, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20353192/?tool=EBI}, DOI={10.1021/cr900300p}, abstractNote={ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTImaging and Photodynamic Therapy: Mechanisms, Monitoring, and OptimizationJonathan P. Celli†, Bryan Q. Spring†, Imran Rizvi†‡, Conor L. Evans†, Kimberley S. Samkoe‡, Sarika Verma†, Brian W. Pogue†‡, and Tayyaba Hasan*†View Author Information Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 03755* To whom correspondence should be addressed. E-mail: [email protected]†Massachusetts General Hospital and Harvard Medical School.‡Dartmouth College.Cite this: Chem. Rev. 2010, 110, 5, 2795–2838Publication Date (Web):March 30, 2010Publication History Received4 September 2009Published online30 March 2010Published inissue 12 May 2010https://pubs.acs.org/doi/10.1021/cr900300phttps://doi.org/10.1021/cr900300preview-articleACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views23102Altmetric-Citations1936LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Biological imaging,Cancer,Fluorescence,Fluorescence imaging,Tumors Get e-Alerts}, number={5}, journal={Chemical reviews}, publisher={American Chemical Society}, author={Celli, JP and Spring, BQ and Rizvi, Imran and Evans, CL and Samkoe, KS and Verma, S and Pogue, Brian W. and Hasan, Tayyaba}, year={2010}, pages={2795–2838} }
 @article{rahmanzadeh_rai_celli_rizvi_baron-luehr_gerdes_hasan_2010, title={Ki-67 as a Molecular Target for Therapy in an In vitro Three-Dimensional Model for Ovarian Cancer}, volume={70}, DOI={10.1158/0008-5472.can-10-1190}, abstractNote={Targeting molecular markers and pathways implicated in cancer cell growth is a promising avenue for developing effective therapies. Although the Ki-67 protein (pKi-67) is a key marker associated with aggressively proliferating cancer cells and poor prognosis, its full potential as a therapeutic target has never before been successfully shown. In this regard, its nuclear localization presents a major hurdle because of the need for intracellular and intranuclear delivery of targeting and therapeutic moieties. Using a liposomally encapsulated construct, we show for the first time the specific delivery of a Ki-67-directed antibody and subsequent light-triggered death in the human ovarian cancer cell line OVCAR-5. Photoimmunoconjugate-encapsulating liposomes (PICEL) were constructed from anti-pKi-67 antibodies conjugated to fluorescein 5(6)-isothiocyanate, as a photoactivatable agent, followed by encapsulation in noncationic liposomes. Nucleolar localization of the PICELs was confirmed by confocal imaging. Photodynamic activation with PICELs specifically killed pKi-67-positive cancer cells both in monolayer and in three-dimensional (3D) cultures of OVCAR-5 cells, with the antibody TuBB-9 targeting a physiologically active form of pKi-67 but not with MIB-1, directed to a different epitope. This is the first demonstration of (a) the exploitation of Ki-67 as a molecular target for therapy and (b) specific delivery of an antibody to the nucleolus in monolayer cancer cells and in an in vitro 3D model system. In view of the ubiquity of pKi-67 in proliferating cells in cancer and the specificity of targeting in 3D multicellular acini, these findings are promising and the approach merits further investigation.}, number={22}, journal={Cancer Research}, author={Rahmanzadeh, Ramtin and Rai, Prakash and Celli, Jonathan P. and Rizvi, Imran and Baron-Luehr, Bettina and Gerdes, Johannes and Hasan, Tayyaba}, year={2010}, pages={9234–9242} }
 @article{celli_rizvi_evans_abu-yousif_hasan_2010, title={Quantitative imaging reveals heterogeneous growth dynamics and treatment-dependent residual tumor distributions in a three-dimensional ovarian cancer model}, volume={15}, DOI={10.1117/1.3483903}, abstractNote={Three-dimensional tumor models have emerged as valuable in vitro research tools, though the power of such systems as quantitative reporters of tumor growth and treatment response has not been adequately explored. We introduce an approach combining a 3-D model of disseminated ovarian cancer with high-throughput processing of image data for quantification of growth characteristics and cytotoxic response. We developed custom MATLAB routines to analyze longitudinally acquired dark-field microscopy images containing thousands of 3-D nodules. These data reveal a reproducible bimodal log-normal size distribution. Growth behavior is driven by migration and assembly, causing an exponential decay in spatial density concomitant with increasing mean size. At day 10, cultures are treated with either carboplatin or photodynamic therapy (PDT). We quantify size-dependent cytotoxic response for each treatment on a nodule by nodule basis using automated segmentation combined with ratiometric batch-processing of calcein and ethidium bromide fluorescence intensity data (indicating live and dead cells, respectively). Both treatments reduce viability, though carboplatin leaves micronodules largely structurally intact with a size distribution similar to untreated cultures. In contrast, PDT treatment disrupts micronodular structure, causing punctate regions of toxicity, shifting the distribution toward smaller sizes, and potentially increasing vulnerability to subsequent chemotherapeutic treatment.}, number={5}, journal={Journal of Biomedical Optics}, author={Celli, Jonathan P. and Rizvi, Imran and Evans, Conor L. and Abu-Yousif, Adnan O. and Hasan, Tayyaba}, year={2010} }
 @article{rizvi_celli_evans_abu-yousif_muzikansky_pogue_finkelstein_hasan_2010, title={Synergistic Enhancement of Carboplatin Efficacy with Photodynamic Therapy in a Three-Dimensional Model for Micrometastatic Ovarian Cancer}, volume={70}, DOI={10.1158/0008-5472.can-10-1783}, abstractNote={Abstract Metastatic ovarian cancer (OvCa) frequently recurs due to chemoresistance, highlighting the need for nonoverlapping combination therapies that mechanistically synergize to eradicate residual disease. Photodynamic therapy (PDT), a photochemistry-based cytotoxic modality, sensitizes ovarian tumors to platinum agents and biologics and has shown clinical promise against ovarian carcinomatosis. We introduce a three-dimensional (3D) model representing adherent ovarian micrometastases and high-throughput quantitative imaging methods to rapidly screen the order-dependent effects of combining benzoporphyrin-derivative (BPD) monoacid A–based PDT with low-dose carboplatin. 3D ovarian micronodules grown on Matrigel were subjected to BPD-PDT either before or after carboplatin treatment. We developed custom fluorescence image analysis routines to quantify residual tumor volume and viability. Carboplatin alone did not eradicate ovarian micrometastases at a dose of 400 mg/m2, leaving surviving cores that were nonsensitive or impermeable to chemotherapy. BPD-PDT (1.25 μmol/L·J/cm2) created punctate cytotoxic regions within tumors and disrupted micronodular structure. Treatment with BPD-PDT prior to low-dose carboplatin (40 mg/m2) produced a significant synergistic reduction [P < 0.0001, analysis of covariance (ANCOVA)] in residual tumor volume [0.26; 95% confidence interval (95% CI), 0.19–0.36] compared with PDT alone (0.76; 95% CI, 0.63–0.92) or carboplatin alone (0.95; 95% CI, 0.83–1.09), relative to controls. This synergism was not observed with the reverse treatment order. Here, we demonstrate for the first time the use of a 3D model for micrometastatic OvCa as a rapid and quantitative reporter to optimize sequence and dosing regimens of clinically relevant combination strategies. This approach combining biological modeling with high-content imaging provides a platform to rapidly screen therapeutic strategies for a broad array of metastatic tumors. Cancer Res; 70(22); 9319–28. ©2010 AACR.}, number={22}, journal={Cancer Research}, author={Rizvi, Imran and Celli, Jonathan P. and Evans, Conor L. and Abu-Yousif, Adnan O. and Muzikansky, Alona and Pogue, Brian W. and Finkelstein, Dianne and Hasan, Tayyaba}, year={2010}, pages={9319–9328} }
 @article{samkoe_chen_rizvi_ohara_hoopes_pereira_hasan_pogue_2010, title={Imaging Tumor Variation in Response to Photodynamic Therapy in Pancreatic Cancer Xenograft Models}, volume={76}, DOI={10.1016/j.ijrobp.2009.08.041}, abstractNote={A treatment monitoring study investigated the differential effects of orthotopic pancreatic cancer models in response to interstitial photodynamic therapy (PDT), and the validity of using magnetic resonance imaging as a surrogate measure of response was assessed.Different orthotopic pancreatic cancer xenograft models (AsPC-1 and Panc-1) were used to represent the range of pathophysiology observed in human beings. Identical dose escalation studies (10, 20, and 40J/cm) using interstitial verteporfin PDT were performed, and magnetic resonance imaging with T2-weighted and T1-weighted contrast were used to monitor the total tumor volume and the vascular perfusion volume, respectively.There was a significant amount of necrosis in the slower-growing Panc-1 tumor using high light dose, although complete necrosis was not observed. Lower doses were required for the same level of tumor kill in the faster-growing AsPC-1 cell line.The tumor growth rate and vascular pattern of the tumor affect the optimal PDT treatment regimen, with faster-growing tumors being relatively easier to treat. This highlights the fact that therapy in human beings shows a heterogeneous range of outcomes, and suggests a need for careful individualized treatment outcomes assessment in clinical work.}, number={1}, journal={International Journal of Radiation Oncology Biology Physics}, publisher={Elsevier }, author={Samkoe, Kimberley S. and Chen, Alina and Rizvi, Imran and OHara, Julia A. and Hoopes, P. Jack and Pereira, Stephen P. and Hasan, Tayyaba and Pogue, Brian W.}, year={2010}, pages={251–259} }
 @article{evans_rizvi_hasan_boer_2009, title={In vitro ovarian tumor growth and treatment response dynamics visualized with time-lapse OCT imaging}, volume={17}, number={11}, journal={Optics Express}, author={Evans, Conor L. and Rizvi, Imran and Hasan, Tayyaba and Boer, Johannes F.}, year={2009}, pages={8892–8906} }
 @article{zhong_celli_rizvi_mai_spring_yun_hasan_2009, title={In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring}, volume={101}, DOI={10.1038/sj.bjc.6605436
10.1038/sj.bjc.6605436. Epub 2009 Nov 17.}, journal={British journal of cancer}, author={Zhong, W. and Celli, J. P. and Rizvi, I. and Mai, Z. and Spring, B. Q. and Yun, S. H. and Hasan, T.}, year={2009}, pages={2015–22} }
 @article{abu-yousif_rizvi_evans_celli_hasan_2009, title={PuraMatrix encapsulation of cancer cells}, DOI={10.3791/1692}, abstractNote={Increasing evidence suggests that culturing cancer cells in three dimensions more accurately recapitulates the complexity of tumor biology.Many of these models utilize reconstituted basement membrane derived from animals which contain a variable amount of growth factors and cytokines that can influence the growth of these cell culture models.Here, we describe in detail the preparation and use of PuraMatrix, a commercially available self assembling peptide gel that is devoid of animal-derived material and pathogens to encapsulate and propagate the ovarian cancer cell line, OVCAR-5.We begin by describing how to prepare the PuraMatrix prior to use.Next, we demonstrate how to properly mix the PuraMatrix and cell suspension to encapsulate the cells in the hydrogel.Upon the addition of cell culture media or injection into a physiological environment, the peptide component of PuraMatrix rapidly self assembles into a 3D hydrogel that exhibits a nanometer scale fibrous structure with an average pore size of 5-200 nm 1 .In addition, we demonstrate how to propagate cultures grown in encapsulated PuraMatrix.When encapsulated in PuraMatrix, OVCAR-5 cells assemble into three dimensional acinar structures that more closely resemble the morphology of micrometastatic nodules observed in the clinic than monolayer in vitro models.Using confocal microscopy we illustrate the appearance of representative OVCAR-5 cells encapsulated in PuraMatrix on day 1, 3, 5, and 7 post plating.The use of PuraMatrix to culture cancer cells should improve our understanding of the disease and allow us to assess treatment response in more clinically predictive model systems.}, number={34}, journal={Journal of visualized experiments : JoVE}, author={Abu-Yousif, Adnan O. and Rizvi, Imran and Evans, Conor L. and Celli, Jonathan P. and Hasan, Tayyaba}, year={2009} }
 @article{chang_rizvi_solban_hasan_2008, title={In vivo optical molecular imaging of vascular endothelial growth factor for monitoring cancer treatment}, volume={14}, DOI={10.1158/1078-0432.ccr-07-4536}, abstractNote={Vascular endothelial growth factor (VEGF) expression is a critical component in tumor growth and metastasis. Capabilities to monitor VEGF expression in vivo can potentially serve as a useful tool for diagnosis, prognosis, treatment planning, monitoring, and research. Here, we present the first report of in vivo hyperspectral molecular imaging strategy capable of monitoring treatment-induced changes in VEGF expression.VEGF was targeted with an anti-VEGF antibody conjugated with a fluorescent dye and was imaged in vivo using a hyperspectral imaging system. The strategy was validated by quantitatively monitoring VEGF levels in three different tumors as well as following photodynamic treatment. Specificity of the molecular imaging strategy was tested using in vivo competition experiments and mathematically using a quantitative pharmacokinetic model.The molecular imaging strategy successfully imaged VEGF levels quantitatively in three different tumors and showed concordance with results from standard ELISA. Changes in tumoral VEGF concentration following photodynamic treatment and Avastin treatment were shown. Immunohistochemistry shows that (a) the VEGF-specific contrast agent labels both proteoglycan-bound and unbound VEGF in the extracellular space and (b) the bound VEGF is released from the extracellular matrix in response to photodynamic therapy. In vivo competition experiments and quantitative pharmacokinetic model-based analysis confirmed the high specificity of the imaging strategy.This first report of in vivo quantitative optical molecular imaging-based monitoring of a secreted cytokine in tumors may have implications in providing tools for mechanistic investigations as well as for improved treatment design and merits further investigation.}, number={13}, journal={Clinical Cancer Research}, author={Chang, Sung K. and Rizvi, Imran and Solban, Nicolas and Hasan, Tayyaba}, year={2008}, pages={4146–4153} }
 @article{laubach_chang_lee_rizvi_zurakowski_davis_taylor_hasan_2008, title={In-vivo singlet oxygen dosimetry of clinical 5-aminolevulinic acid photodynamic therapy}, volume={13}, DOI={10.1117/1.2981813}, abstractNote={Photodynamic therapy (PDT) is a viable treatment option for a wide range of applications, including oncology, dermatology, and ophthalmology. Singlet oxygen is believed to play a key role in the efficacy of PDT, and on-line monitoring of singlet oxygen during PDT could provide a methodology to establish and customize the treatment dose clinically. This work is the first report of monitoring singlet oxygen luminescence in vivo in human subjects during PDT, demonstrating the correlation of singlet oxygen levels during PDT with the post-PDT photobiological response.}, number={5}, journal={Journal of Biomedical Optics}, author={Laubach, Hans-Joachim and Chang, Sung K. and Lee, Seonkyung and Rizvi, Imran and Zurakowski, David and Davis, Steven J. and Taylor, Charles R. and Hasan, Tayyaba}, year={2008} }
 @article{kosharskyy_solban_chang_rizvi_chang_hasan_2006, title={A mechanism-based combination therapy reduces local tumor growth and metastasis in an orthotopic model of prostate cancer}, volume={66}, DOI={10.1158/0008-5472.can-06-1793}, abstractNote={Abstract Therapy-induced stimulation of angiogenic molecules can promote tumor angiogenesis leading to enhanced tumor growth and cancer metastasis. Several standard and emerging therapies, such as radiation and photodynamic therapy (PDT), can induce angiogenic molecules, thus limiting their effectiveness. PDT is approved for the treatment of several cancers; however, its induction of vascular endothelial growth factor (VEGF) creates conditions favorable to enhanced tumor growth and metastasis, therefore mitigating its cytotoxic and antivascular effects. This is the first report showing that subcurative PDT in an orthotopic model of prostate cancer (LNCaP) increases not only VEGF secretion (2.1-fold) but also the fraction of animals with lymph node metastases. PDT followed by administration of an antiangiogenic agent, TNP-470, abolished this increase and reduced local tumor growth. On the other hand, administration of TNP-470 before PDT was less effective at local tumor control. In addition, animals in all groups, except in the PDT + TNP-470 group, had a weight loss of >3 g at the time of sacrifice; the weight of the animals in the PDT + TNP-470 group did not change. The significant reduction (P < 0.05) in tumor weight and volume observed between the PDT + TNP-470 group and the control group suggests that the combination of PDT and antiangiogenic treatment administered in the appropriate sequence was not only more effective at controlling local tumor growth and metastases but also reduced disease-related toxicities. Such molecular response-based combinations merit further investigations as they enhance both monotherapies and lead to improved treatment outcomes. (Cancer Res 2006; 66(22): 10953-8)}, number={22}, journal={Cancer Research}, author={Kosharskyy, B. and Solban, N. and Chang, S. K. and Rizvi, I. and Chang, Y. C. and Hasan, T.}, year={2006}, pages={10953–10958} }
 @inproceedings{chang_rizvi_solban_hasan_2006, title={In vivo Imaging of VEGF Expression for Monitoring Molecular Response to Cancer Therapy}, DOI={10.1364/bio.2006.tuc4}, abstractNote={We developed a novel optical molecular specific contrast agent that targets vascular endothelial growth factor (VEGF). We tested the agent in mouse tumor models and detected increased VEGF expression in vivo following cobalt chloride treatment.}, booktitle={Biomedical Optics}, publisher={Optical Society of America}, author={Chang, Sung and Rizvi, Imran and Solban, Nicolas and Hasan, Tayyaba}, year={2006}, pages={TuC4} }
 @article{solban_rizvi_hasan_2006, title={Targeted photodynamic therapy}, volume={38}, DOI={10.1002/lsm.20345}, abstractNote={Abstract Background and Objectives Photodynamic therapy (PDT) is an emerging modality for the treatment of various neoplastic and non‐neoplastic pathologies. Study Design/Materials and Methods PDT usually occurs when reactive oxygen species (ROS) generated from light‐activated chemicals (photosensitizer, PS) destroy the target. For non‐dermatologic applications the PS are delivered systemically and accumulate, at different concentrations, in most organs. Results and Conclusion Typically there is a modest enhanced accumulation of the PS in tumor tissues, providing a first level of selectivity. Additional selectivity is provided by the confined illumination of the target area with the appropriate wavelength of light. For the treatment of pathologies in complex anatomical sites, such as in the peritoneal cavity, where restricted illumination is difficult; improved targeting of the PS is necessary to prevent damage to the surrounding healthy tissue. This article will focus on targeted PDT. Lasers Surg. Med. © 2006 Wiley‐Liss, Inc.}, number={5}, journal={Lasers in Surgery and Medicine}, author={Solban, Nicolas and Rizvi, Imran and Hasan, Tayyaba}, year={2006}, pages={522–531} }
 @article{shah_islam_dakshanamurthy_rizvi_rao_herrell_zinser_valrance_aranda_moras_et al._2006, title={The Molecular Basis of Vitamin D Receptor and β-Catenin Crossregulation}, volume={21}, DOI={10.1016/j.molcel.2006.01.037}, abstractNote={<h2>Summary</h2> The signaling/oncogenic activity of β-catenin can be repressed by activation of the vitamin D receptor (VDR). Conversely, high levels of β-catenin can potentiate the transcriptional activity of 1,25-dihydroxyvitamin D3 (1,25D). We show here that the effects of β-catenin on VDR activity are due to interaction between the activator function-2 (AF-2) domain of the VDR and C terminus of β-catenin. Acetylation of the β-catenin C terminus differentially regulates its ability to activate TCF or VDR-regulated promoters. Mutation of a specific residue in the AF-2 domain, which renders the VDR trancriptionally inactive in the context of classical coactivators, still allows interaction with β-catenin and ligand-dependent activation of VDRE-containing promoters. VDR antagonists, which block the VDRE-directed activity of the VDR and recruitment of classical coactivators, do allow VDR to interact with β-catenin, which suggests that these and perhaps other ligands would permit those functions of the VDR that involve β-catenin interaction.}, number={6}, journal={Molecular Cell}, author={Shah, S. and Islam, N. and Dakshanamurthy, S. and Rizvi, I. and Rao, M. and Herrell, R. and Zinser, G. and Valrance, M. and Aranda, A. and Moras, D. and et al.}, year={2006}, pages={799–809} }
 @article{yelin_rizvi_white_motz_hasan_bouma_tearney_2006, title={Three-dimensional miniature endoscopy}, volume={443}, DOI={10.1038/443765a}, abstractNote={A single optical fibre acts as a flexible probe to transmit a superior image of an internal landscape. Microendoscopy, using devices a millimetre or so in diameter, is an accepted technique in ophthalmics, tumour diagnosis and other medical specialities. Submillimetre-diameter devices have been used in some clinical applications but have not been widely adopted because of their rigidity and poor image quality. A new type of endoscope has now been developed that can transmit video-rate, three-dimensional images from flexible probes that are the diameter of a single optical fibre, at 80–250 μm, comparable in size to a human hair.}, journal={Nature}, author={Yelin, D. and Rizvi, I. and White, W. M. and Motz, J. T. and Hasan, T. and Bouma, B. E. and Tearney, G. J.}, year={2006}, pages={765} }
 @article{carmen_rizvi_chang_moor_oliva_sherwood_pogue_hasan_2005, title={Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo}, volume={97}, DOI={10.1093/jnci/dji314}, abstractNote={Epithelial ovarian cancer often develops resistance to standard treatments, which is a major reason for the high mortality associated with the disease. We examined the efficacy of a treatment regimen that combines immunotherapy to block the activity of epidermal growth factor receptor (EGFR), overexpression of which is associated with the development of resistant ovarian cancer, and photodynamic therapy (PDT), a mechanistically distinct photochemistry-based modality that is effective against chemo- and radioresistant ovarian tumors.We tested a combination regimen consisting of C225, a monoclonal antibody that inhibits the receptor tyrosine kinase activity of EGFR, and benzoporphyrin derivative monoacid A (BPD)-based PDT in a mouse model of human ovarian cancer. Therapeutic efficacy was evaluated in acute treatment response and survival studies that used 9-19 mice per group. Analysis of variance and Wilcoxon statistics were used to analyze the data. All statistical tests were two-sided.Mice treated with PDT + C225 had the lowest mean tumor burden compared with that in the no-treatment control mice (mean percent tumor burden = 9.8%, 95% confidence interval [CI] = 2.3% to 17.3%, P < .001). Mean percent tumor burden for mice treated with C225 only or PDT only was 66.6% (95% CI = 58.7% to 74.4%, P < .001) and 38.2% (95% CI = 29.3% to 47.0%, P < .001), respectively. When compared with PDT only or C225 only, PDT + C225 produced synergistic reductions in mean tumor burden (P < .001, analysis of variance) and improvements in survival (P = .0269, Wilcoxon test). Median survival was approximately threefold greater for mice in the PDT + C225 group than for mice in the no-treatment control group (80 days versus 28 days), and more mice in the PDT + C225 group were alive at 180 days (3/9; 33% [95% CI = 7% to 70%]) than mice in the C225-only (0/12; 0% [95% CI = 0% to 22%]) or PDT-only (1/10; 10% [95% CI = 0.2% to 44%]) groups.A mechanistically nonoverlapping combination modality consisting of receptor tyrosine kinase inhibition with C225 and BPD-PDT is well tolerated, effective, and synergistic in mice.}, number={20}, journal={Journal of the National Cancer Institute}, author={Carmen, M. G. and Rizvi, I. and Chang, Y. C. and Moor, A. C. E. and Oliva, E. and Sherwood, M. and Pogue, B. and Hasan, T.}, year={2005}, pages={1516–1524} }
 @article{hamblin_miller_rizvi_loew_hasan_2003, title={Pegylation of charged polymer-photosensitiser conjugates: effects on photodynamic efficacy}, volume={89}, DOI={10.1038/sj.bjc.6601210}, abstractNote={Conjugates between photosensitisers (PS) and charged polymeric carriers are under investigation for photodynamic therapy of cancer and may allow targeting to certain cell types or compartments in tumours. Covalent attachment of polyethylene glycol to macromolecules (pegylation) may alter their pharmacokinetics, cell type targeting, and photophysical properties. Macrophages may take up large amounts of aggregated PS, thus lessening the selectivity for cancer cells in tumours. We investigated the effect of pegylation on the uptake and phototoxicity of poly-L-lysine chlorine6 conjugates with either cationic or anionic charges in two cell lines, human ovarian cancer cells and mouse macrophages. The cationic conjugate after pegylation became less aggregated, consumed less oxygen and had reduced cellular uptake. However, the phototoxicity corrected for cellular uptake increased three- to five-fold. In contrast, the anionic succinylated conjugate on pegylation became more aggregated, consumed similar amounts of oxygen, and had higher cellular uptake. The anionic conjugate showed the highest relative phototoxicity towards both the cell lines (compared to the other three conjugates) and it decreased most towards the macrophages after pegylation. Pegylation reduced the amount of oxygen consumed per chlorine6 molecule when photosensitised cells were illuminated. These in vitro studies suggest that pegylation alters the phototoxicity of PS conjugates depending on the effect produced on the aggregation state.}, journal={British journal of cancer}, author={Hamblin, M. R. and Miller, J. L. and Rizvi, I. and Loew, H. G. and Hasan, T.}, year={2003}, pages={937–43} }
 @article{hamblin_miller_rizvi_ortel_2002, title={Degree of substitution of chlorin e(6) on charged poly- L-lysine chains affects their cellular uptake, localization and phototoxicity towards macrophages and cancer cells}, volume={10}, number={3-4}, journal={Journal of X-Ray Science and Technology}, author={Hamblin, M. R. and Miller, J. L. and Rizvi, I. and Ortel, B.}, year={2002}, pages={139–152} }
 @article{hamblin_miller_rizvi_ortel_maytin_hasan_2001, title={Pegylation of a chlorin(e6) polymer conjugate increases tumor targeting of photosensitizer}, volume={61}, journal={Cancer research}, author={Hamblin, M. R. and Miller, J. L. and Rizvi, I. and Ortel, B. and Maytin, E. V. and Hasan, T.}, year={2001}, pages={7155–62} }
 @article{hamblin_del governatore_rizvi_hasan_2000, title={Biodistribution of charged 17.1A photoimmunoconjugates in a murine model of hepatic metastasis of colorectal cancer}, volume={83}, DOI={10.1054/bjoc.2000.1486}, abstractNote={Optimizing photodynamic therapy involves attempting to increase both the absolute tumour content of photosensitizer and the selectivity between tumour and surrounding normal tissue. One reason why photodynamic therapy has not been considered suitable for treatment of metastatic tumours in the liver, is the poor selectivity of conventional photosensitizers for tumour compared to normal liver. This report details an alternative approach to increasing this selectivity by the use of antibody-targeted photosensitizers (or photoimmunoconjugates) to target intrahepatic tumours caused by human colorectal cancer cells in the nude mouse, and explores the role of molecular charge on the tumour-targeting efficiency of macromolecules. The murine monoclonal antibody 17.1A (which recognizes an antigen expressed on HT 29 cells) was used to prepare site-specific photoimmunoconjugates with the photosensitizer chlorine6. The conjugates had either a predominant cationic or anionic charge and were injected i.v. into tumour-bearing mice. Biodistribution 3 or 24 h later was measured by extraction of tissue samples and quantitation of chlorine6 content by fluorescence spectroscopy. The photoimmunoconjugates were compared to the polylysine conjugates in an attempt to define the effect of molecular charge as well as antibody targeting. The anionic 17.1A conjugate delivered more than twice as much photosensitizer to the tumour at 3 h than other species (5 times more than the cationic 17.1A conjugate) and had a tumour:normal liver ratio of 2.5. Tumour-to-liver ratios were greater than one for most compounds at 3 h but declined at 24 h. Tumour-to-skin ratios were high (> 38) for all conjugates but not for free chlorine6. Cationic species had a high uptake in the lungs compared to anionic species. The photoimmunoconjugates show an advantage over literature reports of other photosensitizers, which can result in tumour:normal liver ratios of less than 1. © 2000 Cancer Research Campaign http://www.bjcancer.com}, journal={British journal of cancer}, author={Hamblin, M. R. and Del Governatore, M. and Rizvi, I. and Hasan, T.}, year={2000}, pages={1544–51} }
 @article{del governatore_hamblin_shea_rizvi_molpus_tanabe_hasan_2000, title={Experimental photoimmunotherapy of hepatic metastases of colorectal cancer with a 17.1A chlorin(e6) immunoconjugate}, volume={60}, journal={Cancer research}, author={Del Governatore, M. and Hamblin, M. R. and Shea, C. R. and Rizvi, I. and Molpus, K. G. and Tanabe, K. K. and Hasan, T.}, year={2000}, pages={4200–5} }
 @article{molpus_hamblin_rizvi_hasan_2000, title={Intraperitoneal photoimmunotherapy of ovarian carcinoma xenografts in nude mice using charged photoimmunoconjugates}, volume={76}, DOI={10.1006/gyno.1999.5705}, abstractNote={<h2>Abstract</h2> <i>Objective.</i> The objective of this study was to compare the efficacy of photoimmunoconjugates with cationic and anionic molecular charges on intraperitoneal photoimmunotherapy of ovarian cancer xenografts in nude mice. <i>Methods.</i> The photosensitizer chlorin<i><sub>e6</sub></i> (c<i><sub>e6</sub></i>) was conjugated via a poly-l-lysine linker to the F(ab′)<sub>2</sub> fragment of the murine anti-ovarian cancer monoclonal antibody OC125, resulting in a photoimmunoconjugate with a pronounced cationic charge. Alternatively, by succinylating the poly-l-lysine conjugate, a photoimmunoconjugate with a pronounced anionic charge was obtained. A murine model of ovarian cancer derived from intraperitoneal inoculation of NIH:OVCAR-5 cells was employed. The conjugate was injected intraperitoneally followed after 3 h by red light delivered through a fiber into the peritoneal cavity. These photoimmunotherapy treatments were repeated three times, and the results obtained with the anionic and cationic photoimmunoconjugates were compared with those obtained with free c<i><sub>e6</sub></i> and control. The extent of residual macroscopic disease and death from disease were the evaluable outcomes for tumoricidal and survival studies, respectively. <i>Results.</i> In contrast to other intraperitoneal photosensitizers, mice showed no systemic toxicity or morbidity from the treatment. In this initial study the mean residual tumor weights in all treatment groups ranged from 33 to 73 mg, as compared with 330 mg in untreated controls (<i>P</i> < 0.0001), and the response to the cationic conjugate was significantly better than that to the anionic conjugate or free c<i><sub>e6</sub></i> (<i>P</i> < 0.005). The median survival for mice treated with cationic photoimmunoconjugate was 41 days, compared with 35 days in controls (<i>P</i> = 0.009). <i>Conclusion.</i> Photoimmunotherapy with a cationic photoimmunoconjugate produces results superior to those obtained with an anionic conjugate, and further optimization of the treatment regimen may lead to a potential treatment for advanced ovarian cancer.}, journal={Gynecologic oncology}, author={Molpus, K. L. and Hamblin, M. R. and Rizvi, I. and Hasan, T.}, year={2000}, pages={397–404} }
 @article{hamblin_miller_rizvi_hasan_1997, title={Pegylated poly-L-lysine chlorin-e6 conjugates as photosensitizers}, volume={65}, number={SPEC. ISSUE}, journal={Photochemistry and Photobiology}, author={Hamblin, M. R. and Miller, J. L. and Rizvi, I. and Hasan, T.}, year={1997}, pages={8S} }