@misc{madamsetty_tavakol_moghassemi_dadashzadeh_schneible_fatemi_shirvani_zarrabi_azedi_dehshahri_et al._2022, title={Chitosan: A versatile bio-platform for breast cancer theranostics}, volume={341}, ISSN={["1873-4995"]}, DOI={10.1016/j.jconrel.2021.12.012}, abstractNote={Breast cancer is considered one of the utmost neoplastic diseases globally, with a high death rate of patients. Over the last decades, many approaches have been studied to early diagnose and treat it, such as chemotherapy, hormone therapy, immunotherapy, and MRI and biomarker tests; do not show the optimal efficacy. These existing approaches are accompanied by severe side effects, thus recognizing these challenges, a great effort has been done to find out the new remedies for breast cancer. Main finding: Nanotechnology opened a new horizon to the treatment of breast cancer. Many nanoparticulate platforms for the diagnosis of involved biomarkers and delivering antineoplastic drugs are under either clinical trials or just approved by the Food and Drug Administration (FDA). It is well known that natural phytochemicals are successfully useful to treat breast cancer because these natural compounds are safer, available, cheaper, and have less toxic effects. Chitosan is a biocompatible and biodegradable polymer. Further, it has outstanding features, like chemical functional groups that can easily modify our interest with an exceptional choice of promising applications. Abundant studies were directed to assess the chitosan derivative-based nanoformulation's abilities in delivering varieties of drugs. However, the role of chitosan in diagnostics and theranostics not be obligated. The present servey will discuss the application of chitosan as an anticancer drug carrier such as tamoxifen, doxorubicin, paclitaxel, docetaxel, etc. and also, its role as a theranostics (i.e. photo-responsive and thermo-responsive) moieties. The therapeutic and theranostic potential of chitosan in cancer is promising and it seems that to have a good potential to get to the clinic.}, journal={JOURNAL OF CONTROLLED RELEASE}, author={Madamsetty, Vijay Sagar and Tavakol, Shima and Moghassemi, Saeid and Dadashzadeh, Arezoo and Schneible, John D. and Fatemi, Iman and Shirvani, Abdolsamad and Zarrabi, Ali and Azedi, Fereshteh and Dehshahri, Ali and et al.}, year={2022}, month={Jan}, pages={733–752} }
 @article{prodromou_day_saberi-bosari_schneible_mabe_san miguel_daniele_pozdin_menegatti_2021, title={Engineering Next Generation Cyclized Peptide Ligands for Light-Controlled Capture and Release of Therapeutic Proteins}, volume={31}, ISSN={["1616-3028"]}, url={http://dx.doi.org/10.1002/adfm.202101410}, DOI={10.1002/adfm.202101410}, abstractNote={Photo‐affinity adsorbents (i.e., translucent matrices functionalized with ligands featuring light‐controlled biorecognition) represent a futuristic technology for purifying labile biologics. In this study, a framework for prototyping photo‐affinity adsorbents comprising azobenzene‐cyclized peptides (ACPs) conjugated to translucent porous beads (ChemMatrix) is presented. This approach combines computational and experimental tools for designing ACPs and investigating their light‐controlled isomerization kinetics and protein biorecognition. First, a modular design for tailoring ACP's conformation, facilitating sequencing, and streamlining the in silico modeling of cis/trans isomers and their differential protein binding is introduced. Then, a spectroscopic system for measuring the photo‐isomerization kinetics of ACPs on ChemMatrix beads is reported; using this device, it is demonstrated that the isomerization at different light intensities is correlated to the cyclization geometry, specifically the energy difference of trans versus cis isomers as calculated in silico. Also, a microfluidic device for sorting ACP‐ChemMatrix beads to select and validate photo‐affinity ligands using Vascular Cell Adhesion Molecule 1 (VCAM‐1) as target protein and cycloAZOB[GVHAKQHRN‐K*]‐G‐ChemMatrix as model photo‐affinity adsorbent is presented. The proposed ACPs exhibit rapid and defined light‐controlled isomerization and biorecognition. Controlling the adsorption and release of VCAM‐1 using light demonstrates the potential of photo‐affinity adsorbents for targets whose biochemical liability poses challenges to its purification.}, number={27}, journal={ADVANCED FUNCTIONAL MATERIALS}, publisher={Wiley}, author={Prodromou, Raphael and Day, Kevin N. and Saberi-Bosari, Sahand and Schneible, John D. and Mabe, Matthew D. and San Miguel, Adriana and Daniele, Michael A. and Pozdin, Vladimir and Menegatti, Stefano}, year={2021}, month={Jul} }
 @article{chu_prodromou_day_schneible_bacon_bowen_kilgore_catella_moore_mabe_et al._2021, title={Peptides and pseudopeptide ligands: a powerful toolbox for the affinity purification of current and next-generation biotherapeutics}, volume={1635}, ISSN={["1873-3778"]}, DOI={10.1016/j.chroma.2020.461632}, abstractNote={Following the consolidation of therapeutic proteins in the fight against cancer, autoimmune, and neurodegenerative diseases, recent advancements in biochemistry and biotechnology have introduced a host of next-generation biotherapeutics, such as CRISPR-Cas nucleases, stem and car-T cells, and viral vectors for gene therapy. With these drugs entering the clinical pipeline, a new challenge lies ahead: how to manufacture large quantities of high-purity biotherapeutics that meet the growing demand by clinics and biotech companies worldwide. The protein ligands employed by the industry are inadequate to confront this challenge: while featuring high binding affinity and selectivity, these ligands require laborious engineering and expensive manufacturing, are prone to biochemical degradation, and pose safety concerns related to their bacterial origin. Peptides and pseudopeptides make excellent candidates to form a new cohort of ligands for the purification of next-generation biotherapeutics. Peptide-based ligands feature excellent target biorecognition, low or no toxicity and immunogenicity, and can be manufactured affordably at large scale. This work presents a comprehensive and systematic review of the literature on peptide-based ligands and their use in the affinity purification of established and upcoming biological drugs. A comparative analysis is first presented on peptide engineering principles, the development of ligands targeting different biomolecular targets, and the promises and challenges connected to the industrial implementation of peptide ligands. The reviewed literature is organized in (i) conventional (α-)peptides targeting antibodies and other therapeutic proteins, gene therapy products, and therapeutic cells; (ii) cyclic peptides and pseudo-peptides for protein purification and capture of viral and bacterial pathogens; and (iii) the forefront of peptide mimetics, such as β-/γ-peptides, peptoids, foldamers, and stimuli-responsive peptides for advanced processing of biologics.}, journal={JOURNAL OF CHROMATOGRAPHY A}, author={Chu, Wenning and Prodromou, Raphael and Day, Kevin N. and Schneible, John D. and Bacon, Kaitlyn B. and Bowen, John D. and Kilgore, Ryan E. and Catella, Carly M. and Moore, Brandyn D. and Mabe, Matthew D. and et al.}, year={2021}, month={Jan} }
 @article{bowen_schneible_bacon_labar_menegatti_rao_2021, title={Screening of Yeast Display Libraries of Enzymatically Treated Peptides to Discover Macrocyclic Peptide Ligands}, volume={22}, ISSN={["1422-0067"]}, url={https://www.mdpi.com/1422-0067/22/4/1634}, DOI={10.3390/ijms22041634}, abstractNote={We present the construction and screening of yeast display libraries of cyclic peptides wherein site-selective enzymatic cyclization of linear peptides is achieved using bacterial transglu-taminase. To this end, we developed two alternative routes, namely (i) yeast display of linear peptides followed by treatment with recombinant transglutaminase in solution; or (ii) intracellular co-expression of linear peptides and transglutaminase to achieve cyclization in the endoplasmic reticulum prior to yeast surface display. The cyclization yield was evaluated via orthogonal detection of epitope tags integrated in the yeast-displayed peptides by flow cytometry, and via comparative cleavage of cyclic vs. linear peptides by tobacco etch virus (TEV) protease. Subsequently, yeast display libraries of transglutaminase-cyclized peptides were screened to isolate binders to the N-terminal region of the Yes-Associated Protein (YAP) and its WW domains using magnetic selection and fluorescence activated cell sorting (FACS). The identified cyclic peptide cyclo[E-LYLAYPAH-K] featured a KD of 1.67 µM for YAP and 0.84 µM for WW as well as high binding selectivity against albumin and lysozyme. These results demonstrate the usefulness of yeast surface display for screening transglutaminase-cyclized peptide libraries, and efficient identification of cyclic peptide ligands.}, number={4}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Bowen, John and Schneible, John and Bacon, Kaitlyn and Labar, Collin and Menegatti, Stefano and Rao, Balaji M.}, year={2021}, month={Feb} }
 @article{nandi_mihalko_nellenbach_castaneda_schneible_harp_deal_daniele_menegatti_barker_et al._2021, title={Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses}, volume={4}, ISSN={["2366-3987"]}, DOI={10.1002/adtp.202100010}, abstractNote={Native platelets are crucial players in wound healing. Key to their role is the ability of their surface receptor GPIIb/IIIa to bind fibrin at injury sites, thereby promoting clotting. When platelet activity is impaired as a result of traumatic injury or certain diseases, uncontrolled bleeding can result. To aid clotting and tissue repair in cases of poor platelet activity, synthetic platelet‐like particles capable of promoting clotting and improving wound healing responses have been previously developed in the lab. These are constructed by functionalizing highly deformable hydrogel microparticles (microgels) with fibrin‐binding ligands including a fibrin‐specific whole antibody or a single‐domain variable fragment. To improve the translational potential of these clotting materials, the use of fibrin‐binding peptides as cost‐effective, robust, high‐specificity alternatives to antibodies are explored. Herein, the development and characterization of soft microgels decorated with the peptide AHRPYAAK that mimics fibrin knob “B” and targets fibrin hole “b” are presented. These “fibrin‐affine microgels with clotting yield” (FAMCY) are found to significantly increase clot density in vitro and decrease bleeding in a rodent trauma model in vivo. These results indicate that FAMCYs are capable of recapitulating the platelet‐mimetic properties of previous designs while utilizing a less costly, more translational design.}, number={5}, journal={ADVANCED THERAPEUTICS}, author={Nandi, Seema and Mihalko, Emily and Nellenbach, Kimberly and Castaneda, Mario and Schneible, John and Harp, Mary and Deal, Halston and Daniele, Michael and Menegatti, Stefano and Barker, Thomas H. and et al.}, year={2021}, month={May} }
 @article{singhal_schneible_lilova_hall_menegatti_grafmueller_2020, title={A multiscale coarse-grained model to predict the molecular architecture and drug transport properties of modified chitosan hydrogels}, volume={16}, ISSN={["1744-6848"]}, DOI={10.1039/d0sm01243b}, abstractNote={Hydrogels constructed with functionalized polysaccharides are of interest in a multitude of applications, chiefly the design of therapeutic and regenerative formulations. Tailoring the chemical modification of polysaccharide-based hydrogels to achieve specific drug release properties involves the optimization of many tunable parameters, including (i) the type, degree (χ), and pattern of the functional groups, (ii) the water-polymer ratio, and (iii) the drug payload. To guide the design of modified polysaccharide hydrogels for drug release, we have developed a computational toolbox that predicts the structure and physicochemical properties of acylated chitosan chains, and their impact on the transport of drug molecules. Herein, we present a multiscale coarse-grained model to investigate the structure of networks of chitosan chains modified with acetyl, butanoyl, or heptanoyl moieties, as well as the diffusion of drugs doxorubicin (Dox) and gemcitabine (Gem) through the resulting networks. The model predicts the formation of different network structures, in particular the hydrophobically-driven transition from a uniform to a cluster/channel morphology and the formation of fibers of chitin chains. The model also describes the impact of structural and physicochemical properties on drug transport, which was confirmed experimentally by measuring Dox and Gem diffusion through an ensemble of modified chitosan hydrogels.}, number={47}, journal={SOFT MATTER}, author={Singhal, Ankush and Schneible, John D. and Lilova, Radina L. and Hall, Carol K. and Menegatti, Stefano and Grafmueller, Andrea}, year={2020}, month={Dec} }
 @article{schneible_young_daniele_menegatti_2020, title={Chitosan Hydrogels for Synergistic Delivery of Chemotherapeutics to Triple Negative Breast Cancer Cells and Spheroids}, volume={37}, ISBN={1573-904X}, DOI={10.1007/s11095-020-02864-2}, abstractNote={This study aimed to develop a hydrogel system for treating aggressive triple negative breast cancer (TNBC) via kinetically-controlled delivery of the synergistic drug pair doxorubicin (DOX) and gemcitabine (GEM). A 2D assay was adopted to evaluate therapeutic efficacy by determining combination index (CI), and a 3D assay using cancer spheroids was implemented to assess the potential for translation in vivo. The release of DOX and GEM from an acetylated-chitosan (ACS, degree of acetylation χAc = 40 ± 5%) was characterized to identify a combined drug loading that affords release kinetics and dose that are therapeutically synergistic. The selected DOX/GEM-ACS formulation was evaluated in vitro with 2-D and 3-D models of TNBC to determine the combination index (CI) and the tumor volume reduction, respectively. Therapeutically desired release dosages and kinetics of GEM and DOX were achieved. When evaluated with a 2-D model of TNBC, the hydrogel afforded a CI of 0.14, indicating a stronger synergism than concurrent administration of DOX and GEM (CI = 0.23). Finally, the therapeutic hydrogel accomplished a notable volume reduction of the cancer spheroids (up to 30%), whereas the corresponding dosages of free drugs only reduced growth rate. The ACS hydrogel delivery system accomplishes drug release kinetics and molar ratio that affords strong therapeutically synergism. These results, in combination with the choice of ACS as affordable and highly abundant source material, provide a strong pre-clinical demonstration of the potential of the proposed system for complementing surgical resection of aggressive solid tumors.}, number={7}, journal={PHARMACEUTICAL RESEARCH}, author={Schneible, John D. and Young, Ashlyn T. and Daniele, M. A. and Menegatti, S.}, year={2020} }
 @article{schneible_shi_young_ramesh_he_dowdey_dubnansky_libya_gao_santiso_et al._2020, title={Modified gaphene oxide (GO) particles in peptide hydrogels: a hybrid system enabling scheduled delivery of synergistic combinations of chemotherapeutics}, volume={8}, ISSN={["2050-7518"]}, DOI={10.1039/d0tb00064g}, abstractNote={The scheduled delivery of synergistic drug combinations is increasingly recognized as highly effective against advanced solid tumors. Of particular interest are composite systems that release a sequence of drugs with defined kinetics and molar ratios to enhance therapeutic effect, while minimizing the dose to patients. In this work, we developed a homogeneous composite comprising modified graphene oxide (GO) nanoparticles embedded in a Max8 peptide hydrogel, which provides controlled kinetics and molar ratios of release of doxorubicin (DOX) and gemcitabine (GEM). First, modified GO nanoparticles (tGO) were designed to afford high DOX loading and sustained release (18.9% over 72 h and 31.4% over 4 weeks). Molecular dynamics simulations were utilized to model the mechanism of DOX loading as a function of surface modification. In parallel, a Max8 hydrogel was developed to release GEM with faster kinetics and achieve a 10-fold molar ratio to DOX. The selected DOX/tGO nanoparticles were suspended in a GEM/Max8 hydrogel matrix, and the resulting composite was tested against a triple negative breast cancer cell line, MDA-MB-231. Notably, the composite formulation afforded a combination index of 0.093 ± 0.001, indicating a much stronger synergism compared to the DOX-GEM combination co-administered in solution (CI = 0.396 ± 0.034).}, number={17}, journal={JOURNAL OF MATERIALS CHEMISTRY B}, author={Schneible, John D. and Shi, Kaihang and Young, Ashlyn T. and Ramesh, Srivatsan and He, Nanfei and Dowdey, Clay E. and Dubnansky, Jean Marie and Libya, Radina L. and Gao, Wei and Santiso, Erik and et al.}, year={2020}, month={May}, pages={3852–3868} }
 @article{day_schneible_young_pozdin_driessche_gaffney_prodromou_freytes_fourches_daniele_et al._2020, title={Photoinduced reconfiguration to control the protein-binding affinity of azobenzene-cyclized peptides}, volume={8}, ISSN={["2050-7518"]}, DOI={10.1039/d0tb01189d}, abstractNote={The impact of next-generation biorecognition elements (ligands) will be determined by the ability to remotely control their binding activity for a target biomolecule in complex environments. Compared to conventional mechanisms for regulating binding affinity (pH, ionic strength, or chaotropic agents), light provides higher accuracy and rapidity, and is particularly suited for labile targets. In this study, we demonstrate a general method to develop azobenzene-cyclized peptide ligands with light-controlled affinity for target proteins. Light triggers a cis/trans isomerization of the azobenzene, which results in a major structural rearrangement of the cyclic peptide from a non-binding to a binding configuration. Critical to this goal are the ability to achieve efficient photo-isomerization under low light dosage and the temporal stability of both cis and trans isomers. We demonstrated our method by designing photo-switchable peptides targeting vascular cell adhesion marker 1 (VCAM1), a cell marker implicated in stem cell function. Starting from a known VCAM1-binding linear peptide, an ensemble of azobenzene-cyclized variants with selective light-controlled binding were identified by combining in silico design with experimental characterization via spectroscopy and surface plasmon resonance. Variant cycloAZOB[G-VHAKQHRN-K] featured rapid, light-controlled binding of VCAM1 (KD,trans/KD,cis ∼ 130). Biotin-cycloAZOB[G-VHAKQHRN-K] was utilized to label brain microvascular endothelial cells (BMECs), showing co-localization with anti-VCAM1 antibodies in cis configuration and negligible binding in trans configuration.}, number={33}, journal={JOURNAL OF MATERIALS CHEMISTRY B}, author={Day, Kevin and Schneible, John D. and Young, Ashlyn T. and Pozdin, Vladimir A. and Driessche, George and Gaffney, Lewis A. and Prodromou, Raphael and Freytes, Donald O. and Fourches, Denis and Daniele, Michael and et al.}, year={2020}, month={Sep}, pages={7413–7427} }
 @article{schneible_singhal_lilova_hall_grafmueller_menegatti_2019, title={Tailoring the Chemical Modification of Chitosan Hydrogels to Fine-Tune the Release of a Synergistic Combination of Chemotherapeutics}, volume={20}, ISSN={["1526-4602"]}, DOI={10.1021/acs.biomac.9b00707}, abstractNote={Combination chemotherapy with defined ratio and sequence of drug release is a clinically established and effective route to treat advanced solid tumors. In this context, a growing body of literature demonstrates the potential of hydrogels constructed with chemically modified polysaccharides as depots for controlled release of chemotherapeutics. Identifying the appropriate modification in terms of physicochemical properties of the functional group and its degree of substitution (χ) to achieve the desired release profile for multiple drugs is, however, a complex multivariate problem. To address this issue, we have developed a computational toolbox that models the migration of a drug pair through a hydrated network of polysaccharide chains modified with hydrophobic moieties. In this study, we chose Doxorubicin (DOX) and Gemcitabine (GEM) as model drugs, as their synergistic effect against breast cancer has been thoroughly investigated, and chitosan as model polymer. Our model describes how the modification of chitosan chains with acetyl, butanoyl, and heptanoyl moieties at different values χ governs both the structure of the hydrogel network and drug migration through it. Our experimental data confirm the in silico predictions for both single and dual-drug release, and, most notably, the counterintuitive inversion of release vs. χ that occurs when switching from a single to a dual-drug system. Consensus between predicted and experimental data indicates that acetyl modifications (χ = 32-42%) and butanoyl-modifications (χ = 19-24%) provide synergistic GEM/DOX release molar ratios (5-10 i.e.,). Collectively, these results demonstrate the potential of this model in guiding the design of chemotherapeutic hydrogels to combat cancer.}, number={8}, journal={BIOMACROMOLECULES}, author={Schneible, John D. and Singhal, Ankush and Lilova, Radina L. and Hall, Carol K. and Grafmueller, Andrea and Menegatti, Stefano}, year={2019}, month={Aug}, pages={3126–3141} }