@article{moody_durham_dayton_brudno_2023, title={Loading Intracranial Drug-Eluting Reservoirs Across the Blood-Brain Barrier With Focused Ultrasound}, volume={49}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2023.03.012}, abstractNote={Objective Efficient, sustained and long-term delivery of therapeutics to the brain remains an important challenge to treatment of diseases such as brain cancer, stroke and neurodegenerative disease. Focused ultrasound can assist movement of drugs into the brain, but frequent and long-term use has remained impractical. Single-use intracranial drug-eluting depots show promise but are limited for the treatment of chronic diseases as they cannot be refilled non-invasively. Refillable drug-eluting depots could serve as a long-term solution, but refilling is hindered by the blood–brain barrier (BBB), which prevents drug refills from accessing the brain. In this article, we describe how focused ultrasound enables non-invasive loading of intracranial drug depots in mice. Methods Female CD-1 mice (n = 6) were intracranially injected with click-reactive and fluorescent molecules that are capable of anchoring in the brain. After healing, animals were treated with high-intensity focused ultrasound and microbubbles to temporarily increase the permeability of the blood–brain barrier and deliver dibenzocyclooctyne (DBCO)–Cy7. The mice were perfused, and the brains were imaged via ex vivo fluorescence imaging. Results Fluorescence imaging indicated small molecule refills are captured by intracranial depots as long as 4 wk after administration and are retained for up to 4 wk based on fluorescence imaging. Efficient loading was dependent on both focused ultrasound and the presence of refillable depots in the brain as absence of either prevented intracranial loading. Conclusion The ability to target and retain small molecules at predetermined intracranial sites with pinpoint accuracy provides opportunities to continuously deliver drugs to the brain over weeks and months without excessive BBB opening and with minimal off-target side effects. Efficient, sustained and long-term delivery of therapeutics to the brain remains an important challenge to treatment of diseases such as brain cancer, stroke and neurodegenerative disease. Focused ultrasound can assist movement of drugs into the brain, but frequent and long-term use has remained impractical. Single-use intracranial drug-eluting depots show promise but are limited for the treatment of chronic diseases as they cannot be refilled non-invasively. Refillable drug-eluting depots could serve as a long-term solution, but refilling is hindered by the blood–brain barrier (BBB), which prevents drug refills from accessing the brain. In this article, we describe how focused ultrasound enables non-invasive loading of intracranial drug depots in mice. Female CD-1 mice (n = 6) were intracranially injected with click-reactive and fluorescent molecules that are capable of anchoring in the brain. After healing, animals were treated with high-intensity focused ultrasound and microbubbles to temporarily increase the permeability of the blood–brain barrier and deliver dibenzocyclooctyne (DBCO)–Cy7. The mice were perfused, and the brains were imaged via ex vivo fluorescence imaging. Fluorescence imaging indicated small molecule refills are captured by intracranial depots as long as 4 wk after administration and are retained for up to 4 wk based on fluorescence imaging. Efficient loading was dependent on both focused ultrasound and the presence of refillable depots in the brain as absence of either prevented intracranial loading. The ability to target and retain small molecules at predetermined intracranial sites with pinpoint accuracy provides opportunities to continuously deliver drugs to the brain over weeks and months without excessive BBB opening and with minimal off-target side effects.}, number={7}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Moody, Christopher T. and Durham, Phillip G. and Dayton, Paul A. and Brudno, Yevgeny}, year={2023}, month={Jul}, pages={1679–1685} }
 @article{moody_brown_massaro_patel_agarwalla_simpson_brown_zheng_pierce_brudno_2022, title={Restoring Carboxylates on Highly Modified Alginates Improves Gelation, Tissue Retention and Systemic Capture}, volume={138}, ISSN={1742-7061}, url={http://dx.doi.org/10.1016/j.actbio.2021.10.046}, DOI={10.1016/j.actbio.2021.10.046}, abstractNote={Alginate hydrogels are gaining traction for use in drug delivery, regenerative medicine, and as tissue engineered scaffolds due to their physiological gelation conditions, high tissue biocompatibility, and wide chemical versatility. Traditionally, alginate is decorated at the carboxyl group to carry drug payloads, peptides, or proteins. While low degrees of substitution do not cause noticeable mechanical changes, high degrees of substitution can cause significant losses to alginate properties including complete loss of calcium cross-linking. While most modifications used to decorate alginate deplete the carboxyl groups, we propose that alginate modifications that replenish the carboxyl groups could overcome the loss in gel integrity and mechanics. In this report, we demonstrate that restoring carboxyl groups during functionalization maintains calcium cross-links as well as hydrogel shear-thinning and self-healing properties. In addition, we demonstrate that alginate hydrogels modified to a high degree with azide modifications that restore the carboxyl groups have improved tissue retention at intramuscular injection sites and capture blood-circulating cyclooctynes better than alginate hydrogels modified with azide modifications that deplete the carboxyl groups. Taken together, alginate modifications that restore carboxyl groups could significantly improve alginate hydrogel mechanics for clinical applications. Chemical modification of hydrogels provides a powerful tool to regulate cellular adhesion, immune response, and biocompatibility with local tissues. Alginate, due to its biocompatibility and easy chemical modification, is being explored for tissue engineering and drug delivery. Unfortunately, modifying alginate to a high degree of substitution consumes carboxyl group, which are necessary for ionic gelation, leading to poor hydrogel crosslinking. We introduce alginate modifications that restore the alginate's carboxyl groups. We demonstrate that modifications that reintroduce carboxyl groups restore gelation and improve gel mechanics and tissue retention. In addition to contributing to a basic science understanding of hydrogel properties, we anticipate our approach will be useful to create tissue engineered scaffolds and drug delivery platforms.}, journal={Acta Biomaterialia}, publisher={Elsevier BV}, author={Moody, CT and Brown, AE and Massaro, NP and Patel, AS and Agarwalla, PA and Simpson, AM and Brown, AC and Zheng, H and Pierce, JG and Brudno, Y}, year={2022}, month={Jan}, pages={208–217} }
 @article{palvai_moody_pandit_brudno_2021, title={On-Demand Drug Release from Click-Refillable Drug Depots}, volume={18}, ISSN={["1543-8392"]}, DOI={10.1021/acs.molpharmaceut.1c00535}, abstractNote={Stimuli-responsive, on-demand release of drugs from drug-eluting depots could transform the treatment of many local diseases, providing intricate control over local dosing. However, conventional on-demand drug release approaches rely on locally implanted drug depots, which become spent over time and cannot be refilled or reused without invasive procedures. New strategies to noninvasively refill drug-eluting depots followed by on-demand release could transform clinical therapy. Here we report an on-demand drug delivery paradigm that combines bioorthogonal click chemistry to locally enrich protodrugs at a prelabeled site and light-triggered drug release at the target tissue. This approach begins with introduction of the targetable depot through local injection of chemically reactive azide groups that anchor to the extracellular matrix. The anchored azide groups then capture blood-circulating protodrugs through bioorthogonal click chemistry. After local capture and retention, active drugs can be released through external light irradiation. In this report, a photoresponsive protodrug was constructed consisting of the chemotherapeutic doxorubicin (Dox), conjugated to dibenzocyclooctyne (DBCO) through a photocleavable ortho-nitrobenzyl linker. The protodrug exhibited excellent on-demand light-triggered Dox release properties and light-mediated in vitro cytotoxicity in U87 glioblastoma cell lines. Furthermore, in a live animal setting, azide depots formed in mice through intradermal injection of activated azide-NHS esters. After i.v. administration, the protodrug was captured by the azide depots with intricate local specificity, which could be increased with multiple refills. Finally, doxorubicin could be released from the depot upon light irradiation. Multiple rounds of depot refilling and light-mediated release of active drug were accomplished, indicating that this system has the potential for multiple rounds of treatment. Taken together, these in vitro and in vivo proof of concept studies establish a novel method for in vivo targeting and on-demand delivery of cytotoxic drugs at target tissues.}, number={10}, journal={MOLECULAR PHARMACEUTICS}, author={Palvai, Sandeep and Moody, Christopher T. and Pandit, Sharda and Brudno, Yevgeny}, year={2021}, month={Oct}, pages={3920–3925} }
 @article{palvai_bhangu_akgun_moody_hall_brudno_2020, title={In Vivo Targeting Using Arylboronate/Nopoldiol Click Conjugation}, volume={31}, ISSN={["1520-4812"]}, url={https://doi.org/10.1021/acs.bioconjchem.0c00453}, DOI={10.1021/acs.bioconjchem.0c00453}, abstractNote={Bioorthogonal click reactions yielding stable and irreversible adducts are in high demand for in vivo applications, including in biomolecular labelling, diagnostic imaging and drug delivery. Previously, we reported a novel bioorthogonal "click" reaction based on the coupling of ortho-acetyl arylboronates and thiosemicarbazide-functionalized nopoldiol. We now report that a detailed structural analysis of the arylboronate/nopoldiol adduct by X-ray crystallography and 11B NMR reveals that the bioorthogonal reactants form, unexpectedly, a tetracyclic adduct through the cyclization of the distal nitrogen into the semithiocarbazone leading to a strong B-N dative bond and two new 5-membered rings. The cyclization adduct, which protects the boronate unit against hydrolytic breakdown, sheds light on the irreversible nature of this polycondensation. The potential of this reaction to work in a live animal setting was studied through in vivo capture of fluorescently labelled molecules in vivo. Arylboronates were introduced into tissues through intradermal injection of their activated NHS esters, which react with amines in the extracellular matrix. Fluorescently labelled nopoldiol molecules were administered systemically and were efficiently captured by the arylboronic acids in a location-specific manner. Taken together, these in vivo proof of concept studies establish arylboronate/nopoldiol bioorthogonal chemistry as a candidate for wide array of applications in chemical biology and drug delivery.}, number={10}, journal={BIOCONJUGATE CHEMISTRY}, publisher={American Chemical Society (ACS)}, author={Palvai, Sandeep and Bhangu, Jasmine and Akgun, Burcin and Moody, Christopher T. and Hall, Dennis G. and Brudno, Yevgeny}, year={2020}, month={Oct}, pages={2288–2292} }
 @article{adams_moody_sollinger_brudno_2019, title={Extracellular-Matrix-Anchored Click Motifs for Specific Tissue Targeting}, volume={17}, ISSN={1543-8384 1543-8392}, url={http://dx.doi.org/10.1021/acs.molpharmaceut.9b00589}, DOI={10.1021/acs.molpharmaceut.9b00589}, abstractNote={Local presentation of cancer drugs by injectable drug eluting depots reduces systemic side effects and improves efficacy. However, local depots deplete their drug stores and are difficult to introduce into stiff tissues, or organs, such as the brain, that can not accommodate increased pressure. We present a method for introducing targetable depots through injection of activated ester molecules into target tissues that react with and anchor themselves to local extracellular matrix (ECM) and subsequently capture systemically-administered small molecules through bioorthogonal click chemistry. A computational model of tissue anchoring depot formation and distribution was verified by histological analysis and confocal imaging of cleared tissues. ECM-anchored click groups do not elicit any noticeable local or systemic toxicity or immune response and specifically capture systemically-circulating molecules at intradermal, intratumoral, and intracranial sites for multiple months. Taken together, ECM-anchoring of click chemistry motifs is a promising approach to specific targeting of both small and large therapeutics, enabling repeated local presentation for cancer therapy and other diseases.}, number={2}, journal={Molecular Pharmaceutics}, publisher={American Chemical Society (ACS)}, author={Adams, Mary R. and Moody, Christopher T. and Sollinger, Jennifer L. and Brudno, Yevgeny}, year={2019}, month={Dec}, pages={392–403} }
 @article{brudno_pezone_snyder_uzun_moody_aizenberg_mooney_2018, title={Replenishable drug depot to combat post-resection cancer recurrence}, volume={178}, ISSN={["1878-5905"]}, DOI={10.1016/j.biomaterials.2018.05.005}, abstractNote={Local drug presentation made possible by drug-eluting depots has demonstrated benefits in a vast array of diseases, including in cancer, microbial infection and in wound healing. However, locally-eluting depots are single-use systems that cannot be refilled or reused after implantation at inaccessible sites, limiting their clinical utility. New strategies to noninvasively refill drug-eluting depots could dramatically enhance their clinical use. In this report we present a refillable hydrogel depot system based on bioorthogonal click chemistry. The click-modified hydrogel depots capture prodrug refills from the blood and subsequently release active drugs locally in a sustained manner. Capture of the systemically-administered refills serves as an efficient and non-toxic method to repeatedly refill depots. Refillable depots in combination with prodrug refills achieve sustained release at precancerous tumor sites to improve cancer therapy while eliminating systemic side effects. The ability to target tissues without enhanced permeability could allow the use of refillable depots in cancer and many other medical applications.}, journal={BIOMATERIALS}, author={Brudno, Yevgeny and Pezone, Matthew J. and Snyder, Tracy K. and Uzun, Oktay and Moody, Christopher T. and Aizenberg, Michael and Mooney, David J.}, year={2018}, month={Sep}, pages={373–382} }