@article{pandit_palvai_massaro_pierce_brudno_2022, title={Tissue-reactive drugs enable materials-free local depots}, volume={343}, ISSN={["1873-4995"]}, DOI={10.1016/j.jconrel.2022.01.023}, abstractNote={Local, sustained drug delivery of potent therapeutics holds promise for the treatment of a myriad of localized diseases while eliminating systemic side effects. However, introduction of drug delivery depots such as viscous hydrogels or polymer-based implants is highly limited in stiff tissues such as desmoplastic tumors. Here, we present a method to create materials-free intratumoral drug depots through Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs diffuse into tissue and attach locally for sustained drug release. In TRAPs, potent drugs are modified with ECM-reactive groups and then locally injected to quickly react with accessible amines within the ECM, creating local drug depots. We demonstrate that locally injected TRAPs create dispersed, stable intratumoral depots deep within mouse and human pancreatic tumor tissues. TRAPs depots based on ECM-reactive paclitaxel (TRAP paclitaxel) had better solubility than free paclitaxel and enabled sustained in vitro and in vivo drug release. TRAP paclitaxel induced higher tumoral apoptosis and sustained better antitumor efficacy than the free drug. By providing continuous drug access to tumor cells, this material-free approach to sustained drug delivery of potent therapeutics has the potential in a wide variety of diseases where current injectable depots fall short.}, journal={JOURNAL OF CONTROLLED RELEASE}, author={Pandit, Sharda and Palvai, Sandeep and Massaro, Nicholas P. and Pierce, Joshua G. and Brudno, Yevgeny}, year={2022}, month={Mar}, pages={142–151} }
 @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} }