Palvai Sandeep, Moody Christopher T, Pandit Sharda, Brudno Yevgeny
Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Raleigh, North Carolina 27607, United States.
Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States.
Mol Pharm. 2021 Oct 4;18(10):3920-3925. doi: 10.1021/acs.molpharmaceut.1c00535. Epub 2021 Sep 8.
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 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 and proof of concept studies establish a novel method for targeting and on-demand delivery of cytotoxic drugs at target tissues.
刺激响应性、按需从药物洗脱储库释放药物可以改变许多局部疾病的治疗方式，实现对局部给药的精细控制。然而，传统的按需药物释放方法依赖于局部植入的药物储库，这些储库会随着时间的推移而耗尽，并且在不进行侵入性操作的情况下无法重新填充或重复使用。非侵入性重新填充药物洗脱储库并随后按需释放的新策略可能会改变临床治疗。在此，我们报告了一种按需给药模式，该模式结合了生物正交点击化学，在预先标记的位点局部富集前药，并在靶组织处进行光触发药物释放。这种方法首先通过局部注射与细胞外基质结合的化学反应性叠氮基团来引入可靶向的储库。然后，锚定的叠氮基团通过生物正交点击化学捕获血液循环中的前药。在局部捕获和保留后，活性药物可以通过外部光照射释放。在本报告中，构建了一种光响应前药，其由化疗药物阿霉素（Dox）组成，通过可光裂解的邻硝基苄基连接子与二苯并环辛炔（DBCO）共轭。该前药在U87胶质母细胞瘤细胞系中表现出优异的按需光触发阿霉素释放特性和光介导的细胞毒性。此外，在活体动物模型中，通过皮内注射活化的叠氮-NHS酯在小鼠体内形成叠氮储库。静脉注射后，前药以复杂的局部特异性被叠氮储库捕获，多次重新填充可增加捕获量。最后，阿霉素可在光照射下从储库中释放。实现了多轮储库重新填充和活性药物的光介导释放，表明该系统具有进行多轮治疗的潜力。综上所述，这些研究和概念验证研究建立了一种在靶组织处靶向和按需递送细胞毒性药物的新方法。
