On-Demand Drug Release from Click-Refillable Drug Depots,Molecular Pharmaceutics

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On-Demand Drug Release from Click-Refillable Drug Depots
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-09-08 , DOI: 10.1021/acs.molpharmaceut.1c00535
Sandeep Palvai ₁ , Christopher T Moody _{1,

2} , Sharda Pandit _{1,

2} , Yevgeny Brudno _{1,

2,

3}

Affiliation

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.

中文翻译：

可点击再填充药库的按需药物释放

从药物洗脱库中对刺激反应、按需释放药物可以改变许多局部疾病的治疗，提供对局部剂量的复杂控制。然而，传统的按需药物释放方法依赖于局部植入的药物贮库，这些贮库会随着时间的推移而耗尽，并且在没有侵入性程序的情况下无法重新填充或重复使用。以无创方式重新填充药物洗脱库然后按需释放的新策略可能会改变临床治疗。在这里，我们报告了一种按需药物递送范例，该范例结合了生物正交点击化学以在预标记位点局部富集原始药物并在目标组织处进行光触发药物释放。这种方法首先通过局部注射锚定到细胞外基质的化学反应性叠氮基团来引入可靶向库。然后锚定的叠氮化物基团通过生物正交点击化学捕获血液循环的原始药物。经局部捕获和滞留后，可通过外光照射释放活性药物。在本报告中，构建了一种光响应性原药，该药物由化学治疗性阿霉素 (Dox) 组成，通过可光裂解的邻硝基苄基接头与二苯并环辛炔 (DBCO) 结合。原药表现出优异的按需光触发 Dox 释放特性和光介导通过可光裂解的邻硝基苄基接头与二苯并环辛炔 (DBCO) 结合。原药表现出优异的按需光触发 Dox 释放特性和光介导通过可光裂解的邻硝基苄基接头与二苯并环辛炔 (DBCO) 结合。原药表现出优异的按需光触发 Dox 释放特性和光介导U87胶质母细胞瘤细胞系的体外细胞毒性。此外，在活体动物环境中，通过皮内注射活化的叠氮化物-NHS 酯在小鼠体内形成叠氮化物贮库。iv 给药后，原始药物被具有复杂局部特异性的叠氮化物库捕获，可以通过多次补充来增加。最后，多柔比星可以在光照射下从仓库中释放出来。完成了多轮补给和活性药物的光介导释放，表明该系统具有多轮治疗的潜力。总之，这些体外和体内概念验证研究建立了一种新的体内方法在靶组织靶向和按需递送细胞毒性药物。

更新日期：2021-10-04

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