CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, China.
MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, 55 Zhongshan Avenue West, Guangzhou, 510631, China.
Adv Mater. 2018 May;30(21):e1706307. doi: 10.1002/adma.201706307. Epub 2018 Apr 10.
Combination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water-soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug-gated crosslinked vesicles (GCVs) via the self-assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol-gel reaction is reported. Polyprodrug-GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation (t > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu-triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36-fold increase). The reduction-activated combination chemotherapeutic potency based on polyprodrug-GCVs is confirmed by both in vitro and in vivo explorations.
联合应用疏水性和亲水性治疗药物的化疗对于持续性癌症的治疗具有重要的临床意义。虽然具有疏水性双层和亲水性内部的常规脂质体和聚合物囊泡可以作为共递药纳米载体，但由于不同的包封机制，实现这两种药物的同步释放仍然是一个相当大的挑战；从不稳定的脂质体和破裂的囊泡中过早释放水溶性货物也是一个主要问题。在此，通过喜树碱（CPT）多前药两亲分子的自组装和通过无痕迹溶胶-凝胶反应进行原位双层交联，报告了通过物理稳定的聚前药门控交联囊泡（GCV）的制备。聚前药-GCV 具有高 CPT 负载量（>30wt%）和最小化包裹的亲水性阿霉素（DOX）盐酸盐的泄漏，由于交联膜的渗透率降低，在生理循环中表现出延长的血液循环（t > 13 h）和封闭的细胞毒性。在癌细胞摄取后，通过细胞溶质还原环境从囊泡双层中弹出 CPT 被证明会产生亲水性网状通道，使膜具有高通透性。同时，它将促进亲水性腔室中 DOX 的共释放（≈36 倍增加）。基于聚前药-GCV 的还原激活联合化疗功效通过体外和体内研究得到了证实。
