Photoactivatable Prodrug-Backboned Polymeric Nanoparticles for Efficient Light-Controlled Gene Delivery and Synergistic Treatment of Platinum-Resistant Ovarian Cancer
Photoactivatable Prodrug-Backboned Polymeric Nanoparticles for Efficient Light-Controlled Gene Delivery and Synergistic Treatment of Platinum-Resistant Ovarian Cancer
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用于有效光控基因传递和协同治疗铂耐药卵巢癌的光活化前药支撑聚合物纳米颗粒
DOI：
10.1021/acs.nanolett.9b04981
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发表时间：
2020
期刊：
影响因子：
10.8
通讯作者：
Huang Yubin
中科院分区：
文献类型：
--
作者：
Zhang Qingfei;Kuang Gaizhen;He Shasha;Lu Hongtong;Cheng Yilong;Zhou Dongfang;Huang Yubin
化疗和基因治疗的结合为癌症治疗提供了有效的策略。然而，缺乏具有有效内/溶酶体逃逸和可控药物释放/基因解包的合适共递送系统是最大化组合治疗功效的主要瓶颈。在这项工作中，我们开发了一种光激活的 Pt(IV) 前药骨架聚合物纳米粒子系统 (CNPPtCP/si(c-fos))，用于光控 si(c-fos) 递送以及对铂耐药卵巢癌 (PROC) 的协同光激活化疗 (PACT) 和 RNA 干扰 (RNAi)。在蓝光照射 (430 nm) 下，CNPPtCP/si(c-fos) 生成具有温和氧化能的不依赖于氧的 N3•，通过 N3• 辅助的光化学内化实现有效的内/溶酶体逃逸，同时减少基因失活。此后，随着 Pt(IV) 前药的激活，CNPPtCP/si(c-fos) 解离以释放活性 Pt(II) 并同时解包 si(c-fos)。体外和体内结果均表明 CNPPtCP/si(c-fos) 对 PROC 表现出优异的协同治疗效果，且毒性较低。这种以 PACT 前药为骨架的聚合物纳米平台可能为治疗各种难以治疗的癌症提供一种有前景的基因/药物共传递策略。
Combination of chemotherapy and gene therapy provides an effective strategy for cancer treatment. However, the lack of suitable codelivery systems with efficient endo/lysosomal escape and controllable drug release/gene unpacking is the major bottleneck for maximizing the combinational therapeutic efficacy. In this work, we developed a photoactivatable Pt(IV) prodrug-backboned polymeric nanoparticle system (CNPPtCP/si(c-fos)) for light-controlled si(c-fos) delivery and synergistic photoactivated chemotherapy (PACT) and RNA interference (RNAi) on platinum-resistant ovarian cancer (PROC). Upon blue-light irradiation (430 nm), CNPPtCP/si(c-fos)generates oxygen-independent N3•with mild oxidation energy for efficient endo/lysosomal escape through N3•-assisted photochemical internalization with less gene deactivation. Thereafter, along with Pt(IV) prodrug activation, CNPPtCP/si(c-fos)dissociates to release active Pt(II) and unpack si(c-fos) simultaneously. Both in vitro and in vivo results demonstrated that CNPPtCP/si(c-fos)displayed excellent synergistic therapeutic efficacy on PROC with low toxicity. This PACT prodrug-backboned polymeric nanoplatform may provide a promising gene/drug codelivery tactic for treatment of various hard-to-tackle cancers.