A polymer‑calcium phosphate nanocapsule for RNAi-induced oxidative stress and cascaded chemotherapy

• Published in: Journal of controlled release Vol. 340; pp. 259 - 270
• Main Authors: Huang, Jinsheng, Zheng, Chujie, Xiao, Hong, Huang, Huiling, Wang, Yiyao, Lin, Minzhao, Pang, Jun, Wang, Yong, Yuan, Yuanyuan, Shuai, Xintao
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10-12-2021
• Subjects: ADP-Ribosylation Factor 6; Animals; Calcium Phosphates; Cascaded treatment; Cell Line, Tumor; Chemotherapy; Mice; Mitochondrial modulation; Nanocapsules; Nanoparticles; Oxidative Stress; Polymer prodrug; Polymers; Prodrugs; RNA Interference; siRNA delivery; siRNA delivery; Oxidative stress; Chemotherapy; Polymer prodrug; Mitochondrial modulation; Cascaded treatment
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2021.10.030

As most of intracellular reactive oxygen species (ROS) is produced in the mitochondria, mitochondrial modulation of cancer cell is a promising strategy for maximizing the in situ-activable combination therapy of oxidative catastrophe and cascaded chemotherapy. Herein, a serum-stable polymer‑calcium phosphate (CaP) hybrid nanocapsule carrying siRNA against ADP-ribosylation factor 6 (Arf6) overexpressed in cancer cells and parent drug camptothecin (CPT), designated as PTkCPT/siRNA, was developed for the RNAi-induced oxidative catastrophe and cascaded chemotherapy. A copolymer of mPEG-P(Asp-co-TkCPT), covalently tethered with chemotherapeutic CPT via a ROS-labile dithioketal (Tk) linker, was synthesized and self-assembled into a PTkCPT micelle as a nanotemplate for the CaP mineralization. The as-prepared PTkCPT/siRNA nanoparticle showed a core-shell-distinct nanocapsule which was consisted of a spherical polymeric core enclosed within a CaP shell capable of releasing siRNA in response to lysosomal acidity. Blocking Arf6 signal pathway of cancer cells led to their mitochondrial aggregation and subsequently induced a burst of ROS for oxidative catastrophe, which further triggered the cascaded CPT chemotherapy via the breakage of ROS-labile dithioketal linker. This strategy of RNAi-induced oxidative catastrophe and cascaded chemotherapy resulted in a significant combination effect on cancer cell killing and tumor growth inhibition in mice with low side effects, and provided a promising paradigm for precise cancer therapy.
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•The hybrid nanocapsule was consisted of a ROS-sensitive polymeric core enclosed within a pH-sensitive calcium phosphate shell.•This nanocapsule enabled a tumor-targeting codelivery of Arf6 siRNA and camptothecin.•Arf6 siRNA amplified endogenous ROS in cancer cell for oxidative catastrophe and cascaded camptothecin chemotherapy.•This treatment strategy resulted in a significant combination anti-cancer effect in vitro and in vivo with low side effects.