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

Abstract

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.

• Authors: Jinsheng Huang, Chujie Zheng, Hong Xiao, Huiling Huang, Yiyao Wang, Minzhao Lin, Jun Pang, Yong Wang, Yuanyuan Yuan, Xintao Shuai
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 340 Pg. 259-270 (12 10 2021) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 34740724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• ADP-Ribosylation Factor 6
• Calcium Phosphates
• Nanocapsules
• Polymers
• Prodrugs

Topics

• ADP-Ribosylation Factor 6
• Animals
• Calcium Phosphates
• Cell Line, Tumor
• Mice
• Nanocapsules
• Nanoparticles
• Oxidative Stress
• Polymers
• Prodrugs
• RNA Interference