Enhanced
Cancer Starvation Therapy Enabled by an Autophagy
Inhibitors-Encapsulated Biomimetic ZIF‑8 Nanodrug: Disrupting
and Harnessing Dual Pro-Survival Autophagic Responses
posted on 2022-05-04, 17:10authored byFenglan Li, Tao Chen, Fang Wang, Jinfa Chen, Yuanyuan Zhang, Danting Song, Ning Li, Xin-Hua Lin, Lisen Lin, Junyang Zhuang
Autophagy
is an important protective mechanism in maintaining or
restoring cell homeostasis under physiological and pathological conditions.
Nanoparticles (NPs) with certain components and morphologies can induce
autophagic responses in cancer cells, providing a new perspective
for establishing cancer therapy strategies. Herein, a novel nanodrug
system, cell membranes-coated zeolitic imidazolate framework-8 (ZIF-8)
NPs encapsulating chloroquine (CQ) and glucose oxidase (GOx) (defined
as mCG@ZIF), is designed to achieve an enhanced anticancer effect
with the combination of starvation therapy and an autophagy regulation
strategy. It is found that ZIF-8 as a nanocarrier can induce autophagy
to promote survival of cancer cells via the upstream Zn2+-stimulated mitochondrial reactive oxygen species (ROS) so that the
anticancer effect is directly achieved by inhibiting this pro-survival
autophagy using CQ released from mCG@ZIF under a tumor acidic microenvironment.
Moreover, a cancer cell under starvation caused by GOx harnesses autophagy
to maintain intracellular ATP levels and resist starvation therapy.
The released CQ further inhibits the starvation-induced pro-survival
autophagy and cuts off the protective pathway of cancer cells, enhancing
the anticancer efficiency of GOx-based starvation therapy. Significantly,
the cell membrane coating endows mCG@ZIF with excellent in vivo homotypic
targeting ability. Both in vitro and in vivo results have confirmed
the enhanced anticancer effect achieved by mCG@ZIF with a negligible
side effect.