A multichannel Ca2+ nanomodulator amplifies exogenous and endogenous calcium overload for efficient antitumor and antimetastasis therapy
Xiaoai Chen, Chang Xu, Peng Zhao, Yu Zhang, Jingzhe Guo, Xiuli Hu, Hui Gao, Chuangnian Zhang, Xiongwei Qu, Jimin Zhang
Abstract
Calcium overload–based antitumor therapy via disruption of Ca 2+ homeostasis has attracted significant attention, although the efficient elevation of calcium overload is extremely challenging. We designed an exogenous and endogenous Ca 2+ multichannel nanomodulator (Lipo CaO 2 –TA–Fe 3+ /PArg). The material comprises tannic acid (TA) and Fe 3+ assembled with calcium peroxide (CaO 2 ) (CaO 2 –TA–Fe 3+ ) and polyarginine (PArg) incorporated into a pH-responsive liposome. Upon internalization by the tumor cell, lysosomal acidity triggers TA and Fe 3+ dissociation, stimulating CaO 2 disintegration to self-supply Ca 2+ and hydrogen peroxide (H 2 O 2 ). The dissociated TA reduced Fe 3+ to Fe 2+ , which reacted with H 2 O 2 by the Fenton reaction, yielding self-circulating oxidative hydroxyl radicals (•OH). Most important, •OH oxidizes PArg for sustained nitric oxide (NO) production. The Lipo CaO 2 –TA–Fe 3+ /PArg nanomodulator amplified calcium overload via multiple channels: self-supplied exogenous Ca 2+ , •OH-opened Ca 2+ influx channel (TRPA1), and closed outflux pump (PMCA4), and NO opened the ryanodine receptors (RyRs) on endoplasmic reticulum (ER) calcium stores. Amplification of calcium overload activated mitochondrial-mediated apoptosis pathways and resulted in 81.33% tumor inhibition in vivo . It also induced Calpain1 protease-inhibited depolymerization of action cytoskeleton, thereby inhibiting tumor metastasis. This exogenous and endogenous multichannel Ca 2+ nanomodulator amplifies calcium overload and holds great promise for efficient ion interference-based antitumor and anti-metastasis therapy.