Activatable Biomineralized Nanoplatform Remodels the Intracellular Environment of Multidrug‐Resistant Tumors for Enhanced Ferroptosis/Apoptosis Therapy

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2021-11, Vol.17 (47), p.e2102269-n/a
• Main Authors: Wang, Xuan, Zhao, Yuanyuan, Hu, Yan, Fei, Yang, Zhao, Youbo, Xue, Chencheng, Cai, Kaiyong, Li, Menghuan, Luo, Zhong
• Format: Article
• Language: English
• Subjects: Acidification; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Apoptosis; biomineralized nanoplatforms; Calcium phosphates; Cell death; Cell Line, Tumor; Cytoplasm; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Efflux; Ferroptosis; ferroptosis therapies; Glycolysis; Glycoproteins; Hydrogen peroxide; iron‐drug nanocomplexes; Lactic acid; Lipid peroxidation; Lipids; Lysosomes; Mice; multidrug‐resistant tumors; Nanotechnology; tumor intracellular remodeling; Tumors
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.202102269

Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug‐resistant tumor cells is challenging due to their ability to effuse antitumor agents via p‐glycoprotein (P‐gp) and anti‐lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)‐based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4‐mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin‐Fe2+ (DOX‐Fe2+) complex and MCT4‐inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX‐Fe2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis‐generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform‐induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P‐gp‐dependent DOX effusion to enhance H2O2 production, but also increase the overall catalytic efficiency of Fe2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor‐bearing mice. This study may provide new avenues for the treatment of multidrug‐resistant tumors. The development of ferroptosis‐based therapy against multidrug‐resistant tumors has been impeded by their innate ability to effuse the therapeutic agents via p‐glycoprotein and the alkaline intracellular environment. This study reports a biomineralized nanoplatform that could remodel the tumor intracellular environment by blocking the MCT4‐mediated export of lactic acid and sensitize these multidrug‐resistant tumor cells for combinational ferroptosis/apoptosis therapy.