A Cell Selective Fluoride-Activated MOF Biomimetic Platform for Prodrug Synthesis and Enhanced Synergistic Cancer Therapy.

Abstract

As a burgeoning bioorthogonal reaction, the fluoride-mediated desilylation is capable of prodrug activation. However, due to the reactions lack of cell selectivity and unitary therapy modality, this strongly impedes their biomedical applications. Herein, we construct a cancer cell-selective biomimetic metal-organic framework (MOF)-F platform for prodrug activation and enhanced synergistic chemodynamic therapy (CDT). With cancer cell membranes camouflage, the designed biomimetic nanocatalyst displays preferential accumulation to homotypic cancer cells. Then, pH-responsive nanocatalyst releases fluoride ions and ferric ions. For activation of our designed prodrug <i>tert</i>-butyldimethyl silyl (TBS)-hydroxycamptothecin (TBSO-CPT), fluoride ions can desilylate TBS and cleave the designed silyl ether linker to synthesize the OH-CPT (10-hydroxycamptothecin) drug molecule, which effectively kills cancer cells. Intriguingly, the bioorthogonal-synthesized OH-CPT drug upregulates intracellular H₂O₂ by activating nicotinamide adenine dinucleotide phosphate oxidase (NOX), amplifying the released iron induced Fenton reaction for synergistic CDT. Both <i>in vitro</i> and <i>in vivo</i> studies demonstrate our strategy presents a versatile fluoride-activated bioorthogonal catalyst for cancer cell-selective drug synthesis. Our work may accelerate the biomedical applications of fluoride-activated bioorthogonal chemistry.