A Self‐Reinforcing Nanoplatform for Highly Effective Synergistic Targeted Combinatary Calcium‐Overload and Photodynamic Therapy of Cancer

Abstract

AbstractWhile calcium‐overload‐mediated therapy (COMT) is a promising but largely untapped therapeutic strategy, combinatory therapy greatly boosts treatment outcomes with integrated merits of different therapies. Herein, a BPQD@CaO2‐PEG‐GPC3Ab nanoplatform is formulated by integrating calcium peroxide (CaO2) and black phosphorus quantum dot (BPQD, photosensitizer) with active‐targeting glypican‐3 antibody (GPC3Ab), for combinatory photodynamic therapy (PDT) and COMT in response to acidic pH and near‐infrared (NIR) light, wherein CaO2 serves as the reservoir of calcium ions (Ca2+) and hydrogen peroxide (H2O2). Navigated by GPC3Ab to tumor cells at acidic pH, the nanoparticle disassembles to CaO2 and BPQD; CaO2 produces COMT Ca2+ and H2O2, while H2O2 makes oxygen (O2) to promote PDT; under NIR irradiation BPQD facilitates not only the conversion of O2 to singlet oxygen (1O2) for PDT, but also moderate hyperthermia to accelerate NP dissociation to CaO2 and BPQD, and conversions of CaO2 to Ca2+ and H2O2, and H2O2 to O2, to enhance both COMT and PDT. After supplementary ionomycin treatment to induce intracellular Ca2+ bursts, the multimodal therapeutics strikingly induce hepatocellular carcinoma apoptosis, likely through the activation of the calpains and caspases 12, 9, and 3, up‐regulation of Bax and down‐regulation of Bcl‐2 proteins. This nanoplatform enables a mutually‐amplifying and self‐reinforcing synergistic therapy.