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

Abstract

While 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 (H₂ O₂ ). Navigated by GPC3Ab to tumor cells at acidic pH, the nanoparticle disassembles to CaO₂ and BPQD; CaO₂ produces COMT Ca²⁺ and H₂ O₂ , while H₂ O₂ makes oxygen (O₂ ) to promote PDT; under NIR irradiation BPQD facilitates not only the conversion of O₂ to singlet oxygen (¹ O₂ ) for PDT, but also moderate hyperthermia to accelerate NP dissociation to CaO₂ and BPQD, and conversions of CaO₂ to Ca²⁺ and H₂ O₂ , and H₂ O₂ 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.