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

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@CaO ₂ -PEG-GPC3Ab nanoplatform is formulated by integrating calcium peroxide (CaO ₂ ) 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 CaO ₂ serves as the reservoir of calcium ions (Ca ²⁺ ) and hydrogen peroxide (H ₂ O ₂ ). Navigated by GPC3Ab to tumor cells at acidic pH, the nanoparticle disassembles to CaO ₂ and BPQD; CaO ₂ produces COMT Ca ²⁺ and H ₂ O ₂ , while H ₂ O ₂ makes oxygen (O ₂ ) to promote PDT; under NIR irradiation BPQD facilitates not only the conversion of O ₂ to singlet oxygen ( ¹ O ₂ ) for PDT, but also moderate hyperthermia to accelerate NP dissociation to CaO ₂ and BPQD, and conversions of CaO ₂ to Ca ²⁺ and H ₂ O ₂ , and H ₂ O ₂ to O ₂ , to enhance both COMT and PDT. After supplementary ionomycin treatment to induce intracellular Ca ²⁺ 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.
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