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 (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.

Controlled Release of Oxygen from Calcium Peroxide in a Weak Acidic Condition by Stabilized Amorphous Calcium Carbonate Nanocoating for Biomedical Applications

“…In addition, pH-dependent oxygen release from ACC-CaO 2 was also observed in DMEM probably because ACC on CaO 2 dissolved under weak acidic condition. Although many researchers who used CaO 2 for cancer therapies have mentioned the specific dissolution behavior of CaO 2 in weak acidic cancer environments, − the detailed mechanism has not been widely discussed. In this research, we found that CaO 2 easily dissolved even in HEPES with neutral pH.…”

“…However, the uncontrollability of oxygen release after immersion in water is an issue, especially for the oxygen-releasing hydrogels. CaO 2 nanoparticles have also recently been used in cancer therapies such as reactive oxygen-species-based chemodynamic therapy, , calcium overload cancer therapy, − and photodynamic therapy. − Although many researchers have used CaO 2 in cell culture conditions, the nanoscale surface chemistry of CaO 2 in these conditions has not been taken into account.…”

Recent Developments in CaCO3 Nano-Drug Delivery Systems: Advancing Biomedicine in Tumor Diagnosis and Treatment

“…Calcium overload, as the name implies, is the accumulation of free Ca 2+ in the cell cytoplasm resulting in an abnormally high concentration of Ca 2+ , which can lead to severe cellular damage or even cell death [ 93 ]. Normally, calcium signaling acts as a second messenger of cellular signaling to control important physiological processes by modulating the activity of specific targets, which are essentially achieved in response to fluctuations in local calcium concentrations [ 94 ].…”

In Situ Mitochondrial Biomineralization for Drug‐Free Cancer Therapy

“…[13] The mechanism of calcification is usually induced by ischemic necrosis of tumor tissue, meaning that the tumor growth is in a quiescent state and there is less risk of distant metastasis. [14] Biological calcification, also named biomineralization, can be accurately modulated by solution medium homeostasis or calcification site selection. [15][16][17][18] If abnormal biomineralization occurs at the tissue surface, this can lead to calcified lesions and accelerated cell death.…”