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@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.

Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer.

Dasatinib (DAS) is a multikinase inhibitor that acts on several signaling kinases. DAS is used as a second-line treatment for chronic accelerated myeloid and Philadelphia chromosome-positive acute lymphoblastic leukemia. The therapeutic potential of DAS in other solid tumours is under evaluation. As for many other compounds, an improvement in their pharmacokinetic and delivery properties would potential augment the efficacy. Antibody-targeted biodegradable nanoparticles can be useful in targeted cancer therapy. DAS has shown activity in human epidermal growth factor receptor 2 (HER2) positive tumors, so conjugation of this compound with the anti-HER2 antibody trastuzumab (TAB) with the use of nanocarriers could improve its efficacy. TAB-targeted DAS-loaded nanoparticles were generated by nanotechnology. The guided nanocarriers enhanced in vitro cytotoxicity of DAS against HER2 human breast cancer cell lines. Cellular mechanistic, release studies and nanoparticles stability were undertaken to provide evidences for positioning DAS-loaded TAB-targeted nanoparticles as a potential strategy for further development in HER2-overexpressing breast cancer therapy.