Tumor therapy utilizing dual-responsive nanoparticles: A multifaceted approach integrating calcium-overload and PTT/CDT/chemotherapy

• Published in: Journal of controlled release 2024-12, Vol.376, p.646-658
• Main Authors: Yang, Xiaorong, Zhang, Hong, Wu, Zehua, Chen, Qin, Zheng, Wei, Shen, Qiying, Wei, Qiaolin, Shen, Jia-Wei, Guo, Yong
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Ca2+-overloading; CaCO3; calcium; Calcium - metabolism; calcium carbonate; Calcium Carbonate - administration & dosage; Calcium Carbonate - chemistry; CDT; Cell Line, Tumor; chemotherapy; Copper - administration & dosage; Copper - chemistry; doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Drug Liberation; drug therapy; Humans; irradiation; Mice; mitochondria; nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; neoplasms; Neoplasms - drug therapy; Neoplasms - therapy; Photothermal Therapy - methods; photothermotherapy; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; PTT; sulfides; synergistic therapy; toxicity; Tumor Microenvironment - drug effects
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2024.10.029

The advancement of rational nano drug delivery systems offers robust tools for achieving synergistic therapeutic outcomes in tumor treatment. In this study, we present the development of pH and near-infrared laser dual-responsive nanoparticles (DOX-CuS@CaCO3@PL-PEG, DCCP NPs) based on calcium carbonate, utilizing a one-pot gas diffusion reaction. These nanoparticles enable combined photothermal therapy (PTT), chemodynamic therapy (CDT), chemotherapy, and Ca2+-overloading synergistic therapy. Doxorubicin (DOX) and copper sulfide (CuS) NPs were co-loaded in CaCO3, followed by PEG surface functionalization. The presence of PEG enhanced the stability of DCCP NPs in aqueous environments. Controlled release of DOX, CuS NPs, and Ca2+ occurs specifically in the acidic tumor microenvironment. Released DOX enhances chemotherapy efficiency, while CuS NPs, upon laser irradiation, induce thermal damage, promoting further drug release and cellular uptake. Additionally, CuS NPs in our system consume excess GSH and generate toxic hydroxyl radicals (·OH) through a Fenton-like reaction, contributing to CDT. These radicals not only directly eliminate tumor cells but also disrupt mitochondrial Ca2+ buffering capacity. Furthermore, Ca2+ released from CaCO3 induces Ca2+-overloading, intensifying mitochondrial disruption and oxidative damage. The synergistic combination of PTT, CDT, chemotherapy, and Ca2+-overloading showcases significant therapeutic potential, indicating broad applications in tumor therapy. This multifaceted approach holds promise for advancing the field of tumor therapeutics. pH and NIR laser dual-responsive multimodal nanoplatform DCCP NPs can achieve Ca2+-overloading therapy, PTT, CDT and chemotherapy after entering tumor tissues and irradiated by NIR laser. Photothermal light improves chemotherapy effect and CDT efficiency, while ROS generated by CDT disrupts Ca2+ buffer capacity and synergizes with CaCO3 degradation to release large amount of Ca2+, leading to Ca2+-overloading. [Display omitted] •CuS NPs produce effective thermal ablation under NIR laser irradiation.•Photothermal promotes CuS-mediated Fenton-like catalytic activityto generate ROS.•The large amount of Ca2+ released by CaCO3 degradation causes Ca2+-overloading to damage mitochondria.•Dual-responsive multimodal nanoplatform achieves enhanced cancer therapeutic effects.