Combination of Chemical and Physical Cancer Therapeutics Developed with Microcapsules Made of κ-Casein and Gold Nanoparticles in the Presence of Drug-Loaded Phase Change Materials.

Tumor heterogeneity requires development of an anticancer system equipped with both chemical and physical therapeutics to eradicate cancer exhibiting drug resistance and clonal evolution into diverse tumor cells. Assortment of various toxic components into one platform without compromising their individual toxic activity remains a formidable task. Herein, a novel drug delivery system (DDS) exerting potent cytotoxicity toward cancer cells was fabricated with gold nanoparticles (AuNPs) coated with an innocuous self-assembly protein of κ-casein (κC). Pickering emulsions of the κC-AuNP conjugates in the presence of chloroform inside led to the κC-AuNP microcapsules being stabilized via robust β-sheet formation between κC molecules located on the single-layered shell made of κC-AuNPs. Phase change material (PCM) comprising a eutectic mixture of lauric acid and myristic acid with the melting point of 43 °C was encapsulated in the presence of a hydrophilic anticancer drug of doxorubicin (Dox), in which the PCM has played multiple functions such as drug-holding matrix and thermoresponsive gating material for drug release. Once liberated with the heat generated by the AuNPs upon a near-infrared (NIR) irradiation at 808 nm, the PCM by itself exhibited not only chemical cytotoxicity but also physical toxic effects such as membrane destabilization of the cells and a possible cellular fixative effect toward cancer cells by the solidified PCM at body temperature. Moreover, the PCM was shown to facilitate the intranuclear localization of Dox. As a result, the DDS comprising κC-AuNP microcapsules containing Dox-loaded PCM was demonstrated to show a powerful anticancer effect upon the NIR irradiation, which unleashed several toxic agents such as Dox, PCM, heat-generating AuNPs, and tissue-immobilizing solidified PCM. Therefore, the κC-AuNP microcapsules would serve as an anticancer system into which diverse chemical and physical therapeutic agents could be combined to effectively remove the heterogeneous and drug resistant cancer cells.