Nested Nanotherapeutics for Drug Synergy Enhancement in Breast Cancer Therapy.

摘要

Time-staggered and sequential combination chemotherapy strategies show immense potential in controlled cell culture systems, but fail to successfully translate to the clinic due to different routes of administration and disparate formulation parameters that preclude a specific order of drug presentation. We have rationally designed a novel nanoparticle construct capable of releasing drugs in a time- and sequence-dependent manner specifically within tumors. The platform consists of drug containing PLGA polymer nanoparticles stably fashioned with an outer shell composed of drug complexed with cationic cyclodextrin. Morphological examination of nanoparticles, measuring 150 nm in diameter, highlighted compartmentalization of model drugs, rhodamine and bodipy, within the core and shell, respectively. Sequential release was observed in vitro, kinetics that were also observed in breast cancer cells following internalization. Sequential-based release was corroborated via confocal microscopy in a murine model of breast cancer following intravenous administration. Incorporation of rapamycin in the outer shell and paclitaxel in the inner core demonstrated sequential release kinetics, significant cell-killing potential, and a substantial reduction of tumor growth in murine models of breast cancer, highlighting the synergistic mechanism of action arising from sequential delivery.