Gold nanocage decorated pH-sensitive micelle for highly effective photothermo-chemotherapy and photoacoustic imaging.

A pH-sensitive copolymer PAsp(DIP)-b-PAsp(MEA) (PDPM) was synthesized and self-assembled to micelle loading chemotherapeutic drug doxorubicin (DOX) and introducing a gold nanocage structure for photothermo-chemotherapy and photoacoustic imaging. After further surface modification with polyethylene glycol (PEG), the DOX-loaded pH-sensitive gold nanocage (D-PGNC) around 100 nm possessed a uniform spherical structure with a pH-sensitive core of PAsp(DIP) incorporating DOX, an interlayer crosslinked via disulfide bonds and decorated with discontinuous gold shell, and a PEG corona. The release of DOX from D-PGNC was turned off in bloodstream due to the cross-linking and gold decoration of interlayer but turned on inside tumor tissue by multiple stimulations including the low pH value of tumor tissue (≈6.8), the low lysosomal pH value of cancer cells (≈5.0) and near-infrared (NIR) irradiation. The gold nanocage receiving NIR irradiation could generate hyperthermia to ablate tumor cells. Moreover, the photoacoustic (PA) imaging and analysis of DOX fluorescence inside tumor tissue demonstrated that photothermal therapy based on the gold nanocage effectively drove DOX penetration inside tumor. Owing to the rapid intratumor release and deep tissue penetration of drug favorable for killing cancer cells survived the photothermal therapy, the combined therapy based on D-PGNC via NIR irradiation exhibited a synergistic treatment effect superior to either chemotherapy or NIR-induced photothermal therapy alone. STATEMENT OF SIGNIFICANCE: The novelty of the manuscript is its multifunctional system which incorporates anticancer drug DOX in its pH-sensitive core and acts as a template to introduce a gold nanocage. This nanomedicine presents potentials of sequestrating drug molecules in blood circulation but releasing them inside tumor upon responding to the acidic microenvironment therein. Exposure to NIR laser further expedited the pH-sensitive DOX release and promoted DOX penetration into cancer tissues far away from the vasculature. Consequently, the combined photothermo-chemotherapy showed synergistic effects to inhibit tumor growth and prolong animal survival in nude mice bearing human SKOV-3 ovarian tumor. Moreover, owing to the decoration with gold nanocage, the tumor accumulation and intratumor diffusion of the micelles were easily trackable using photoacoustic imaging.