Mitochondrion- and nucleus-acting polymeric nanoagents for chemo-photothermal combination therapy

Abstract

Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable. Here, we conjugate the cluster determinant 44 (CD44)-targetable hyaluronic acid (HA) with cholesterol-poly(ethylene glycol)2k-NH2 and mitochondria-acting IR825-NH2 (a cyanine dye) to construct a self-assembled nanostructure (abbreviated as HA-IR825-Chol) for photothermal therapy. The HA-IR825-Chol exhibits improved photostability and desirable photothermal properties, and can rapidly and substantially enter CD44-over-expressed cancer cells and selectively accumulate in the mitochondria of the cells. Upon near-infrared laser irradiation, it can induce severe mitochondrial damage, which causes cytochrome c release and triggers cell apoptosis. Furthermore, we demonstrate the feasibility of loading the chemother-apeutics 10-hydroxycamptothecin (HCPT) into the hydrophobic cores of HA-IR825-Chol NPs for combined chemo-photothermal therapy. HCPT encapsulated within HA-IR825-Chol achieves significantly increased cellular uptake and simultaneous mitochondrial and nuclear localization, leading to the release of cytochrome c from mitochondria and upregulation of cleaved caspase-3, both of which contribute to the cell apop-tosis/death. In vivo experiments reveal the excellent tumor-targeting ability of HA-IR825-Chol/HCPT, ensuring the efficient tumor eradication by the chemo-photothermal therapy. This work exemplifies the development of an intrinsically mitochon-dria-targetable nanocarrier for precise subcellular structure-localized drug delivery, and the Choi-mediated rapid and massive endocytosis of the nanoagents may represent a robust strategy for enhancing the efficacies of nanomedicines.