PEGylated hydrazided gold nanorods for pH-triggered chemo/photodynamic/photothermal triple therapy of breast cancer

Integration of multimodal therapies into one nanoplatform holds great promise to overcome the drawbacks of conventional single-modal therapy and pursues enhanced anticancer efficacy. Herein, we developed a PEGylated gold nanorods (GNRs)-based nanoplatform (GNRs-MPH^-ALA/DOX-PEG) with pH-responsive drug release property for triple-combined chemotherapy (CT), photodynamic therapy (PDT) and photothermal therapy (PTT) of breast cancer. GNRs were first decorated with mercaptopropionylhydrazide (MPH) and thiol-terminated monomethoxyl poly(ethylene glycol) (mPEG-SH) via Au-thiol linkage, and subsequently conjugated with chemotherapeutant doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (ALA) through acid-liable hydrazone bonds between drugs and MPH molecules. The resulting nanoplatform GNRs-MPH^-ALA/DOX-PEG exhibited excellent stability in physiological solutions and pH-responsive DOX and ALA release behaviors. In vitro studies showed that GNRs-MPH^-ALA/DOX-PEG could efficiently enter human breast cancer MCF-7 cells and release DOX and ALA into cytoplasm. Furthermore, DOX could locate in the cell nucleus and ALA was productively metabolized into protoporphyrin IX (PpIX). Upon near-infrared (NIR) irradiation, PpIX produced enough reactive oxygen species for PDT and meanwhile GNRs could efficiently induce hyperthermia for PTT. Compared with single CT and dual-modal CT/PDT or CT/PTT treatment, the triple-combined CT/PDT/PTT treatment could more efficiently kill MCF-7 cells via a superadditive antitumor effect. Furthermore, the circulation half-life of GNRs-MPH^-ALA/DOX-PEG in the blood was as long as approximately 52 min and it exhibited a tumor accumulation of 3.3%. The triple-combined CT/PDT/PTT treatment could completely suppress tumor growth without obvious systemic toxicity. Our study paves a new avenue for multimodal therapy of breast cancer. Statement of significance: The development of a simple but effective strategy to construct a versatile nanoplatform for multi-combined therapy still remains an enormous challenge. In this work, we developed a novel and simple nanoplatform GNRs-MPH^-ALA/DOX-PEG with pH-responsive drug release for triple-combined chemotherapy (CT), photodynamic therapy (PDT) and photothermal therapy (PTT) of breast cancer. The nanoplatform could be efficiently internalized by MCF-7 cells. The intracellular GNRs-MPH^-ALA/DOX-PEG could release DOX for CT, induce hyperthermia for PTT and generate high levels of ROS for PTT. Compared with single CT and dual-modal CT/PDT or CT/PTT treatments, the triple-combined CT/PDT/PTT treatment could more efficiently kill MCF-7 cells via a superadditive antitumor effect. Furthermore, upon triple-combined CT/PDT/PTT treatment, the tumor growth was completely suppressed without obvious systemic toxicity.