Size-Tunable and Multi-Responsive Nanoplatform for Deep Tumor Penetration and Targeted Combinatorial Radio/Chemotherapy

Nowadays, the design of multistimuli-responsive and deep penetrating nanotherapeutics remains an auspicious means for improving the efficiency of anticancer therapeutics. Herein, we develop a targeted size-tunable nanosystem that would concurrently and uniformly release its therapeutic cargo into tumor cells by exploiting both extracellular and intracellular signals. This nanosystem (HPDAu) is composed of self-assembled pH-responsive DOX–PAMAM (PD) conjugates and ultrasmall PAMAM-stabilized gold nanoparticles (AuNPs), incorporated into a hyaluronidase-responsive hyaluronic acid nanoshell. HPDAu nanoparticles with an initial particle size of ∼100 nm could disassemble into tiny cationic nanostructures (∼5 nm, PD and AuNPs) upon incubation with HAase, and showed a burst drug-release under tumor microenvironment-mimicking conditions (HAase and acidic conditions). Such characteristics resulted in significantly improved tumor penetration both in vitro and in vivo, along with a higher cellular uptake efficiency and tumor accumulation as compared to free drug solutions. Taking advantage of these features along with the chemotherapeutic effect (DOX) and AuNP/DOX-induced radiosensitization, HPDAu plus radiotherapy (RT) treatment resulted in a substantial increase of apoptotic and cytotoxic effects against 4T1 cells. More importantly, the radio-/chemotherapeutic feasibility of HPDAu was further validated in a 4T1 orthotropic model, revealing a prominent antitumor efficacy and reduced side-toxicity compared to monotherapy and free drug solutions. Therefore, this versatile nanoplatform with active targeting, size tunability and radio-/chemotherapeutic features could be a promising tool for tumor combinatorial therapy.