A Nano-in-Nano Polymer-Dendrimer Nanoparticle-Based Nanosystem for Controlled Multidrug Delivery

Codelivery of multiple chemotherapeutics with different action mechanisms is a promising strategy for cancer treatment. In this study, we developed a novel polymer-dendrimer hybrid nanoparticle-based nanosystem for efficient and controlled codelivery of two model chemotherapeutics, doxorubicin (DOX) and paclitaxel (PTX). The nanosystem was characterized to have a nano-in-nano structure with a size of around 150 nm. The model drugs could feasibly be loaded into the nanosystem ratiometrically with high drug-loading contents by controlling the feeding drug ratios. Also, the model drugs could be released from the nanosystem following a sequential release manner-specifically, quick PTX release and sustained DOX release. Acidic pH was found to enhance the release of both drugs. Moreover, the nanosystem was taken up by cancer cells rapidly and efficiently, and the delivered drugs could release sustainably and efficiently in cells to reach their action targets. In vitro cytotoxicity results demonstrated that, by optimizing drug ratios, the dual-drug-loaded nanosystem could result in better antitumor efficacy than the single-drug-loaded nanosystem or free dual-drug combination. Furthermore, the dual-drug-loaded nanosystem could induce significant changes in both the nucleus and tubulin patterns synergistically. All data suggest that the nano-in-nano polymer-dendrimer hybrid nanoparticle-based nanosystem is a promising candidate to achieve controlled multidrug delivery for effective combination cancer therapy.