Novel fluorescent pH/reduction dual stimuli-responsive polymeric nanoparticles for intracellular triggered anticancer drug release

Fluorescent poly(methacrylic acid- co -poly(ethylene glycol) methyl ether methacrylate- co -N′-rhodamine B-acrylhydrazine) (P(MAA- co -PEGMA- co -RhBAh), PMPR) nanoparticles were designed as pH/reduction dual stimuli-responsive drug delivery system (DDS) for anti-cancer drug via facile distillation-precipitation copolymerization with bio-reducible disulfide-containing crosslinker. As a carrier for doxorubicin (DOX), high drug-loading capacity (DLC) and drug-loading efficiency (DLE) of 53.1% and 97.3% were achieved respectively, via the strong electrostatic interaction between the carboxyl groups of PMAA segments and the amino group of DOX. Due to the disulfide crosslinking structure and their drug-loading mode, the DOX-loaded PMPR nanoparticles were relatively stable under extracellular conditions with low drug leakage , while a rapid intracellular drug release took place in acidic and reductive environment of tumor cells. The fluorescence microscope analysis showed that the DOX-loaded PMPR nanoparticles could be successfully endocytosed by HepG2 cells and the released DOX was mainly accumulated in cell nuclei. These features make them potential DDS for tumor-environment-responsive controlled release. Furthermore, the PMPR nanoparticles showed strong fluorescence only at low pH media, which might be used for the real-time fluorescent imaging in cancer diagnosis as a potential theranostic nanoplatform for imaging-guided therapy of cancer.