Hyaluronan Based Tumor-Targeting and pH-Responsive Shell Cross-Linkable Nanoparticles for the Controlled Release of Doxorubicin

In this study, a series of amphiphilic polymeric prodrugs (Azido-functionalized hyaluronan-triazole-imine-doxorubicin, HAimine-DOX) were designed and synthesized by the "Click" reaction with a remarkable grafting ratio of DOX. Nanoparticles with a core-shell structure can be obtained by self-assembling in aqueous media, which exhibited a particle size of 137-170 nm. Moreover, the HA-imine-DOX nanoparticles exhibited good stability in vitro, and the drug release was obviously mediated by the pH gradient. Subsequently, the CCK-8 assay indicated that this nano-system exhibited lower cytotoxicity in normal cells (Mouse fibroblast cell lines, L929) and a higher inhibition ratio in the tumor cells (Human cervical cancer cells, HeLa) in response to drug release with the endo/lysosomal pH environment. The cellular uptake and flow cytometric profiles of HeLa cells indicated an efficient internalization due to the receptor-mediated affinity of CD44 for HA with high specificity. It was believed that this pH-dependent polymeric prodrug had a potential application in cancer therapy.