One-Step Synthesis of Targeted Acid-Labile Polysaccharide Prodrug for Efficiently Intracellular Drug Delivery.

The therapeutic potential of the active targeting and acid-sensitive polysaccharide prodrug was investigated. The active targeting of polysaccharide prodrug was based on the specific interaction between cyclo(Arg-Gly-Asp-d-Phe-Lys) peptide (c(RGDfK)) and its receptor αvβ3 integrin overexpressed on the membrane of tumor cells. The cRGD-modified doxorubicin-conjugated hydroxyethyl starch (HES=DOX/cRGD) was synthesized via a one-step Schiff base reaction between oxidized HES, and DOX and c(RGDfK) that achieved an acid-accelerated drug release profile. The targeted polysaccharide prodrug self-assembled into micelle in aqueous environment with a moderate hydrodynamic diameter of 77.1 nm. All data in vitro indicated enhanced cell uptake and elevated cytotoxicity of HES=DOX/cRGD toward human malignant melanoma A375 cells compared with HES=DOX and DOX. Moreover, the smart prodrug also exhibited upregulated accumulation in the tumor, improved antitumor efficacy, and reduced systemic cytotoxicity in vivo. The cRGD-decorated acid-sensitive polysaccharide prodrug was advantageous in both antitumor efficacy and systemic security, showing great prospect in clinical application.