Design of pH-Sensitive Nanovesicles via Cholesterol Analogue Incorporation for Improving in Vivo Delivery of Chemotherapeutics.

pH-responsive polymersomes have emerged as promising nanocarriers for antitumor drugs to realize their fast release and action in a weakly acidic microenvironment of tumor cells. Herein, however, we designed a remarkably pH-responsive polymersome self-assembled from amphiphilic benzimidazole-based polyphosphazenes via the incorporation of cholesteryl hemisuccinate (CholHS), a type of cholesteric molecule, into the polymersome bilayers to inhibit the drug release during blood circulation. Actually, unwanted premature drug leakage before arriving at the acidic tumor site has become a serious problem for polymersomes encapsulating water-soluble drugs, especially when the drug loading is at a high level, thus limiting the therapeutic efficacy. In this study, polymersomes displayed high loading capability of doxorubicin hydrochloride as 12.83%. More importantly, CholHS incorporation decreased the membrane permeability of the polymersome and effectively retarded the cargo release under physiological conditions but induced the fast drug-release rate at pH 5.5, demonstrating a more remarkably acid-responsive release behavior when compared to that of the CholHS-free polymersomes. Further in vivo investigations including pharmacokinetic and antitumor activity studies verified the extended circulation time and enhanced antitumor efficacy of the drug-loaded CholHS-incorporated polymersomes.