Azo-inserted responsive hybrid liposomes for hypoxia-specific drug delivery

Stimuli-responsive drug delivery systems using endogenous stimuli from tumor microenvironments such as acidic pH, over-expressed enzyme, and high redox potential as triggers have shown tremendous promise in cancer therapy. However, their clinical application is severely limited because of tumor heterogeneity. Hypoxia, a physiological feature observed in almost all solid tumors and even in nodules with very small size, has currently emerged as a more general but efficient stimulus to trigger release. Herein, we developed hypoxia-responsive hybrid liposomes (HR-HLPs), composed of azo-inserted organokoxysilane-based lipid analogue as a responsive component and commercial phospholipid for reducing the rigidity of liposomal membrane caused by azo, for drug delivery targeting tumor hypoxia. HR-HLPs had the advantages of high structural stability to avoid premature drug leakage when circulating in the blood and high sensitivity in responding to hypoxia once reaching tumor sites. HR-HLPs exhibit deep tumor penetration capability, enabling effective delivery to hypoxic regions distant from tumor vessels. Moreover, HR-HLPs could selectively release their payload, co-localizing with over-expressed hypoxia inducible factor 1α (HIF-1α) in vitro and in vivo. As a result, HR-HLPs showed improved therapeutic outcome accompanied by reduced adverse effects. The results highlighted the potential application of azo-inserted responsive hybrid liposomes for hypoxia-targeted drug delivery. STATEMENT OF SIGNIFICANCE.