Anticancer Effect Of Hyaluronic Acid Micelles Responsive To Reducing Microenvironment Of Tumor

In the past decades, drug delivery system (DDS) has attracted wide attention for its reducing drug side effect, improving drug efficacy, drug stability and bioavailability compared with traditional preparations. And various types of new drug delivery systems have been developed, including liposomes, micelles and nanoparticles. But at the same time, DDS is facing problems such as lacking active targeting capacity and selectively releasing drug as an active moity in the lesion. As far as we are concerned, there is a natural redox physiological difference, the concentration of glutathione (GSH) in tumor microenvironment is much higher than normal tissue (100-1000 folds), between tumor and normal tissue. In this study, we fabricated a smart micelle based on hyaluronic acid that could selectively target CD44 receptor in tumor cells and selectively release drug in tumor high GSH microenvironment in order to achieve active targeting and selective release of drug.Vitamin E succinate (TOS) as hydrophobic segment was conjugated onto hydrophilic hyaluronic acid (HA) backbone with the bridge chain of cystamine (with disulfide bond) and hexamethylene diamine (without disulfide bond) to obtain HA-SS-TOS (redox sensitive, HSST) and HA-CC-TOS (non-redox sensitive, HCCT). The critical micelle concentrations (CMC) were 48.0?g/mL and 64.9 ?g/mL, respectively, indicating good micelle formation ability of HSST and HCCT. The particle sizes were 114±11.6 nm and 108±16.2 nm, and their zeta potentials were-20.9 mV±4.3 mV and-18.2±4.2 mV, respectively. The highest entrapment efficiency (EE) and drug loading (DL) were 88.3%,27.2% and 89.7%,28.5%(w/w), respectively.No significant difference was observed in the cellular uptake of HSST and HCCT in SKOV3 (high GSH) and BSO-pretreated SKOV3 (low GSH) cells. HSST released drug rapidly in intracellular high GSH tumor cells rather than low GSH tumor cells. Combination of PTX and TOS could enhance the anti-tumor effect PTX. Since the drug release of HSST was faster than HCCT, it exhibited stronger ability to inhibit tumor cell proliferation and selectively killed tumor cells.The expression of CD44 receptor on SKOV3 and A549 cells was confirmed by immune blotting, and the SKOV3/A549 mouse model was established. S180 unilateral mouse tumor model, S180 bilateral tumor model, CT26 unilateral mouse tumor model and CT26-Luc orthotropic colon cancer tumor mouse model were successfully constructed. The CD44 receptors targeting and biodistribution and the release of HSST micelles in vivo were systematically investigated. The results showed that the accumulation of HSST in tumor was mediated by CD44 receptor and its rapid drug releasing in high GSH tumor, indicating that hyaluronic acid micelles could selectively release drug in the lesion. The inhibition effect of paclitaxel-loaded hyaluronic acid micelles on tumor was dose-dependent. The drug-loaded micelles had better inhibitory effect on the growth of tumor than Taxol.