Hyaluronic acid modified liposomes for targeted delivery of doxorubicin and paclitaxel to CD44 overexpressing tumor cells with improved dual-drugs synergistic effect

Tumor targeted drug delivery system has been developed as a promising approach to improve cancer chemotherapy. The design of hyaluronic acid (HA)-modified nanocarriers has been proven to be effective for targeting CD44 overexpressing tumor cells. Moreover, combination therapy can improve the therapeutic effect and delay the development of drug resistance. In this study, doxorubicin (DOX) and paclitaxel (PTX) co-loaded liposomal delivery system modified with an acid-cleavable cholesterol-HA conjugate (Chol-HA) was prepared by post-insertion method. The dual-drug co-loaded HA modified liposome (HA-D/P-Lip), had a suitable particle size of 125.5 +/- 0.79 nm with negative surface charge of - 9.56 +/- 0.62 mV, and acceptable encapsulation efficacy of 93.6 +/- 0.51% (DOX) and 70.4 +/- 1.46% (PTX). In vitro drug release study showed that the cumulative release of both drugs over 72 h were much higher in pH 5.5 phosphate buffer than that in pH 7.4 phosphate buffer. In vitro cytotoxicity study against MCF-7 breast cancer cells illustrated superior cytotoxicity and obvious synergistic effect in comparison to free drug or single drug loaded liposome via MTT assay. In vitro cellular uptake study demonstrated a higher cell internalization of HA-DOX-Lip compared with DOX loaded non-modified liposome (DOX-Lip) and free DOX. Therefore, the pH-sensitive HA-targeted liposome may be a useful targeted nanocarrier for efficient tumor therapy.