Dually Active Targeting Nanomedicines Based on a Direct Conjugate of Two Purely Natural Ligands for Potent Chemotherapy of Ovarian Tumor

Actively targeted nanomedicines have promised to revolutionize cancer treatment, however, their clinical translation has been limited by either low targetability, use of unsafe materials, or tedious fabrication. Here, we developed CD44 and folate receptor (FR) dually targeted nanoparticulate doxorubicin (HA/FA-NP-DOX) based on a direct conjugate of two purely natural ligands, hyaluronic acid and folic acid (FA), for safe, highly specific and potent treatment of ovarian tumor in vivo. HA/FA-NP-DOX had a small size and high DOX loading, wherein, particle size decreased from 115, 93 to 89 nm with increasing the degree of substitution of FA from 6.4, 8.5 to 11.1 while increased from 80, 93 to 103 nm with increasing DOX loading from 15.0, 23.1 to 31.4 wt.%. Interestingly, HA/FA-NP-DOX exhibited superb lyophilization-redispersibility and long-term storage stability with negligible drug leakage while released 91% of DOX in 48 h at pH 5.0. Cellular studies corroborated that HA/FA-NP-DOX possessed high selectivity...