Integrated Multifunctional Micelles Co-Self-Assembled from Polypeptides Conjugated with Natural Ferulic Acid and Lipoic Acid for Doxorubicin Delivery

The development of safe, easily accessible, and multifunctional nanocarriers is a big topic in nanomedicine research. Here, integrated multifunctional micelles (IMM) were developed by co-self-assembly of poly(ethylene glycol)-b-poly(l-lysine) derivatives with natural ferulic acid (FA) or lipoic acid (LA). FA confers IMM with intrinsic antitumor activity, improved loading of doxorubicin (DOX) through - stacking, and reduced DOX cardiotoxicity. LA provides IMM with reversible crosslinking property, which leads to a high colloidal stability with inhibited drug leakage and triggered intracellular DOX release. Notably, our results showed that cRGD-decorated IMM (cRGD-IMM) had a small size (approximate to 56nm) and superior loading of DOX (27.1wt.%). Blank cRGD-IMM, though nontoxic to normal cells, exhibited obvious antiproliferative activity against cancer cells including B16F10 and HCT-116 cells at 150gFAequiv.mL(-1). DOX-loaded cRGD-IMM displayed enhanced growth inhibition of (v3)-positive B16F10 and HCT-116 cells, a long elimination half-life of 3.85h, and a high maximum-tolerated dose of over 100mgDOXequiv.kg(-1). Histological analysis revealed that DOX-loaded cRGD-IMM at 100mgDOXequiv.kg(-1) caused negligible cardiotoxicity, which is a major issue for the clinical use of DOX. These integrated multifunctional micelles with excellent safety and accessibility have emerged as a new platform for targeted cancer chemotherapy.