A reduction-responsive drug delivery with improved stability: disulfide crosslinked micelles of small amiphiphilic molecules

Micelles self-assembled from small amphiphilic molecules are unstable in biological fluids, and thus are poor drug carriers. In contrast, amphiphilic polymer micelles can encapsulate hydrophobic drugs in their core to greatly enhance their aqueous solubility and extend their retention time in blood circulation owing to their hydrophilic shell. However, the major disadvantages of conventional polymer micelles are the heterogeneity of the amphiphilic polymer structure and premature drug leakage. Thus, herein, to address these shortcomings, disulfide crosslinked micelles composed of a small amphiphilic molecule, di-lipoyl-glycerophosphorylcholine (di-LA-PC), were developed as redox-responsive drug carriers. Specifically, di-LA-PC was synthesized and self-assembled to form crosslinked micelles under catalysis by dithiothreitol. The disulfide crosslinked micelles maintained high stability in a simulated physiological environment, but rapidly disassembled under reductive conditions. Furthermore, paclitaxel (PTX), as a model drug, was encapsulated in the core of the crosslinked micelles with a high loading content of 8.13%. The in vitro release studies indicated that over 80% of PTX was released from the micelles in the reductive environment, whereas less than 20% PTX was released without reduction in the 68 h test. Benefiting from their nanoscale characteristics, the PTX-loaded micelles showed efficient cellular internalization and effectively induced the death of cancer cells, as revealed in the MTT, apoptosis and cell cycle tests. Moreover, pharmacokinetic studies demonstrated that the crosslinked micelles prolonged the circulation of the incorporated PTX in the bloodstream and increased its accumulation in the tumor tissue via the EPR effect. Finally, the PTX-loaded micelles displayed prominent in vivo anti-tumor activity in a 4T1 xenograft tumor model. In summary, the di-LA-PC crosslinked micelle platform possesses excellent stability, high loading capacity and reduction-responsive release profile, which may have applications in the delivery of PTX and other anti-cancer drugs.

Reduction-responsive crosslinked di-LA-PC micelles from amphiphilic bis-LA-PC conjugate for PTX loading and GSH-triggered release of PTX.