DPD simulations on mixed polymeric DOX-loaded micelles assembled from PCL-SS-PPEGMA/PDEA-PPEGMA and their dual pH/reduction-responsive release

The design of mixed polymeric micelles by a combination of two or more dissimilar polymers is a potential strategy to achieve multiple stimuli-response for anti-cancer drug delivery. However, their drug loading co-micellization behavior and multiple stimuli-responsive drug release mechanism have been poorly understood at the mesoscopic level, especially in the system that involves reduction-response due to the difficulty of simulation on the cleavage of chemical bonds. In this work, the co-micellization behavior, drug distribution regularities and dual pH/reduction-responsive drug release process of mixed micelles formed by disulfide-linked polycaprolactone- b -polyethylene glycol methyl ether methacrylate (PCL-SS-PPEGMA) and poly(ethylene glycol) methyl ether- b -poly( N , N -diethylamino ethyl methacrylate) (PDEA-PPEGMA) were studied by dissipative particle dynamics (DPD) mesoscopic simulations. A dedicated bond-breaking script was employed to accomplish the disulfide bond-breaking simulations. The results showed that PCL 55 -SS-PPEGMA 10 and PDEA 34 -PPEGMA 11 could be well mixed to form superior DOX-loaded micelles with good drug-loading capacity and drug-controlled release performance. To prepare the DOX-loaded micelles with optimized properties, the simulation results suggested the feed ratio of DOX:PCL 55 -SS-PPEGMA 10 :PDEA 34 -PPEGMA 11 set to 3:4:4. Compared with the two single stimuli-response, the dual pH/reduction-response process perfectly combined both pH-response and reduction-response together, providing a higher release rate of DOX. Therefore, this study provides theoretical guidance aimed at the property optimization and micellar structure design of the dual pH/reduction-responsive mixed micelles. The dual reduction/pH-responsive DOX release mechanism was revealed by DPD mesoscopic simulations with a dedicated disulfide bond-breaking script.