Mesoscopic simulations of drug-loaded diselenide crosslinked micelles: Stability, drug loading and release properties.

Intelligent reversible crosslinked micelles that have a good balance of structure stability in normal tissue and controlled drug release responded to the tumor microenvironment are highly promising novel drug delivery systems. However, to date, there have been very few reports about mesoscale simulations of drug-loaded polymeric reversible crosslinked micelles. Here, dissipative particle dynamics (DPD) simulation, the nearest-neighbor bonding principle, and the nearest media-bead bond breaking principle were used to investigate the influence of physiological environment along with low tumor pH and reduction microenvironment on the stability and doxorubicin (DOX) distribution of the star polymer [PCL-b-P(HEMA-Se-Se˜)-b-PPEGMA] diselenide crosslinked micelles with different diselenide crosslinking levels (CLs). The self-assembly process results obtained by DPD simulations reveal the formation of three-layer spherical micelles with the loaded DOX mainly distributed at the interfacial regions of the inner PCL core and middle HEMA layer. The structural stability and DOX loading capacity of the micelles can be improved by appropriately increasing the CL based on the nearest-neighbor bonding principle due to the effect of the pressure exerted by the crosslink that squeezes the loaded drugs from the intermediate and interfacial layers into the micelle core. Furthermore, the effect of breaking of the diselenide bond on the drug release properties was investigated through the use of the nearest media-bead bond breaking principle. A low CL gives rise to intense drug release, increasing the toxic side effects on the system. With the increase in the CL, the micelles show the transformation from local crosslinking to compact crosslinking, leading to slower drug release. Therefore, this work can provide some guidance on the mesoscale for the structural design and controlled construction of reversible crosslinked micelles for smart drug delivery systems.