Compatibility studies between an amphiphilic pH-sensitive polymer and hydrophobic drug using multiscale simulations

The compatibility of an amphiphilic pH-sensitive polymer (docosahexaenoic acid-histidine-lysine, DHA-His(X)Lys(10)) and hydrophobic drug (doxorubicin, DOX) was investigated using multiscale simulations at different pH conditions, including Blends and dissipative particle dynamics simulations. Some important elements obtained from the computer simulations were analyzed, such as Flory-Huggins interaction parameters, binding energy distributions, phase diagrams and radius distribution function. In conclusion, the pH values and the number of pH-sensitive segments (histidine) significantly influence the compatibility of DHA-His(X)Lys(10) and DOX, resulting in different drug loading capacity and system structural stability. According to the simulation results, the compatibility of the systems at pH > 6.0 is better than that at pH < 6.0. Moreover, when the number of histidine residues is 10 or 15, the compatibility is best at pH > 6.0. Using DPD simulation, the compatibility of DHA-His(X)Lys(10) (X = 10 or 15) and DOX is optimal when the pH is higher than 6.0, which falls in line with the results obtained from Blends simulation. Overall, when the number of histidine residues is 10 or 15 and the pH is larger than 6.0, DOX and DHA-His(X)Lys(10) have better compatibility. So it is obvious that polymeric micelles selfassembled from DHA-His(10)Lys(10)/ DHA-His(15)Lys(10) as an ideal drug carrier have higher drug-loading capacity and more excellent stability. This work has demonstrated that multiscale simulations could be a powerful method to investigate the compatibility between polymers and drugs.