Unimolecular micelles composed of a single polymeric molecule have recently attracted significant attention in anti-cancer drug delivery due to their high thermodynamic stability and small particle sizes. Applying the prodrug strategy to unimolecular micelles may provide superior nano-drug carriers with simultaneous high stability, low drug leakage, and well-drug loading capacity. However, the formation mechanism of the unimolecular prodrug micelles, the superiority of the prodrug strategy, as well as the prodrug controlled release mechanism were scantily understood at the mesoscopic scale. In this work, dissipative particle dynamics mesoscopic simulations were employed to investigate the self-assembly behavior, formation conditions, drug distribution regularities, and the prodrug release process of the star-like polymeric prodrug unimolecular micelles formed by β-CD-P[CL-co-(ACL-g-DOX)-SS-MPEG]21. A special bond-breaking script was used to accomplish the bond-breaking simulation of the grafted DOX bonds and the disulfide bonds. Results showed that to form well monodispersed and superior DOX-loaded unimolecular micelles, the polymer concentration should be well controlled at low volume fractions (≤10.59%), and the detailed molecular structure of the polymer was suggested as β-cyclodextrin-P[caprolactone-co-(amino caprolactone-g-doxorubicin)-disulfide-methyl polyethylene glycol]21) (β-CD-P[CL30-co-(ACL-g-DOX)8-SS-MPEG49]21). By comparison with the DOX physically loaded micelles, it was found that the prodrug unimolecular micelles with DOX grafted on the polymer displayed no drug leakage and superior drug loading capacity. Simulations on the prodrug release process showed that the prodrug unimolecular micelles assembled by β-CD-P[CL30-co-(ACL-g-DOX)8-SS-MPEG49]21 would provide good dual pH/reduction-responsive DOX release performance.
© 2023 The Authors. Published by American Chemical Society.