Computational design to experimental validation: molecular dynamics-assisted development of polycaprolactone micelles for drug delivery.

Amphiphilic diblock copolymers are used in drug delivery systems for cancer treatments. However, these carriers suffer from lower drug loading capacity, poor water solubility, and non-targeted drug release. Here, we utilized a computational approach to analyze the effect of the functional groups of the hydrophobic block on the drug-polymer interactions. To design effective drug carriers, four different amphiphilic block copolymer micelles with distinct aromatic and heteroaromatic groups at the hydrophobic core were subjected to molecular dynamics simulations. The solvent-accessible surface area, water shell, hydrogen bonding, and radius of gyration of the simulated micelles were determined. Further, we assessed the interactions between the hydrophobic block and drug molecules using linear interaction energy and non-covalent interactions. The computational studies revealed that the micelles containing a novel poly(γ-2-methoxyfuran-ε-caprolactone) (PFuCL) hydrophobic block have the highest polymer-drug interactions. From these findings, we synthesized a novel amphiphilic poly(ethylene glycol)--poly(γ-2-methoxyfuran(ε-caprolactone)) (PEG--PFuCL) block copolymer using ring-opening polymerization of FuCL monomer. The polymer was self-assembled in aqueous media to form micelles. The aromatic segment of PEG--PFuCL micelles enhanced the doxorubicin (DOX) loading through non-covalent interactions, resulting in a 4.25 wt% drug-loading capacity. We also showed that the hydrolysis of the ester bond allowed a faster drug release at pH 5.0 compared to pH 7.4. Cell viability experiments revealed that DOX-loaded PEG--PFuCL micelles show that micelles are cytotoxic and readily uptaken into MDA-MB-231 cells. Therefore, furan-substituted micelles will be an ideal drug carrier with higher polymer-to-drug interactions, enhanced drug loading, and lower premature leakage.