Investigation of Novel Antiproliferative Drugs Interaction with mPEG2k-PCLy Copolymers Using Molecular Dynamics Simulation Approach.

The therapeutic potential of many new drugs is limited by poor aqueous solubility. This work addresses the solubilization improvement of novel fluorescent dihydropyrazole-carbohydrazide derivatives (DPCH), with proven antiproliferative activity against human breast cancer, through encapsulation in three distinct methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) diblock copolymers. All-atom molecular dynamics simulations (100 ns, CHARMM36 force field, NAMD) of 52 distinct configurations revealed favorable interactions between DPCHs and PCL residues, resulting in the formation of micellar supramolecular assemblies with PEG coronae that facilitate enhanced DPCH water solvation. Systematic evaluation of micelle size, composition (5, 14, and 21 copolymer strands; 20, 30, 40, 56, 84, 112, and 168 drug molecules), and hydrophobic chain length (PCL 1k, 2k, and 5k) through radial distribution functions, radius of gyration, solvent accessibility, RMSD analysis, and interaction energy calculations identified optimal encapsulation conditions. Regardless of the DPCH derivative tested, mPEG2k-PCL5k produced the most stable, monodisperse micelle populations with the highest loading efficiency. Molecular docking calculations further confirmed strong drug-polymer affinity. Experimental validation through nanoparticle synthesis and characterization via dynamic light scattering, zeta potential measurements, cryogenic transmission electron microscopy, and fluorescence microscopy confirmed successful self-assembly with entrapment efficiencies up to 97% and internalization of loaded micelles into cancer cells. These findings demonstrate that mPEG-PCL micelles are potential carriers for DPCH derivatives, as computational predictions closely align with experimental data.