Quantum Insights into Partially Molecular Imprinted\nMicrospheres for Anticancer Therapeutics: Experimental\nand Theoretical Studies

Drug\nsolubility is a determining factor for controlled release,\nand solubility-dependent release kinetics can be modified by changing\nthe drug’s state in the polymer matrix through partial molecular\nimprinting (PMI), although research in this area remains limited.\nThis novel PMI approach creates nanocavities within the polymer by\npartially retaining the imprinting molecule and trapping the drug.\nSuch a method holds promise for developing advanced biomaterial-based\ndrug delivery systems for anticancer therapies. In this study, we\ndeveloped microspheres designed for anticancer drug delivery utilizing\nPMI to enhance controlled release properties. Poly(vinyl alcohol)\n(PVA) microspheres were partially imprinted with aspirin (ASP) to\ncreate nanocavities for gemcitabine (GEM) molecules, inducing a polymorphic\nshift of GEM within the polymer matrix. This novel PMI approach enhanced\ndrug release properties by enabling control over the drug crystallinity\nand release rate. The PVA–ASP–GEM complex showed zero-order\nrelease kinetics, releasing 21.6% of GEM over 48 h, maintaining steady\nstate release profile. In contrast, nonimprinted PVA–GEM microspheres\nexhibited first-order kinetics with a faster release of 46.85% in\nthe same period. Quantum insights from density functional theory (DFT)\ncalculations revealed the superior stability of the PVA–ASP–GEM\ncomplex, with a binding free energy of −56.03 kcal/mol, compared\nto −29.07 kcal/mol for PVA–GEM. Molecular dynamics (MD)\nsimulations demonstrated that ASP’s presence created nanocavities\nthat restricted GEM’s movement, further contributing to the\ncontrolled release. Experimental validation through differential scanning\ncalorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction\n(XRD), and Raman spectroscopy confirmed the polymorphic transitions\nwithin the PVA–ASP–GEM complex. This PMI-based approach\noffers a promising method for modulating drug release kinetics and\nimproving the stability of anticancer therapeutics, paving the way\nfor innovative biomaterial-based drug delivery systems.