Fabrication and Computational Study of pH-Responsive Chitosan/Poly(HEMA-co-2-HMBA) Microparticles for Controlled, Site-Specific Doxorubicin Delivery

As a chitosan (CTS)-based drug carrier (DC) for doxorubicin (DOX) delivery, poly(2-hydroxyethyl methacrylate-co-2-hydroxy-4-N-methacrylamidobenzoic acid) [poly(HEMA-co-2-HMBA)] (PHCH) was successfully grafted onto chitosan to fabricate DOX-loaded microparticles, and their in vitro release behavior was systematicaly investigated. Morphological characteristics were analyzed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), while DOX loading was validated through Fourier-transform infrared (FTIR) spectroscopy and thermogravimetric analysis (TGA), comparing pure and drug-loaded microparticles. The maximum loading capacity (~91%) was attributed to the presence of abundant carboxylic acid groups, which imparted pH responsiveness during in vitro DOX release. Furthermore, density functional theory (DFT) calculations revealed that hydrogen bonding interactions between DOX and the functional groups of the microparticles strongly influenced encapsulation efficiency (EE%), drug loading (DL%), and release behavior. The fabricated microparticles exhibited pH-dependent DOX release, with accelerated and more complete release at tumor microenvironment pH 5.5 compared to physiological pH 7.4. These results demonstrate that PHCH grafted CTS microparticles are promising candidates for controlled and site-specific anticancer drug delivery.