Predicting tumor microenvironment-responsive drug delivery: A multiscale MD study of temozolomide release from chitosan-Eudragit nanocarriers

The nature of the intracellular acidic conditions (pH 5, mimicking endosomes/lysosomes tumor cells) compared to healthy tissues (pH 7.4) provides a unique opportunity for targeted cancer therapy using pH-responsive nanocarriers. However, the molecular mechanisms governing drug release under these conditions remain poorly understood, limiting rational design. This study employs a multiscale molecular dynamics approach; integrating all-atom molecular dynamics (AA-MD) and coarse-grained molecular dynamics (CG-MD), to investigate the pH-dependent release mechanism of temozolomide (TMZ), a first-line glioblastoma chemotherapeutic, from chitosan-Eudragit nanocarriers. Simulations were conducted under physiological (pH 7) and lysosomal-mimicking acidic (pH 5) conditions to elucidate how pH modulates drug-nanocarrier interactions. Our results reveal a clear pH-dependent switching mechanism. At neutral (pH 7), the system exhibits negative total interaction energy (dominated by van der Waals attractions ranging from -900 to -650 kJ/mol), extensive hydrogen bonding between TMZ and both polymer components, and a compact nanocarrier conformation as evidenced by a lower radius of gyration. These favorable interactions result in a five-fold larger drug-nanocarrier contact area at pH 7 compared to pH 5, promoting stable drug adsorption and retention. Conversely, under acidic conditions (pH 5), protonation of chitosan amine groups and Eudragit tertiary amine groups generates strong electrostatic repulsion (positive electrostatic energy of 800-1000 kJ/mol), disrupts hydrogen bond networks, and induces nanocarrier swelling, reflected in an increased radius of gyration and solvent-accessible surface area. This structural transformation reduces drug-nanocarrier affinity and facilitates TMZ release into the surrounding environment. The consistency between AA-MD (atomic-level interaction details) and CG-MD (larger-scale morphological changes) validates our findings across spatial and temporal scales. Critically, these results align with experimental observations from related chitosan-Eudragit systems while providing, for the first time, a molecular-level explanation for pH-triggered TMZ release. Our multiscale simulation framework offers predictive power to inform nanocarrier design parameters, such as chitosan degree of deacetylation and Eudragit composition, and provides a foundation for future optimization studies before costly in vitro and in vivo validation. These insights accelerate the development of effective, targeted therapeutic strategies for glioblastoma and other solid tumors characterized by an acidic microenvironment.