Evaluation the synergistic antitumor effect of methotrexate–camptothecin codelivery prodrug from selfassembly process to acid-catalyzed both drugs release: A comprehensive theoretical study

Abstract

Therapeutic efficiency of amphiphilic methotrexate–camptothecin (MTX-CPT) prodrug compared to free drug mixture (MTX/CPT) has been investigated using allatom molecular dynamics simulation and first principles density functional theory calculations. This comparison revealed that MTX–CPT prodrug tends to form spherical self-assembled nanoparticle (NP), while free MTX/CPT mixture forms rod-shape NP. These observations are attributed to a structural defect in the MTX–CPT prodrug and solvation free energies of MTX, CPT and MTX-CPT molecules. The results provided evidence that noncovalent interactions (NCIs) among the pharmaceutical drugs play a very important role in anticancer agents aggregation process, leading to enhanced stability of the self-assembled NPs. It is found that the stability of MTX– CPT self-assembled NP is greater than the MTX/CPT NP due to the synergistic effect of hydrogen bonding between monomers and solvent (water). Moreover, the noncatalyzed as well as catalyzed hydrolysis reactions of MTX–CPT prodrug are theoretically studied at the PCM(water)//M06-2X/6−31G(d,p) computational level to shed additional light on the role of acidic condition in tumor tissues. We found that the ester hydrolysis in mild acidic solutions is a concerted reaction. In an agreement between theory and experiment, we also confirmed that the activation energies of the catalyzed-hydrolysis steps are much lower than the activation energies of the corresponding steps in the noncatalyzed reaction. Thus, the MTX–CPT prodrug reveals very promising properties as a pH-controlled drug delivery system.