Novel strategies for photodynamic therapy and drug delivery by molecular modeling and simulation

Photodynamic therapy (PDT) is a non-invasive cancer treatment in which photosensitizers (PS) are activated by light to produce cytotoxic reactive oxygen species. Despite its clinical potential, PDT efficacy is hindered by limited light penetration into tissues, as well as PS aggregation and solubility issues, which restrict current drugs primarily to topical applications. Consequently, the design and optimization of novel PS molecules remain critical for improving therapeutic outcomes. This thesis investigates tetrapyrrole derivatives as potential PDT agents and examines their interactions with biological environments. The clinically approved PS m-THPC was evaluated in passive delivery strategies, including encapsulation within TM-beta-CD complexes and functionalization with two-photon absorbing units to enable deeper tissue activation. In parallel, microsecond-scale molecular dynamics simulations combined with quantum mechanics/molecular mechanics approaches were employed to study active delivery, focusing on pyropheophorbide-a functionalized with folic acid for selective targeting of folate receptor alpha, which is overexpressed in ovarian cancer cells.