Development of Prodrugs for PDT-Based Combination Therapy Using a Singlet-Oxygen-Sensitive Linker and Quantitative Systems Pharmacology

Photodynamic therapy (PDT) has become an effective treatment for certain types of solid tumors. The combination of PDT with other therapies has been extensively investigated in recent years to improve its effectiveness and expand its applications. This focused review summarizes the development of a prodrug system in which anticancer drugs are activated locally at tumor sites during PDT treatment. The development of a singlet-oxygen-sensitive linker that can be conveniently conjugated to various drugs and efficiently cleaved to release intact drugs is recapitulated. The initial design of prodrugs, preliminary efficacy evaluation, pharmacokinetics study, and optimization using quantitative systems pharmacology is discussed. Current treatment optimization in animal models using physiologically based a pharmacokinetic (PBPK) modeling approach is also explored.