Photodynamic drug delivery for cancer therapy: Designing liposomes for light-controlled release and enhanced drug efficacy

Photodynamics involves the use of photocatalytic compounds that, upon excitation with light, produce reactive oxygen species and have seen widespread applications in the treatment of cancer in the form of photodynamic therapy. Within the field of drug delivery, photodynamics has emerged as a strikingly effective approach for spatiotemporal-controlled drug release by harnessing photochemical redox reactions to destabilize lipid nanoformulations that contain oxidation-susceptible excipients. Despite highly promising outcomes in preclinical models, such controlled release modalities have not yet been explored in clinical cancer trials. This review outlines key design considerations for lipid nanoformulations in photodynamic drug delivery, focusing on their susceptibility to photochemical redox reactions, their ability to induce lysosomal permeabilization, and facilitate microenvironmental priming that enhances tumor permeability. These considerations first highlight the role of specific lipid excipients in determining photodynamic drug release efficiencies. Secondly, the selection of the photosensitizing agents is considered, which ideally absorb light >650 nm and exhibit limited leaching. Thirdly, the selected photosensitizing agent and pharmaceutical cargoes may dictate which drug loading approach should be pursued, and how drug release is detected. We particularly highlight the promise of nuclear magnetic resonance (NMR) spectroscopy as it can provide non-destructive quantification of encapsulated and released pharmaceutical cargoes, alongside structural assessments of the lipid nanoformulations, without the need for prior separation or complex sample preparation. Finally, considering the corollary effects of photodynamics on cancer cells and the cancer microenvironment, we emphasize the utility of a multi-model approach to evaluate novel photodynamic drug delivery systems. By providing these design considerations, this review aims to boost the field of photodynamic drug delivery and encourage its exploitation in translational cancer research. Moreover, these aspects are equally relevant to stimulate investigations towards oxidation-responsive drug release triggered by alternative external stimuli, thereby broadening the drug delivery arsenal against cancer.