Enhancing photodynamic therapy of refractory solid cancers: Combining second-generation photosensitizers with multi-targeted liposomal delivery

Contemporary photodynamic therapy (PDT) for the last-line treatment of refractory cancers such as nasopharyngeal carcinomas, superficial recurrent urothelial carcinomas, and non-resectable extrahepatic cholangiocarcinomas yields poor clinical outcomes and may be associated with adverse events. This is mainly attributable to three factors: (1) the currently employed photosensitizers exhibit suboptimal spectral properties, (2) the route of administration is associated with unfavorable photosensitizer pharmacokinetics, and (3) the upregulation of survival pathways in tumor cells may impede cell death after PDT. Consequently, there is a strong medical need to improve PDT of these recalcitrant cancers. An increase in PDT efficacy and reduction in clinical side-effects may be achieved by encapsulating second-generation photosensitizers into liposomes that selectively target to pharmacologically important tumor locations, namely tumor cells, tumor endothelium, and tumor interstitial spaces. In addition to addressing the drawbacks of clinically approved photosensitizers, this review addresses the most relevant pharmacological aspects that dictate clinical outcome, including photosensitizer biodistribution and intracellular localization in relation to PDT efficacy, the mechanisms of PDT-induced cell death, and PDT-induced antitumor immune responses. Also, a rationale is provided for the use of second-generation photosensitizers such as diamagnetic phthalocyanines (e.g., zinc or aluminum phthalocyanine), which exhibit superior photophysical and photochemical properties, in combination with a multi-targeted liposomal photosensitizer delivery system. The rationale for this PDT platform is corroborated by preliminary experimental data and proof-of-concept studies. Finally, a summary of the different nanoparticulate photosensitizer delivery systems is provided followed by a section on phototriggered release mechanisms in the context of liposomal photosensitizer delivery systems.