Over the past few decades, photodynamic therapy (PDT) has evolved as a minimally invasive treatment modality offering precise control over cancer and various other diseases. To address inherent challenges associated with PDT, researchers have been exploring two promising avenues: the development of intelligent photosensitizers activated through light-induced energy transfers, charges, or electron transfers, and the disruption of photosensitive bonds. Moreover, there is a growing emphasis on the bioorthogonal delivery or activation of photosensitizers within tumors, enabling targeted deployment and activation of these intelligent photosensitive systems in specific tissues, thus achieving highly precise PDT. This concise review highlights advancements made over the last decade in the realm of light-activated or bioorthogonal photosensitizers, comparing their efficacy and shaping future directions in the advancement of photodynamic therapy.

Bioorthogonal pretargeting offers a modular approach to targeted photodynamic therapy (PDT), but its advantages over conventional ligand-photosensitizer conjugates remain insufficiently explored. Here, we aimed to directly compare preformed biotin-containing conjugates with sequential biotin-mediated bioorthogonal delivery. DFT calculations were used to guide the design of new tetrazine dienes with tuned electronic properties for inverse-electron-demand Diels-Alder (IEDDA) chemistry. The selected tetrazines were synthesized and paired with BCN- and s-TCO-functionalized chlorin photosensitizers, and their reactivity was characterized by second-order rate constants and photophysical measurements. In vitro, sequential pretargeting produced substantially higher intracellular fluorescence than administration of preformed 1:1 ligation products; however, this advantage did not translate into enhanced photodynamic activity. Moreover, neither accumulation nor PDT efficacy consistently correlated with SLC5A6 expression in SMVT-high SK-BR-3 versus SMVT-low MDA-MB-231 cells. Free-biotin competition produced heterogeneous, combination-dependent effects, indicating that SMVT is unlikely to be the sole determinant of uptake.

Latest studies highlight boron-dipyrromethene (BODIPY) with meso-methyl moiety as a promising photoremovable protecting group due to its activation within the phototherapeutic window. While BODIPYs inherently generate ROS and act as photosensitizers, few studies have explored combining their photouncaging capability with photodynamic therapy (PDT). Herein, we developed novel meso-methyl-BODIPY conjugates of the DNA alkylator Boc-seco-CBI and the multikinase inhibitor cabozantinib derivative, activated by green or red light. To enhance photodecaging efficiency of conjugates, heavy atoms (Br, I) were introduced, and the boron atom was alkylated. The synthesized compounds were characterized for key photophysical and photochemical properties, including quantum yields of singlet oxygen generation, fluorescence, photolysis and cytostatic release. It was shown, that green-light irradiation of halogenated Boc-seco-CBI conjugates enabled rapid cytostatic release (<1 min), though with modest drug yields due to competing photodegradation. However, efficient uncaging of the cytostatic from the BODIPY-cabozantinib conjugate was achieved only after extended photoirradiation (~80 min) with red light. In vitro evaluation using tumor (MDA-MB-231, A431) and normal (HEK293) cell lines with various EGFR/c-Met expression demonstrated that the BODIPY-cabozantinib conjugate exhibited predominant photosensitizing effects, with minimal cytostatic contribution. During this study, we encountered significant synthetic challenges in developing red-light-absorbing conjugates, coupled with their photodegradation under prolonged irradiation. Our observations reveal key considerations for developing conjugates based on meso-methyl-BODIPY that combine PDT with light-controlled drug release toward antitumor therapy.

In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a β-glucuronidase-responsive linker. Upon activation by β-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of reactive oxygen species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy.