Boosting Type-I and Type-II ROS Production of Water-Soluble Porphyrin for Efficient Hypoxic Tumor Therapy

Abstract

As the most successful clinically approved photosensitizers, porphyrins have been extensively employed in the photodynamic therapy (PDT) of cancers. However, their poor water solubility, aggregation-induced self-quenching on ROS generation, and a low tolerance for a hypoxic condition usually result in unsatisfied therapeutic outcomes. Therefore, great efforts have been dedicated to improving the PDT efficacy of porphyrin-type photosensitizers in treating hypoxic tumors, including combination with additional active components or therapies, which can significantly complicate the therapeutic process. Herein, we report a novel water-soluble porphyrin with O-linked cationic side chains, which exhibits good water solubility, high photostability, and significantly enhanced ROS generation efficacy in both type-I and type-II photodynamic pathways. We have also found that the end charges of side chains can dramatically affect the ROS generation of the porphyrin. The cationic porphyrin exhibited high in vitro PDT efficacy with low IC50 values both in normoxia and hypoxia. Hence, during in vivo PDT study, the cationic porphyrin displayed highly effective tumor ablation capability. This study demonstrates the power of side-chain chemistry in tuning the photodynamic property of porphyrin, which offers a new effective strategy to enhance the anticancer performance of photosensitizers for fulfilling the increasing demands for cancer therapy in clinics.

Exploring Linker-Group-Guided Self-Assembly of Ultrathin 2D Supramolecular Nanosheets in Water for Synergistic Cancer Phototherapy

“…Moreover, the absorbance of DPP 8 nanosheets exhibited no photobleaching even after 40 min of continuous laser irradiation (635 nm and 0.75 W cm –2 ), while complete degradation was recorded for the commercial photosensitizer, Ce6, after only 3 min of laser irradiation (Figure S14a). It is shown in Figure S14b that the monomeric TPP 1 also displayed severe photobleaching upon laser irradiation (40 min), suggesting that aggregation of DPP not only promotes photothermal capability but also enhances the photostability of porphyrin. The other porphyrin-based nanoassemblies with different nanostructures (thick nanosheets, nanofibers, etc. )…”

Recent Advances in Applications of Fluorescent Perylenediimide and Perylenemonoimide Dyes in Bioimaging, Photothermal and Photodynamic Therapy

“…The common 3 PS* triplet species reacts with O 2 via electron or hydrogen transfer (type I) to produce reactive oxygen species (ROS) such as superoxide radical (O 2 −• ), hydroxyl radical (HO • ) and hydrogen peroxide (H 2 O 2 ). The second mechanism (type II) involves an energy transfer process to generate a singlet oxygen ( 1 O 2 ) species [ 58 , 59 ]. Consequently, apart from light and oxygen, the PS is the crucial element of PDT and must present selectivity towards tumour cells [ 60 ].…”

Recent advances in type I organic photosensitizers for efficient photodynamic therapy for overcoming tumor hypoxia

“…In order to improve porphyrins' poor water solubility and aggregation-induced self-quenching on ROS generation, Sun et al synthesized a water-soluble porphyrin (19) with O-linked cationic side chains, which showed significantly enhanced type I/II ROS generation efficacy. 70 The electron-donating linker (oxygen atom) in each chain could promote the electrontransfer process from T 1 state to O 2 molecules, thereby enhancing the type I ROS generation. Based on the excellent type I and type II intracellular ROS production capability, 19 showed IC 50 value to HeLa cells of 0.87 mM in hypoxia and 0.78 mM in normoxia.…”

“…10 Chemical structures of 14-15 64,65 and 16-19. [67][68][69][70] glutathione-hydrogen peroxide (GSH-H 2 O 2 ) co-responsive aPS with a dual type photosensitizing capability. 72 However, endogenous H 2 O 2 was not sufficient enough for aPS activation.…”