Advances in photosensitizer-related design for photodynamic therapy

This review follows the research, development and clinical applications of the photosensitizer 5,10,15,20‐tetra(m‐hydroxyphenyl)chlorin (mTHPC, temoporfin) in photodynamic (cancer) therapy (PDT) and other medical applications. Temoporfin is the active substance in the medicinal product Foscan® authorized in the EU for the palliative treatment of head and neck cancer. Chemistry, biochemistry and pharmacology, as well as clinical and other applications of temoporfin are addressed, including the extensive work that has been done on formulation development including liposomal formulations. The literature has been covered from 2009 to early 2022, thereby connecting it to the previous extensive review on this photosensitizer published in this journal [Senge, M. O. and J. C. Brandt (2011) Photochem. Photobiol. 87, 1240–1296] which followed its way from initial development to approval and clinical application.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/php.13730

The Photosensitizer Temoporfin (mTHPC) – Chemical, Pre‐clinical and Clinical Developments in the Last Decade † ‡

The synthetic fluorinated tetracarboranylchlorin as a versatile antitumor photoradiosensitizer

Photodynamic therapy (PDT) is a promising tumor therapy which utilizes reactive oxygen species (ROSs) to cause tumor cells death. 5-aminolevulinic acid (ALA) and two of its esters are FDA-approved photosensitizers. However, their clinical application suffers from their instability and lack of tumor selectivity. In addition, the overexpression of glutathione (GSH) in some tumor cells reduces the PDT efficiency due to the ROS-scavenging ability of GSH. In this work, we present three multifunctional ALA derivates with the characteristics of dual-targeting and GSH depletion to improve the therapeutic effect of ALA-based PDT. The general structure of these compounds consists of an ALA methyl ester (ALA-OMe) moiety that can metabolize to photosensitive protoporphyin IX (PpIX) inside the cells, a biotin group for targeting biotin receptor-positive tumor cells and a disulfide bond-based self-immolative linker which can be activated by GSH to liberate ALA-OMe. Simultaneously, the reaction between the disulfide bond and GSH also depletes intracellular GSH, causing tumor cells more vulnerable to ROSs. All three compounds exhibited high stability under physiological conditions. In vitro experiments demonstrated that the more lipophilic compounds 1 and 2 were much more efficient in inducing PpIX production in biotin receptor-overexpressed HeLa cells as compared with their parent compound (ALA-OMe). And the PpIX generation induced by compounds 1 and 2 was positively correlated with the overexpression of biotin receptor and GSH level in tumor cells. More importantly, the GSH depletion ability of them significantly increased their phototoxicity. Furthermore, in comparison with ALA-OMe, compound 2 showed much higher in vivo efficiency in PpIX production. All the results demonstrate that the combination strategy of dual-targeting and GSH depletion can be used to concurrently enhance the tumor-specificity and anti-tumor efficiency of ALA-based PDT. And this strategy may be used for designing other ALA-based photosensitizers with higher tumor-specificity and better therapeutic effects.

Dual-targeted 5-aminolevulinic acid derivatives with glutathione depletion function for enhanced photodynamic therapy.

Ferroptosis is one critical kind of regulated cell death for tumor suppression, yet it still presents challenges of low efficiency due to the intracellular alkaline pH and aberrant redox status. Herein, we reported a carbonic anhydrase IX (CA IX)-targeted nanovesicle (PAHC NV) to potentiate ferroptosis by remodeling the intracellular environment. CA IX inhibitor 4-(2-aminoethyl) benzene sulfonamide (AEBS) was anchored onto nanovesicles loaded with hemoglobin (Hb) and chlorin e6 (Ce6). Upon reaching tumor regions, PAHC could be internalized by cancer cells specifically by means of CA IX targeting and intervention. Afterwards, the binding of AEBS could elicit intracellular acidification and alter redox homeostasis to boost the lipid peroxidation (LPO) level, thus aggravating the ferroptosis process. Meanwhile, Hb served as an iron reservoir that could efficiently evoke ferroptosis and release O2 to ameliorate tumor hypoxia. With the help of self-supplied O2, Ce6 produced a plethora of 1O2 for enhanced photodynamic therapy, which in turn favored LPO accumulation to synergize ferroptosis. This study presents a promising paradigm for designing nanomedicines to heighten ferroptosis-based synergetic therapeutics through remodeling the intracellular environment.

Carbonic anhydrase IX-targeted nanovesicles potentiated ferroptosis by remodeling the intracellular environment for synergetic cancer therapy.

Synthesis and pharmacological evaluation of chlorin derivatives for photodynamic therapy of cholangiocarcinoma.

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Synthesis and pharmacological evaluation of chlorin derivatives for photodynamic therapy of cholangiocarcinoma.