One‐Photon and Two‐Photon Photophysical Properties of Tetrafunctionalized 5,10,15,20‐tetrakis(m‐hydroxyphenyl)chlorin (Temoporfin) Derivatives as Potential Two‐Photon‐Induced Photodynamic Therapy Agents

Abstract

Photodynamic therapy (PDT) is a cancer treatment, which exploits a photosensitizing drug and light to produce reactive oxygen species that can cause selective damage to the target tissue. The second‐generation photosensitizer 5,10,15,20‐tetrakis(m‐hydroxyphenyl)chlorin (m‐THPC) is a widely used, clinically tested, and commercially available drug with the market formulation known as Foscan. m‐THPC was used as a starting point to obtain a library of compounds with improved optical properties. Substitution, esterification and Sonogashira coupling reactions were employed to modify the m‐THPC skeleton. Aldehyde and carboxylic acid moieties provided the possibility to enhance the two‐photon absorption (TPA) cross‐section while being suitable synthetic handles in the design of drug delivery systems. Characterization of their linear photophysical properties (fluorescence quantum yield, fluorescence lifetime and singlet oxygen quantum yield) was followed by the evaluation of their potential use in a non‐linear absorption regime. The calculated TPA cross‐section values indicate even a 2.6‐fold enhancement at the TPA maximum (69.3±10.0 GM), compared to m‐THPC (26.7±4.0 GM), which proves that functionalization of the m‐THPC core leads to the improvement of the non‐linear optical properties. Thus, tetrafunctionalized m‐THPC derivatives are promising candidates for application in two‐photon induced PDT.

Systemic anti-tumor immunity mediated by photodynamic therapy using injectable chitosan hydrogels for intra-tumoral and sustained drug delivery

“…Chemicals used for hydrogel synthesis (NHS and EDC hydrochloride) were purchased from Sigma-Aldrich, while PS1, PS2, and PS3 were prepared as reported before. 23 CS PROTASAN UP CL 214 was purchased from NovaMatrix. Difunctionalized PEG was synthesized according to the literature protocol.…”

“…CS-based hydrogel formulations were prepared by taking advantage of the tetrafunctionalized derivatives (PS 1, 2, 3) previously synthesized and characterized by us (Figure 1A). 23 The developed hydrogels were composed of CS, difunctionalized PEG and one of the m-THPC derivatives. PS1-PEG-CS and PS3-PEG-CS hydrogels were prepared using a onepot reaction by directly mixing CS with PS 1, or PS 3, and the difunctionalized PEG (Figure 1B).…”

“…The poor phototoxicity of PS 1, 2 and 3 derivatives was unexpected considering that the photo-physical properties of these molecules are similar to the ones of the m-THPC counterpart. 23 Intrigued by these discrepancies, we next investigated the cell internalization of m-THPC derivatives by taking advantage of their inherent fluorescence.…”

“…21,22 In this work, we developed a novel injectable CS-based hydrogel for the intra-tumoral delivery of tetrafunctionalized m-THPC derivatives, PS 1, 2 and 3, that have been previously described. 23 CS-based hydrogels were formed via amide and/or imine bonds between the CS chains with the tetrafunctionalized m-THPC derivatives and with difunctionalized polyethylene glycol (PEG). The lead hydrogel formulation (herein designated as CS-PEG-PS2) exhibits excellent rheological properties enabling intra-tumoral injection with homogenous distribution of the PS.…”

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

“…Quantum chemical methods were also used to satisfactorily explain the higher photodynamic activity of temoporfin compared to its porphycene analogue, temocene (79). Also, the two-photon absorption properties of temoporfin have been analyzed (see below under 'Dosimetry and Detection') (61,(260)(261)(262).…”