New Halogenated Water‐Soluble Chlorin and Bacteriochlorin as Photostable PDT Sensitizers: Synthesis, Spectroscopy, Photophysics, and in vitro Photosensitizing Efficacy

Abstract

Chlorin and bacteriochlorin derivatives of 5,10,15,20-tetrakis(2-chloro-5-sulfophenyl)porphyrin have intense absorptions in the phototherapeutic window, high water solubility, high photostability, low fluorescence quantum yield, long triplet lifetimes, and high singlet oxygen quantum yields. Biological studies revealed their negligible dark cytotoxicity, yet significant photodynamic effect against A549 (human lung adenocarcinoma), MCF7 (human breast carcinoma) and SK-MEL-188 (human melanoma) cell lines upon red light irradiation (cutoff λ<600 nm) at low light doses. Time-dependent cellular accumulation of the chlorinated sulfonated chlorin reached a plateau at 2 h, as previously observed for the related porphyrin. However, the optimal incubation time for the bacteriochlorin derivative was significantly longer (12 h). The spectroscopic, photophysical, and biological properties of the compounds are discussed in relevance to their PDT activity, leading to the conclusion that the bacteriochlorin derivative is a promising candidate for future in vivo experiments.

Photodynamic Therapy: Current Status and Future Directions

“…PSs rarely participate only in type I or type II processes; therefore, photodynamic activation usually generates a mixture of 1 O 2 and radicals [51]. Recent studies suggest that high PDT efficacy results from a synergistic action of species generated by type I and type II reactions (O 2 - ∙ , HO ∙ and 1 O 2 ) [52,53,54]. …”

“…Serious shortcomings of this first PS (reviewed by Nyman and Hynninen [93]) stimulated intensive research into the development of compounds which can fulfill as many as possible of the formulated requirements for a good PS [94]. Significant success has been achieved in several aspects: (1) synthesis of stable PSs absorbing light in the red and NIR region of the spectrum (650-800 nm), which penetrates deeper into the tissues [52,95,96], (2) improvement of the selectivity (increasing the target/healthy tissue ratio) and (3) accelerating elimination from the body in order to reduce side effects [97,98,99,100]. Increased understanding of the mechanisms of the photodynamic action at cellular and molecular levels helped in formulating strategies for further improvement of PSs.…”

“…Among the natural pigments with strong absorption in the NIR region of the spectrum (720-850 nm) are bacteriochlorins and bacteriopurpurins [103], but they are unstable, easily photobleach, and permit limited chemical modifications [54,104]. Recently developed new synthetic strategies allowed the synthesis of artificial stable bacteriochlorins, which demonstrated improved pharmacokinetics and high PDT efficacy [52,54,95,96,105]. Light with λ >850 nm, however, does not provide enough energy for excitation of 3 O 2 to 1 O 2 [100,106].…”

Modifications of Porphyrins and Hydroporphyrins for their Solubilization in Aqueous Media

“…Alternatively, the chlorosulfonate could also be converted to sulfonamide derivatives by reaction with amines [118]. The corresponding chlorin and bacteriochlorin reduction products 106 and 107, respectively, were made by diimide reduction of the sulfonated porphyrin 105, and were tested as photosensitizers for the PDT of tumors (Scheme 30) [119]. The attachment of sulfonated groups to the β-positions of a tetrapyrrolic macrocycle is an alternative method toward the generation of hydrophilic sulfonated derivatives.…”

mTHPC – A drug on its way from second to third generation photosensitizer?

“…More significant synthetic advances of Temoporfin related compounds are a consequence of general progress in the synthesis of unsymmetrical porphyrins and (bacterio)chlorins [42,43,44,45,46,47,48,49]. These advances have made it possible to prepare porphyrins with different substituent pattern, e.g., different hydrophobic and hydrophilic groups.…”