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METABOLICALLY CONVERTIBLE LIPOPHILIC DERIVATIVES OF pH‐SENSITIVE AMPHIPATHIC PHOTOSENSITIZERS
Author(s) -
Sahai D.,
Lo JL.,
Hagen I. K.,
Bergstrom L.,
Chernomorsky S.,
Poretz R. D.
Publication year - 1993
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/j.1751-1097.1993.tb04973.x
Subject(s) - pheophorbide a , chlorin , chemistry , photodynamic therapy , photosensitizer , photochemistry , porphyrin , fluorescence , combinatorial chemistry , organic chemistry , physics , quantum mechanics
We propose the use of acetoxymethyl esters of pH‐sensitive amphipathic photosensitizers (PS) for photodynamic therapy (PDT). These compounds may be applicable for PDT involving endocytosis of lipophilic carriers leading to lysosomal uptakc of the esterified PS by target cells. Partial and/or total enzymatic de‐esterification may result in the extralysosomal distribution of the photoactive agents, possibly culminating in a multisite photochemical response. We report here the synthesis and properties of chlorin e 6 triacetoxymethyl ester (CAME) and pheophorbide a acetoxymethyl ester (PAME). Chlorin e 6 and pheophorbide a are photocytotoxic chlorins that possess free carboxylate groups and exhibit optimum wavelengths of excitation substantially red shifted relative to hematoporphyrin derivative. Acetoxymethyl esterification of chlorin e 6 and pheophorbide a was accomplished with bromomethyl acetate. High‐performance liquid chromatography allowed for the purification of PAME, in 87% purity, and CAME, in 63% yield and 94% purity, as well as the detection of the presumed mono‐ and diesters of chlorin e 6 as transient intermediates in the synthesis of CAME. The ultraviolet‐visible absorption, fluorescence excitation and emission, NMR and mass spectra of the chlorin e 6 tnester are consistent with those expected for CAME. The pH‐sensitive amphipathicity of pheophorbide a and chlorin e 6 but not CAME was demonstrated using a water/1‐octanol partition assay. The production of pheophorbide a from PAME and the sequential formation of the di‐ and monoesters and free chlorin e 6 from CAME, by the action of lysosomal esterases obtained from cancer cells, demonstrate the potential of cellular enzymes to convert the lipophilic esters to pH‐sensitive amphipathic PS. It is expected that the product of the esterases' action in the acidic lysosome will be hydrophobic and tend to diffuse into the organelle membrane. Contact with the neutral pH of the adjacent cytosol will result in conversion of the PS to a more hydrophilic anionic species, presumably allowing for it lo diffuse into that compartment and partition throughout the lipophilic and aqueous compartments of the cell.