Effect of chirality on cellular uptake, imaging and photodynamic therapy of photosensitizers derived from chlorophyll-a

• Published in: Bioorganic & medicinal chemistry 2015-07, Vol.23 (13), p.3603-3617
• Main Authors: Srivatsan, Avinash, Pera, Paula, Joshi, Penny, Wang, Yanfang, Missert, Joseph R., Tracy, Erin C., Tabaczynski, Walter A., Yao, Rutao, Sajjad, Munawwar, Baumann, Heinz, Pandey, Ravindra K.
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - radiotherapy; Carcinoma, Squamous Cell - ultrastructure; Cell Line, Tumor; Cell-specificity; Chlorophyll - analogs & derivatives; Chlorophyll - chemical synthesis; Chlorophyll - chemistry; Chlorophyll - pharmacology; Chlorophyll A; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colonic Neoplasms - radiotherapy; Colonic Neoplasms - ultrastructure; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Imaging; Iodine Radioisotopes; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Lung Neoplasms - ultrastructure; Mice; Mice, Inbred BALB C; Molecular Imaging - methods; Neoplasm Transplantation; Organ Specificity; Photochemotherapy - methods; Photodynamic therapy; Photosensitizer; Photosensitizing Agents - chemical synthesis; Photosensitizing Agents - pharmacology; Spirulina - chemistry; Stereoisomerism; Tumor Burden - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.04.006

[Display omitted] We have previously shown that the 124I-analog of methyl 3-(1′-m-iodobenzyloxy) ethyl-3-devinyl-pyropheophorbide-a derived as racemic mixture from chlorophyll-a can be used for PET (positron emission tomography)-imaging in animal tumor models. On the other hand, as a non-radioactive analog, it showed excellent fluorescence and photodynamic therapy (PDT) efficacy. Thus, a single agent in a mixture of radioactive (124I-) and non-radioactive (127I) material can be used for both dual-imaging and PDT of cancer. Before advancing to Phase I human clinical trials, we evaluated the activity of the individual isomers as well as the impact of a chiral center at position-31 in directing in vitro/in vivo cellular uptake, intracellular localization, epithelial tumor cell-specific retention, fluorescence/PET imaging, and photosensitizing ability. The results indicate that both isomers (racemates), either as methyl ester or carboxylic acid, were equally effective. However, the methyl ester analogs, due to subcellular deposition into vesicular structures, were preferentially retained. All derivatives containing carboxylic acid at the position-172 were noted to be substrate for the ABCG2 (a member of the ATP binding cassette transporters) protein explaining their low retention in lung tumor cells expressing this transporter. The compounds in which the chirality at position-3 has been substituted by a non-chiral functionality showed reduced cellular uptake, retention and lower PDT efficacy in mice bearing murine Colon26 tumors.