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

[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...

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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
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Summary:[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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2015.04.006