Photoinduced cytotoxicity and biodistribution of prostate cancer cell-targeted porphyrins.
A series of five porphyrin-peptide conjugates bearing one or two sequences containing a cell penetrating peptide (CPP), a nuclear localization signal (NLS), or a bifunctional CPP-NLS or NLS-CPP sequences were synthesized and investigated in vitro using PC-3M human prostate cancer cells, in comparison with FDA-approved purified hematoporphyrin derivative (Porfimer Sodium) and mTHPC. The most promising porphyrin-HIV-1 Tat (48-60) conjugate 2 [lowest dark cytotoxicity (IC50 = 38.0 microM), highest phototoxicity (IC50 = 0.40 microM at 1 J/cm2)] was further evaluated in an in vivo biodistribution study using SCID mice bearing PC-3M tumors, in comparison with purified hematoporphyrin derivative. Porphyrin conjugate 2 was more tumor selective than the hematoporphyrin derivative and accumulated to a significantly greater extent in tumors. Our results show that effective photodynamic cytotoxicity can be induced in human prostate cancer cells with minimal dark toxicity and that selective accumulation in prostate tumors can be achieved in vivo with porphyrin-targeted photosensitizers.
Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA. isehgal@vetmed.lsu.edu
Inder
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Sehgal
Martha
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Sibrian-Vazquez
M Graça H
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Vicente
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D017323:Dihematoporphyrin Ether / Q000494:pharmacology / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008027:Light; D008247:Lysosomes / Q000187:drug effects; D008297:Male; D008652:Mesoporphyrins / Q000494:pharmacology / Q000528:radiation effects; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D010777:Photochemistry; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects*; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013237:Stereoisomerism; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D008652:Mesoporphyrins; D010455:Peptides; D017319:Photosensitizing Agents; D011166:Porphyrins; D017323:Dihematoporphyrin Ether; C072269:temoporfin