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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.

A series of four porphyrin-peptide conjugates bearing one linear bifunctional sequence containing a cell penetrating peptide (CPP) and a nuclear localization signal (NLS) were synthesized and their in vitro biological and stability properties investigated. All conjugates accumulated within human HEp2 cells to a significantly higher extent than their porphyrin-PEG precursor, and the extent of their uptake and cytotoxicity depends on the nature and sequence of the amino acids. Conjugates 2 and 5 bearing a NLS-CPP accumulated the most within cells and were the most phototoxic (IC50 approximately 7 microM at 1 J/cm2). All conjugates localized preferentially within the cell lysosomes, and in addition, conjugate 2 was also found in the ER. All conjugates were highly stable under nonenzymatic conditions, but their peptide sequences were cleaved to some extent (ca. 50% after 24 h) by proteolytic enzymes, such as cathepsin B, cathepsin D, prolidase, and plasmin.