Photodynamic therapy: tumor targeting with adenoviral proteins.
A brief summary of the mechanisms involved in photodynamic therapy (PDT) and the role of delivery vehicles for photosensitizer targeting is addressed. Phthalocyanines (Pc) have been coupled to adenovirus type 2 capsid proteins including the hexon, the penton base and the fiber to enhance their target selectivity. Adenovirus penton base proteins contain the arginine-glycine-aspartic acid peptidic sequence (RGD) motif known to bind with great affinity and high specificity to integrin receptors, expressed by several types of cancer. Tetrasulfonated aluminum phthalocyanine (AlPcS4) was covalently coupled to the various capsid proteins via one or two caproic acid spacer chains (A1 or A2) in 7:1 up to 66:1 molar ratios. The capacity of the bioconjugates for singlet oxygen production, as measured by an L-tryptophan oxidation assay, was strongly reduced, likely reflecting scavenging by the carrier. Cell adsorption and in vitro photocytotoxicity assays were carried out using the A549 and HEp2 human cell lines expressing integrin receptors, and one murine, the EMT-6 cell line, which lacks receptors for the RGD sequence. The AlPcS4A2-protein complexes induced greater cytotoxicity as compared to the analogous AlPcS4A1 preparations. The penton base-AlPcS4A2 derivative was the more phototoxic for all cell lines tested. Tumor response studies using Balb/c mice with EMT-6 tumor implants demonstrated that the free AlPcS4A2 induced complete tumor regression at a dose of 1 mumol/kg and 400 J/cm2, which is comparable to the activity of the known AlPcS2adj. A mixture of adenovirus type 2 soluble proteins covalently labeled with AlPcS4A2 required 0.5 mumol/kg to induce the same response with the same light dose, suggesting that the high affinity RGD/receptor complex is able to target Pc for PDT.
Allen
C M
CM
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Québec, Canada.
Sharman
W M
WM
La Madeleine
C
C
Weber
J M
JM
Langlois
R
R
Ouellet
R
R
van Lier
J E
JE
D000818:Animals; D002213:Capsid / Q000008:administration & dosage; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D017921:Mastadenovirus; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009942:Organometallic Compounds / Q000008:administration & dosage; D014677:Pharmaceutical Vehicles; D010777:Photochemistry; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage; D014364:Tryptophan / Q000528:radiation effects; D014407:Tumor Cells, Cultured
D007211:Indoles; D009942:Organometallic Compounds; D014677:Pharmaceutical Vehicles; D017319:Photosensitizing Agents; C048577:aluminum tetrasulfophthalocyanine; D014364:Tryptophan