Photodynamic therapy enhancement of phthalocyanine targeting from modifications on the macrocycle to the use of protein delivery vehicles
Allen, Cynthia M
Photodynamic therapy is a promising treatment modality that involves the localization of a light-sensitive drug or photosensitizer in the target tissue prior to illumination with visible light. In the presence of molecular oxygen, cytotoxic agents are generated upon illumination and trigger a cascade of biochemical responses that may eradicate both malignant and non-malignant conditions. Phthalocyanine derivatives are second generation photosensitizers with enhanced photophysical, photochemical and photobiological properties as compared to the clinically accepted hematoporphyrin derivative Photofrin ª . The current study aims at improving the targeting of these photosensitizers to cancerous tissues either through modifications on the phthalocyanine macrocycle or through protein carriers. AlPcS[subscript 4] derivatives substituted with long aliphatic chains of varying lengths were photodynamically active in vitro against a lung adenocarcinoma cell line, A549 cells. Activity varied directly with the degree of lipophilicity: AlPcS[subscript 4] (C16) > AlPcS[subscript 4] (C12) > AlPcS[subscript 4] (C8) > AlPcS[subscript 4] (C4)."In vivo" studies using the EMT-6 murine model were promising, requiring 0.2 [mu]mol kg[superscript -1] and 400 J cm[superscript -2] to completely ablate the tumor. LDL receptor expression is often upregulated in cancer cell membranes. Therefore, in order to enhance Pc targeting, LDL was loaded with AlPcS by two different approaches. The AlPcS[subscript 4] (C12) derivative was non-covalently inserted in the phospholipid bilayer of LDL particles. Conversely, AlPcS[subscript 4] substituted with two caproic acid spacer chains were covalently attached to the LDL protein moiety. While the latter had only marginal success, the former proved to be photodynamically active both in vitro and in vivo . To further exploit cell surface receptors as potential targets in PDT, adeno-viral proteins were covalently labeled with AlPcS[subscript 4] . Adenoviruses penetrate the cell via receptor mediated endocytosis. The Ad penton base contains 5 repeats of the peptidic RGD binding sequence. This motif binds with high affinity to several members of the integrin receptor family. Integrin receptors play a major role in tumorigenesis and metastases with altered expression being a factor. The class of integrin receptors with high affinity for the RGD sequence is expressed in high numbers on A549 cells. Cell uptake of the AlPcS[subscript 4]-adenovirus protein conjugates was enhanced over the parental Pc; however, photocytotoxicity results were unfavorable. In vivo studies using the same rodent model as that of the LDL study were encouraging"--Résumé abrégé par UMI.