aluminum-phthalocyanine-disulfonate and Colonic-Neoplasms

Photochemical internalization is under development for improving macromolecular therapy by inducing photochemical damage to endocytic vesicles. This damage leads to the release of therapeutic macromolecules entrapped in endocytic vesicles into the cytosol. The macromolecules may in this way be able to interact with therapeutic targets instead of being degraded by lysosomal hydrolases. Bleomycin is used in several standard cancer chemotherapy regimens. Its hydrophilic and relatively large chemical structure limits its ability to penetrate membrane structures, which causes the accumulation of bleomycin in endocytic vesicles. The purpose of this study was to evaluate the therapeutic potential of aluminum phthalocyanine disulfonate (AlPcS2a)-based photochemical delivery of bleomycin.. Three tumors of different origin were grown s.c. in BALB/c (nu/nu) mice. The photosensitizer AlPcS2a and bleomycin were systemically administered and the tumor area was exposed to red light when the tumor volume had reached 100 mm3. The tumor volume was measured frequently after treatment and the time for the tumor volume to reach 800 to 1,000 mm3 was selected as the end point.. The photochemical delivery of bleomycin induced a delayed tumor regrowth, and in two out of three tumor models, lead to 60% complete response, whereas no complete responses were seen after treatment with bleomycin alone. A statistical model to assess synergism was established. Combination of the photochemical treatment and bleomycin was found to induce a synergistic delay in tumor growth.. AlPcS2a-based photochemical internalization of bleomycin induces a synergistic inhibition of tumor growth in three different tumor models. This treatment combination should be further considered for clinical utilization.

Topics: Aluminum; Animals; Antibiotics, Antineoplastic; Bleomycin; Cells, Cultured; Colonic Neoplasms; Cricetinae; Drug Delivery Systems; Endosomes; Female; Fibroblasts; Humans; Indoles; Lung; Mice; Mice, Inbred BALB C; Mice, Nude; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Sarcoma, Experimental; Survival Rate; Xenograft Model Antitumor Assays

A main issue for further clinical progress of cancer gene therapy is to develop technologies for efficient and specific delivery of therapeutic genes to tumor cells. In this work, we describe a photochemical treatment that substantially improves gene delivery by adenovirus, one of the most efficient gene delivery vectors known. Transduction of two different cell lines was studied by microscopy, flow cytometry, and an enzymatic assay, employing a beta-galactosidase-encoding adenovirus. The photochemical treatment induced a >20-fold increase in gene transduction, compared with conventional adenovirus infection, both when measured as the percentage of cells transduced, and when measured as the total beta-galactosidase activity in the cell population. The effect was most pronounced at lower virus doses, where in some cases the same transduction efficiency could be achieved with a 20 times lower virus dose than with conventional infection. Photochemical treatments are already in clinical use for cancer therapy, and generally are very specific and have few side effects. The photochemical internalization technology described thus has a clear potential for improving both the efficiency and the specificity of gene delivery in cancer gene therapy, making it possible to achieve efficient site-specific in vivo gene delivery by adenoviral vectors.

Topics: Adenocarcinoma; Adenoviridae; beta-Galactosidase; Colonic Neoplasms; Flow Cytometry; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Indoles; Light; Organometallic Compounds; Photosensitizing Agents; Transduction, Genetic; Tumor Cells, Cultured