In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5611-5611
Abstract:
Photochemical internalization (PCI) is a modality for intracellular delivery of drugs which lack an effective transport mechanism into the cell. Such drugs are taken up by means of endocytosis and are transported to the lysosomes where they are degraded before they have exerted their biological effect. PCI utilizes photosensitizers which accumulate in the membranes of these endo/lysosomal compartments. Light exposure causes rupture of these membranes and subsequent cytosolic release of the drug which freely can interact with its target. PCI of the conventional cytostatic drug Bleomycin has been shown to be highly effective in vivo and is currently evaluated in clinical trials with promising results. Bleomycin is, however, probably not optimal for PCI mediated delivery, and therefore cannot fully take use of the technology. Recombinant targeted toxins may be designed to possess all characteristics for an optimal drug to be delivered by PCI: (1) Exclusive uptake in tumor cells, (2) Intracellular target, (3) Not able to penetrate the plasma membrane, (4) Suboptimal escape from endocytic compartments without PCI, (5) Able to diffuse into the tumor tissue. We here present PCI of a recombinant fusion toxin composted of VEGF121, and gelonin, a type I ribosome inactivating protein toxin. VEGF121/rGel administration has previously been shown to be effective in suppressing tumor xenografts and metastasis. Severe adverse effects may, however, limit the possibilities to obtain complete responses with VEGF121/rGel monotherapy. PCI was shown to increase the selectivity of VEGF121/rGel in VEGFR1 and VEGFR2 transfected porcine endothelial cells (PAE) in vitro. The PCI treatment also resulted in a dramatic reduction in the dosage of VEGF121/rGel to 1/100 as measured by a LD90 of 10 nM for the fusion toxin alone compared to 100 pM with the PCI treatment in VEGFR2 expressing PAE cells. For in vivo experiments the murine colon cell line CT26.CL25 was injected subcutaneously in the left hip of BALB c mice and PCI of VEGF121/rGel was administered one week after implantation. By day 24 after PCI all animals in the non-treatment control group were sacrificed due to tumor size ( & gt;1000m3),while a 50% complete response (CR) was found with PCI of VEGF121/rGel. The animals were followed up to day 60 when the experiment was terminated. No tumor regression was observed in CR animals in this time-frame. About 50%CR was also detected in PCI of bleomycin-treated animals. Animals receiving PCI of bleomycin showed an average weight loss of 15% compared to no significant weight loss in the PCI of the VEGF121/rGel treated group. This is the first report on PCI of a tumor vascular targeting drug. In conclusion, the present results indicate PCI of VEGF121/rGel as a highly selective method for destroying tumor vasculature. The project is supported by the Norwegian Cancer Society. Research was conducted, in part, by the Clayton Foundation for Research Citation Format: Anette Weyergang, Lawrence H. Cheung, Michael Rosenblum, Khalid Mohamedali, Johannes Waltenberger, Kristian Berg. Photochemical internalization of VEGF121/rGel: a strategy for optimizing tumor-vasculature targeting. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5611. doi:10.1158/1538-7445.AM2013-5611
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-5611
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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