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139th National Cancer Advisory Board

the tumor tissue. To target the caveolae specifically, nanoparticles were conjugated to existing antibodies that were identified for targets; these then were injected into the circulation to accumulate in the caveolae; this accumulation is not seen in normal tissue. An intravital microscopy was used to see, within seconds of the tail vein injection of the fluorescence antibodies, binding that occurs to the surface of the tumor vasculature and the tumor outline. Within about 1 to 2 hours of this process, the whole field turned completely green, and it was possible to penetrate, bind, transcytose and move the material into the tumors. The amount of fluorescence that is seen inside the micro vessel is always less than what is seen within the tissue; for this reason, active pumping is used. In some models, whole tumors can be turned green in 45 to 60 minutes after intravenous injections.

Dr. Schnitzer showed several images captured by SPECT imaging. One picture of a rat lung with multiple tumors that were SPECT imaged in vivo captured quantified radioactivity; the tumors showed 35 percent of the injected dose per gram, whereas normal organs showed little or no level of targeting. Another image was of a B16 melanoma model with the subcutaneous tumors. A colon cancer model in mice revealed the tumors and radioactivity as well. The Her-2-neu spontaneous tumor model has yielded a similar result. Dr. Schnitzer also shared a movie of an intravital microscopy of solid GFP-tumor eradication by radioimmunotherapy. He noted that the system works well with orthotropic tumors, but non-orthotropic tumors seem to have a significant problem with the expression of some antigens. Complete remissions can be induced with 30 µCi in 80 percent of the cases; in those cases in which fluorescence returns, a second injection is given, and 100 percent of the tumors disappear. This usually occurs 1 to 2 weeks after the first injection.

A variety of other targets are now available. Targets specific to the liver, kidney, lung, and heart are being pursued with the NHLBI as part of IMAT’s proteomic initiative. In some instances, the expression of these proteins can be shared by different organs. There are a number of proteins, however, that are not specific, but rather are common to all endothelial cells. This makes clear that there is a fingerprint or a signature at the surface of the endothelium in each of the tissues, which opens to research different phenotype altering events, such as in the tissue microenvironment and tissue-specific endothelial expression. These data reveal that the caveolae represent a new strategy of delivery in terms of imaging and therapy, and that transcytotic pumping occurs even more rapidly; the caveolae provide a means to extend beyond classic vascular targeting to deliver agents into a specific tissue by crossing the normally restricted endothelial cell barrier and, thereby, increasing bioefficacy by reaching the intended target (i.e., the cells inside the tissue) of most therapies. This may be enabling for many types of drugs, biologics, gene vectors, nanoparticles, and imaging probes.

This discovery platform combines a significant number of technologies dealing with subcellular fractionation, proteomics, bioinformatics, and antibody generation, and combining with rapid validation through in vivo molecular imaging. Data complexity can be reduced a priori from innumerable possible protein targets to between 10 and 100 candidates. A subset of this for research could be the transvascular pumping space. Dr. Schnitzer referred to his summary of the vascular and caveolar targeting strategy (New Engl J Med 1998;339:472-4), and noted that the work that he described today was accomplished with IMAT grant support.



Dr. Croyle, Director, Division of Cancer Control and Population Sciences (DCCPS), introduced the presentation on the Annual Cancer Statistics Report. He referred the NCAB members to a copy of the near-final press release that will appear shortly in The Journal of Cancer. Dr. Croyle also pointed out that their materials include information on GIS, which holds a tremendous promise for understanding health


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