We propose to use phage libraries displaying peptides to identify molecules that are specifically or selectively expressed in the vasculature of individual tissues, including tumors. Endothelial cells, which are primarily targeted by our method, are known to differ in their properties in different tissues, but very few of the molecular differences have been identified at this time. Our method, in vivo screening of phage libraries, makes it possible to identify tissue-specific molecular markers of endothelial cells. We have already shown that it is possible to isolate phage clones capable of targeting selectively the brain and kidney after intravenous injection into mice. Peptides synthesized based on the sequences displayed by phage that home to the brain or the kidney compete with the phage for binding, indicating that they bind to the same structures in these tissues. Moreover, preliminary results suggest that it will be possible to identify peptides capable of homing preferentially to tumors rather than normal tissues. In the work proposed here, we will characterize the target molecules for the brain-homing peptides by targeting selective markers expressed in the vasculature of tumor tissues, which typically is undergoing angiogenesis. Peptides with tissue-specific targeting properties could be used to selectively deliver drugs, genes or cells to the vasculature of a tumor, or of a targeted organ. Major advances in tumor therapies could be realized with this technology. Valuable information on the distinguishing characteristics of different vascular beds, including those undergoing angiogenesis, is also likely to ensue.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074238-03
Application #
2871959
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Mohla, Suresh
Project Start
1997-04-15
Project End
2002-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Laakkonen, Pirjo; Porkka, Kimmo; Hoffman, Jason A et al. (2002) A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat Med 8:751-5
Porkka, Kimmo; Laakkonen, Pirjo; Hoffman, Jason A et al. (2002) A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo. Proc Natl Acad Sci U S A 99:7444-9
Arap, Wadih; Haedicke, Wolfgang; Bernasconi, Michele et al. (2002) Targeting the prostate for destruction through a vascular address. Proc Natl Acad Sci U S A 99:1527-31
Essler, Markus; Ruoslahti, Erkki (2002) Molecular specialization of breast vasculature: a breast-homing phage-displayed peptide binds to aminopeptidase P in breast vasculature. Proc Natl Acad Sci U S A 99:2252-7
Matter, M L; Ruoslahti, E (2001) A signaling pathway from the alpha5beta1 and alpha(v)beta3 integrins that elevates bcl-2 transcription. J Biol Chem 276:27757-63
Assa-Munt, N; Jia, X; Laakkonen, P et al. (2001) Solution structures and integrin binding activities of an RGD peptide with two isomers. Biochemistry 40:2373-8
Gerlag, D M; Borges, E; Tak, P P et al. (2001) Suppression of murine collagen-induced arthritis by targeted apoptosis of synovial neovasculature. Arthritis Res 3:357-61
Yi, M; Ruoslahti, E (2001) A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. Proc Natl Acad Sci U S A 98:620-4
Fukuda, M N; Ohyama, C; Lowitz, K et al. (2000) A peptide mimic of E-selectin ligand inhibits sialyl Lewis X-dependent lung colonization of tumor cells. Cancer Res 60:450-6
Pasqualini, R; Koivunen, E; Kain, R et al. (2000) Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res 60:722-7

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