One of the biggest obstacles for efficient drug delivery is specific cellular targeting. Liposomes have long been used for drug delivery, but do not possess targeting capabilities. This limitation may be circumvented by surface coating of colloidal delivery systems with peptides, proteins, carbohydrates, vitamins, or antibodies that target cell surface receptors or other biomolecules. Each of these coatings has significant drawbacks. One idealized system for drug delivery combines stabilized """"""""mini-protein"""""""" ligands with a colloidal delivery vehicle. Our prior studies have shown that peptide-amphiphiles, whereby both a peptide """"""""head group"""""""" and a lipid-like """"""""tail"""""""" are present in the same molecule, can be used to engineer collagen-like triple-helical or alpha-helical mini-proteins. The tails serve to stabilize the head group structural elements. These peptide-amphiphiles can be designed to bind to specific cell surface receptors with high affinity, while being minimally degraded. In preliminary studies, we have prepared liposomes using a melanoma targeting peptide-amphiphile ligand, and shown that these liposomes were stable, the peptide-amphiphile retained triple-helical structure, and an encapsulated fluorescent dye was selectively delivered to cells. In the present proposal we will develop peptide-amphiphile liposomes and polyPro dendrimers as a new class of drug delivery vehicles, taking advantage of melanoma receptor targeting and liposome activation by melanoma proteases. Transfer of drug into the cell will also be improved by incorporation of cell membrane traversing peptide-amphiphiles. A variety of biophysical and biological techniques will be used to evaluate peptide-amphiphile structure-function relationships. The selectivity of peptideamphiphile colloidal delivery vehicles will be analyzed using metastatic melanoma cells and other cell types (fibroblasts, endothelial cells) found in the melanoma microenvironment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
7R01EB000289-10
Application #
7741045
Study Section
Special Emphasis Panel (ZRG1-BMBI (01))
Program Officer
Henderson, Lori
Project Start
1998-07-15
Project End
2010-06-30
Budget Start
2008-08-01
Budget End
2010-06-30
Support Year
10
Fiscal Year
2008
Total Cost
$276,675
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Fields, Gregg B; Stawikowski, Maciej J (2016) Imaging Matrix Metalloproteinase Activity Implicated in Breast Cancer Progression. Methods Mol Biol 1406:303-29
Ndinguri, Margaret W; Zheleznyak, Alexander; Lauer, Janelle L et al. (2012) Application of Collagen-Model Triple-Helical Peptide-Amphiphiles for CD44-Targeted Drug Delivery Systems. J Drug Deliv 2012:592602
Fields, Gregg B (2010) Synthesis and biological applications of collagen-model triple-helical peptides. Org Biomol Chem 8:1237-58
Ye, Jing; Fox, Sara A; Cudic, Mare et al. (2010) Determination of penetratin secondary structure in live cells with Raman microscopy. J Am Chem Soc 132:980-8
Fields, Gregg B (2010) Using fluorogenic peptide substrates to assay matrix metalloproteinases. Methods Mol Biol 622:393-433
Cudic, Mare; Fields, Gregg B (2009) Extracellular proteases as targets for drug development. Curr Protein Pept Sci 10:297-307
Giricz, Orsolya; Lauer-Fields, Janelle L; Fields, Gregg B (2008) The normalization of gene expression data in melanoma: investigating the use of glyceraldehyde 3-phosphate dehydrogenase and 18S ribosomal RNA as internal reference genes for quantitative real-time PCR. Anal Biochem 380:137-9
Al-Ghoul, Mohammad; Bruck, Thomas B; Lauer-Fields, Janelle L et al. (2008) Comparative proteomic analysis of matched primary and metastatic melanoma cell lines. J Proteome Res 7:4107-18
Khan, David R; Rezler, Evonne M; Lauer-Fields, Janelle et al. (2008) Effects of drug hydrophobicity on liposomal stability. Chem Biol Drug Des 71:3-7
Rezler, Evonne M; Khan, David R; Lauer-Fields, Janelle et al. (2007) Targeted drug delivery utilizing protein-like molecular architecture. J Am Chem Soc 129:4961-72

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