Abstract

The specific aims of this competitive renewal proposal are to develop stimuli-responsive bioconjugates and complexes as molecular switches for controlling (a) biorecognition processes (""""""""bioactivity switches"""""""") and (b) intracellular trafficking of biomolecules (""""""""membrane switches""""""""). Bioactivity switches are responsive polymer-engineered protein (RP-EP) conjugates that can be stimulated to turn protein activity on and off , or trigger release of bound ligand. Applications as on-off switches include affinity separations, diagnostics, drug targeting, and enzyme processes, such as PCR, industrial enzyme processes and detergent and fabric finishing processes. Actions of bioactivity switches as triggered release systems include the delivery of: biotinylated agents, affinity biomolecules, drugs, chemical agents, enzyme substrates, products or inhibitors, and signals. Such actions have many diverse uses in medicine, biotechnology and industry. Membrane switches are pH-responsive polymer bioconjugates or complexes with drug carriers that disrupt endosomal membranes to enhance intracellular delivery of DNA or protein drugs. This action should increase the efficacies of gene, antisense oligonucleotide, and cancer therapies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053771-05
Application #
6180856
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Lewis, Catherine D
Project Start
1996-02-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
5
Fiscal Year
2000
Total Cost
$262,197
Indirect Cost

  Institution

Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Cheung, Charles Y; Stayton, Patrick S; Hoffman, Allan S (2005) Poly(propylacrylic acid)-mediated serum stabilization of cationic lipoplexes. J Biomater Sci Polym Ed 16:163-79
Stayton, Patrick S; Ding, Zhongli; Hoffman, Allan S (2004) Smart polymer-streptavidin conjugates. Methods Mol Biol 283:37-43
Murthy, Niren; Campbell, Jean; Fausto, Nelson et al. (2003) Design and synthesis of pH-responsive polymeric carriers that target uptake and enhance the intracellular delivery of oligonucleotides. J Control Release 89:365-74
Jones, Rachel A; Cheung, Charles Y; Black, Fiona E et al. (2003) Poly(2-alkylacrylic acid) polymers deliver molecules to the cytosol by pH-sensitive disruption of endosomal vesicles. Biochem J 372:65-75
Malmstadt, Noah; Yager, Paul; Hoffman, Allan S et al. (2003) A smart microfluidic affinity chromatography matrix composed of poly(N-isopropylacrylamide)-coated beads. Anal Chem 75:2943-9
Murthy, Niren; Campbell, Jean; Fausto, Nelson et al. (2003) Bioinspired pH-responsive polymers for the intracellular delivery of biomolecular drugs. Bioconjug Chem 14:412-9
Shimoboji, Tsuyoshi; Ding, Zhongli L; Stayton, Patrick S et al. (2002) Photoswitching of ligand association with a photoresponsive polymer-protein conjugate. Bioconjug Chem 13:915-9
Lackey, Chantal A; Press, Oliver W; Hoffman, Allan S et al. (2002) A biomimetic pH-responsive polymer directs endosomal release and intracellular delivery of an endocytosed antibody complex. Bioconjug Chem 13:996-1001
Kyriakides, Themis R; Cheung, Charles Y; Murthy, Niren et al. (2002) pH-sensitive polymers that enhance intracellular drug delivery in vivo. J Control Release 78:295-303
Cheung, C Y; Murthy, N; Stayton, P S et al. (2001) A pH-sensitive polymer that enhances cationic lipid-mediated gene transfer. Bioconjug Chem 12:906-10

Showing the most recent 10 out of 16 publications