The long-term objective of our research is to develop new drug delivery systems for macromolecular drugs that must function inside the target cell. The biotechnology and pharmaceutical industries have developed a wide variety of potential therapeutics based on the molecules of biology: DNA, RNA and proteins. For therapeutics such as plasmid DNA, antisense oligonucleotides, ribozymes, and immunotoxins, their ability to reach their target is dependent on their initial ability to reach the cytoplasm from the endosomal compartment. While these therapeutics have tremendous potential, effectively formulating and delivering them has also been a widely recognized challenge. There are a variety of difficult barriers, including drug stability, tissue penetration and transport. While a number of creative delivery systems show significant potential for overcoming these problems with biomolecules that act at the extracellular membrane, a widespread barrier for those that function intracellularly is cytoplasmic entry. Passive or receptor-mediated endocytosis results in localization of biomolecules to the endosomal compartment, where the predominant trafficking fate is fusion with lysosomes and subsequent degradation. Similarly, the delivery of plasmid-based or protein/peptide based molecular vaccines is also dependent on getting the plasmid to the nucleus, or the peptides or proteins into the cytoplasm for entry into the protein processing and display pathways. This proposal is aimed at developing synthetic polymeric carriers that mimic the highly efficient intracellular delivery systems found in nature, without the immunogenicity and dangerous properties of viral and pathogenic systems. Their most important property ties together the sensing of pH changes to membrane destabilizing activity. The """"""""smart"""""""" polymer carriers thus enable endosomal escape and aid the transport of the macromolecular drugs to the cytoplasm, to circumvent the lysosomal trafficking fate. The carriers should enable the efficient delivery of a wide range of biotherapeutics, and open new families of drug candidates that attack intracellular targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB002991-04
Application #
7102726
Study Section
Special Emphasis Panel (ZRG1-SSS-2 (50))
Program Officer
Laughlin, Maren R
Project Start
2003-09-19
Project End
2008-02-29
Budget Start
2006-08-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2006
Total Cost
$414,211
Indirect Cost
Name
University of Washington
Department
Engineering (All Types)
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Palanca-Wessels, Maria C; Booth, Garrett C; Convertine, Anthony J et al. (2016) Antibody targeting facilitates effective intratumoral siRNA nanoparticle delivery to HER2-overexpressing cancer cells. Oncotarget 7:9561-75
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Roy, Debashish; Berguig, Geoffrey Y; Ghosn, Bilal et al. (2014) Synthesis and characterization of transferrin-targeted chemotherapeutic delivery systems prepared via RAFT copolymerization of high molecular weight PEG macromonomers. Polym Chem 5:1791-1799
Keller, Salka; Wilson, John T; Patilea, Gabriela I et al. (2014) Neutral polymer micelle carriers with pH-responsive, endosome-releasing activity modulate antigen trafficking to enhance CD8(+) T cell responses. J Control Release 191:24-33
Palanca-Wessels, Maria Corinna; Press, Oliver W (2014) Advances in the treatment of hematologic malignancies using immunoconjugates. Blood 123:2293-301
Lundy, Brittany B; Convertine, Anthony; Miteva, Martina et al. (2013) Neutral polymeric micelles for RNA delivery. Bioconjug Chem 24:398-407
Wilson, John T; Keller, Salka; Manganiello, Matthew J et al. (2013) pH-Responsive nanoparticle vaccines for dual-delivery of antigens and immunostimulatory oligonucleotides. ACS Nano 7:3912-25
Nash, Michael A; Waitumbi, John N; Hoffman, Allan S et al. (2012) Multiplexed enrichment and detection of malarial biomarkers using a stimuli-responsive iron oxide and gold nanoparticle reagent system. ACS Nano 6:6776-85

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