The overarching goal of this proposal is to synthesize and evaluate cyclic polymers for applications in anticancer nanomedicine. Cyclic polymers have unique structural characteristics that may unlock new approaches and knowledge for anticancer therapeutics, particularly with regard to their uptake, retention, and biodegradability. Since state-of-the-art cyclic polymer synthesis still suffers many limitations, a major portion of the proposed work focuses on advancements in catalyst design. Generation of cyclic polymers functionalized for biological applications requires the design and synthesis of new Ru-alkylidene catalysts, as well as the corresponding carbo- and heterocyclic monomers, which will be functionalized to allow conjugation of antitumor drugs. A key advantage of using the proposed metathesis-based polymerizations is that the same monomer pool can be used to provide exact linear analogues of the cyclic polymers for comparative analysis. Ultimately, polymer topology will be evaluated for its effects on the efficacy of nanomedicines for anticancer therapeutics. Finally, the polymers will be made available such that the attached drug bioavailability, uptake into tumor cells, cellular localization, and permeability and retention may be evaluated and quantified in collaboration with the Caltech/UCLA MSB Cancer Center.
Specific Aims : 1) To prepare catalysts for the synthesis of cyclic polymers with narrow polydispersities and controlled molecular weights 2) To prepare water-soluble, cyclic catalysts and polymers 3) To synthesize cyclic polymers with biologically relevant pendant substituents 4) To provide cyclic polymer-drug conjugates for biological testing and evaluation of the effects of polymer topology on antitumor therapeutic behavior.

Public Health Relevance

Macromolecules are a promising new approach for treating cancer. Size and topology have been identified as key factors impacting the performance of these nanomedicines. We seek to provide cyclic polymers, an unprecedented class of nanomedicines that may have improved performance for anticancer therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA132539-02
Application #
7651088
Study Section
Special Emphasis Panel (ZRG1-F04A-T (20))
Program Officer
Myrick, Dorkina C
Project Start
2008-05-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$46,826
Indirect Cost
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Boydston, Andrew J; Holcombe, Thomas W; Unruh, David A et al. (2009) A direct route to cyclic organic nanostructures via ring-expansion metathesis polymerization of a dendronized macromonomer. J Am Chem Soc 131:5388-9
Xia, Yan; Boydston, Andrew J; Yao, Yefeng et al. (2009) Ring-expansion metathesis polymerization: catalyst-dependent polymerization profiles. J Am Chem Soc 131:2670-7
Boydston, Andrew J; Xia, Yan; Kornfield, Julia A et al. (2008) Cyclic ruthenium-alkylidene catalysts for ring-expansion metathesis polymerization. J Am Chem Soc 130:12775-82