The overall goal of this research is to develop a new class of in situ-forrning, injectable, and biodegradable polymeric biomaterials based on time-dependent molar mass and lower critical solution temperature (LCST) properties for localized delivery of an anti-cancer agent, phenstatin. Many current biodegradable, injectable, and in situ-forming biomaterials under development have disadvantages including the use of water miscible organic solvents for delivery, low molecular weight toxic byproducts, reactive chemistries and the need for external light sources (i.e., for photopolymerization). Ideal replacement materials for these applications would be easily injected and form in a timely fashion without detrimental effects to surrounding tissue from temperature increases, toxicity or invasive techniques. Many of these difficulties can be addressed using NIPAAm copolymers with time-dependent molar mass and lower critical solution temperature (LCST) properties. Copolymers of N-isopropylacrylamide (NIPAAm), methacrylic anhydride(MA) and maleic anhydride (MAn) will possess time-dependent LCST properties in an aqueous environment due to the conversion of maleic anhydride side chains to maleic acid and time-dependent molar mass due to conversion of methacrylic anhydride to methacrylic acid, both by hydrolysis. Copolymers of NIPAAm, methacrylic anhydride, and maleic anhydride will be synthesized and be characterized for initial and final LCST, initial and final molar mass, the initial strength of the gel, and degradation time. Drug release profiles will be evaluated from selected materials. The cytotoxicity and biocompatibility of these materials will be assessed using cell proliferation (MTT) and live/dead assays on BALB/c 3T3 cells. Tissue irritation potential of these materials will be evaluated in vitro by macrophage and lymphocyte activation experiments. Finally, a selected material will be injected subcutaneously into Sprague Dawley rats to verify injectability and in situ formation. In vivo compatibility will be assessed using selected histological techniques. In vivo efficacy of phenstatin released from this material will be evaluated using a SCID mouse ovarian cancer model.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065917-02
Application #
6768673
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Okita, Richard T
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$231,725
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Cui, Zhanwu; Lee, Bae Hoon; Pauken, Christine et al. (2011) Degradation, cytotoxicity, and biocompatibility of NIPAAm-based thermosensitive, injectable, and bioresorbable polymer hydrogels. J Biomed Mater Res A 98:159-66
Overstreet, Derek J; Dhruv, Harshil D; Vernon, Brent L (2010) Bioresponsive copolymers of poly(N-isopropylacrylamide) with enzyme-dependent lower critical solution temperatures. Biomacromolecules 11:1154-9
Cui, Zhanwu; Lee, Bae Hoon; Pauken, Christine et al. (2010) Manipulating degradation time in a N-isopropylacrylamide-based co-polymer with hydrolysis-dependent LCST. J Biomater Sci Polym Ed 21:913-26
Henderson, Eric; Lee, Bae Hoon; Cui, Zhanwu et al. (2009) In vivo evaluation of injectable thermosensitive polymer with time-dependent LCST. J Biomed Mater Res A 90:1186-97
Cui, Zhanwu; Lee, Bae Hoon; Vernon, Brent L (2007) New hydrolysis-dependent thermosensitive polymer for an injectable degradable system. Biomacromolecules 8:1280-6
Solis, Francisco J; Vernon, Brent (2007) Control of gel swelling and phase separation of weakly charged thermoreversible gels by salt addition. Macromolecules 40:3840-3847
Robb, Stephanie A; Lee, Bae Hoon; McLemore, Ryan et al. (2007) Simultaneously physically and chemically gelling polymer system utilizing a poly(NIPAAm-co-cysteamine)-based copolymer. Biomacromolecules 8:2294-300
Lee, Bae Hoon; West, Bianca; McLemore, Ryan et al. (2006) In-situ injectable physically and chemically gelling NIPAAm-based copolymer system for embolization. Biomacromolecules 7:2059-64
Lee, Bae Hoon; Vernon, Brent (2005) In situ-gelling, erodible N-isopropylacrylamide copolymers. Macromol Biosci 5:629-35