Many diseases of the eye exist, and they are some of the most difficult diseases to treat. The blood-ocular barrier prevents many agents from penetrating the eye when administered orally or by I.V. injection. Many ocular diseases such as proliferative diabetic retinopathy, melanomas, retinoblastoma, and possibly cataracts are characterized by increases matrix-metalloprotease (MMP) and plasminogen activator activity. Both of these classes of natural cellular products are proteases used to promote the wound healing process. During disease progression, these proteases are excreted from diseased cells; the results of protease secretion are exacerbation of the disease state either by neovascularization or by cellular infiltration. A new system will be investigated that will have an impact upon any disease in which extracellular proteases are excreted. These proteases will be utilized to target drug delivery from drug-conjugated systems polymers. Not only will polymer-drug conjugates be utilized, but also microparticle-drug conjugates due to their increased size compared to polymer-drug conjugates. The microparticle-drug conjugates will have a peptide linker that is susceptible to matrix-metalloprotease digestion. Upon digestion by the MMP, free drug will be delivered allowing it to act upon the neighboring cells. The hypothesis to be tested is that targeting therapeutics to a molecular signal of a disease can improve the effectiveness and specificity of established therapeutics over that of the untargeted therapeutic. To test this hypothesis and complete the objectives, three specific aims have been set: 1) to develop and characterize conjugates of conventional therapeutics with polymeric microparticles, 2) to determine in vitro release and effectiveness of microparticle-drug conjugates, and 3) to determine in vivo release and effectiveness of microparticle-drug conjugates. Upon completion of this RO3 grant, sufficient data to conduct further research (RO1 grant) into the mechanisms and possibilities of the use of microparticles that are targeted to a specific molecular signal of an ocular disease .

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
5R03EY014357-02
Application #
6743607
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Dudley, Peter A
Project Start
2003-05-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$152,531
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Yan, Xiaoliang; Gemeinhart, Richard A (2005) Cisplatin delivery from poly(acrylic acid-co-methyl methacrylate) microparticles. J Control Release 106:198-208
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