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In ophthalmic drug delivery, a major problem is retaining an adequate concentration of a therapeutic agent in the pre-corneal area. Polycarboxylic acid carriers such as polyaerylic acid and polyitaconic acid in sub-colloidal, nanoparticulate hydrogel form have a strong potential for sustained release of a drug in ocular delivery. Formulations have been prepared of brimonidine loaded in polyearboxylic (polyaerylic and polyitaconic) acid nanopartieles for potential ophthalmic delivery. These particles were prepared by a reverse micro-emulsion polimerization technique with sizes in the range of 50 nm. The loading efficiencies of the drug brimonidine in the particles were shown to be between 80-85% for polyaerylic acid nanoparticles and between 65-70% for polyitaconic nanoparticles. The loading efficiency was also found to be pH dependent. In a preliminary biocompatibility test, human corneal epithelial cells incubated with polyaerylic acid nanopartieles were found to retain their viability, whereas polyitaconic acid nanoparticles were found to be toxic. Two-photon laser scanning microscopic studies of the fluorescently labelled polyacrylic acid nanopartieles and human cornea shows that they are adhesive on the corneal surface. The polyacrylic acid nanoparticles demonstrated a controlled release of the opthalniotofrical drug (Brimonidine) through the human cornea as compared to that of the commercial formulation, AlphaganTM. [ABSTRACT FROM AUTHOR]

Provides updates on research related to proteomics and genetics. Development of a multidimensional nuclear magnetic resonance spectroscopy for protein characterization; Use of organically modified silica nanoparticles as nonviral vector for in vivo gene delivery and expression in the brain; Application of nonhomologous random recombination to identify the key structural determinants that allow pair of small nontranslated RNA.

Renal cell carcinoma is the most lethal of the common urologic malignancies, with no available effective therapeutics. Tetrac (tetraiodothyroacetic acid) is a deaminated analogue of L-thyroxine (T(4)) that blocks the pro-angiogenesis actions of T(4) and 3, 5, 3'-triiodo-L-thyronine as well as other growth factors at the cell surface receptor for thyroid hormone on integrin alphavbeta3. Since this integrin is expressed on cancer cells and also on endothelial and vascular smooth cells, the possibility exists that Tetrac may act on both cell types to block the proliferative effects of thyroid hormone on tumor growth and tumor-related angiogenesis. To test this hypothesis, we determined the effect of Tetrac on tumor cell proliferation and on related angiogenesis of human renal cell carcinoma (RCC). We used two models: tumor cell implants in the chick chorioallantoic membrane (CAM) system and xenografts in nude mice. To determine the relative contribution of the nuclear versus the plasma membrane action of Tetrac, we compared the effects of unmodified Tetrac to Tetrac covalently linked to poly (lactide-co-glycolide) as a nanoparticle (Tetrac NP) that acts exclusively at the cell surface through the integrin receptor. In the CAM model, Tetrac and Tetrac NP (both at 1 microg/CAM) arrested tumor-related angiogenesis and tumor growth. In the mouse xenograft model, Tetrac and Tetrac NP promptly reduced tumor volume (p<0.01) when administered daily for up to 20 days. Animal weight gain was comparable in the control and treatment groups. Overall, the findings presented here provide evidence for the anti-angiogenic, and anti-tumor actions of Tetrac and Tetrac NP and suggest their potential utility in the treatment of renal cell carcinoma.

Studies have shown the presence of expanded polyQ containing proteins in brain cells related to Huntington disease (HD) and other poly-glutamine disorders. We report the use of organically modified silica (ORMOSIL) nanoparticles as an efficient non-viral gene carrier in an effort to model brain pathology associated with those disorders induced by expanded polyQ peptides. In experiment 1, plasmids expressing Hemaglutinin-tagged polypeptides with 20 glutamine repeats (Q20) or with extended 127-glutamine repeats (Q127) were complexed with ORMOSIL nanoparticles and injected twice (2 weeks apart) into the lateral ventricle of the mouse brain. Fourteen days post-injection of Q127, immunocytochemistry revealed the presence of the characteristic nuclear and cytoplasmic Q127 aggregates in numerous striatal, septal and neocortical neuronal cells as well as ubiquitin-containing aggregates indicative of the neuronal pathology. The mice receiving Q127 showed a marked increase in the reactive GFAP (+) astrocytes in striatum, septum and brain cortex, further indicating the neurodegenerative changes, accompanied by motor impairments. In experiment 2, plasmids Q20 or Q127 were complexed with ORMOSIL and were injected into the brain lateral ventricle or directly into the striatum of adult rats. In both routes of transfection, Q127 induced the appearance of reactive GFAP (+) astrocytes and activated ED1 antigen expressing microglia. An increase in the size of the lateral ventricle was also observed in rats receiving Q127. In transgenic mouse polyQ models, extensive pathologies occur outside the nervous system and the observed brain pathologies could reflect developmental effects of the toxic polyQ proteins. Our experiments show that the nervous tissue restricted expression of poly Q-extended peptides in adult brain is sufficient to evoke neuropathologies associated with HD and other polyQ disorders. Thus, nanotechnology can be employed to model pathological and behavioral aspects of genetic brain diseases in mice as well as in other species, providing a novel research tool for in vivo testing of single or multi-gene therapies.