Pre-Clinical Testing of New Hydroxybutyrate Analogues.

images[4]One of the hallmarks of Parkinson Disease is a deficit in Complex I of the mitochondrial complex chain in the tyrosine hydroxylase (THf)+ neurons in the substantia nigra pars compacta (SNpc) of the brain. This situation allows the dopamine neuron to be put under oxidative stress, thus leaving the DA neuron vulnerable to free radical attack. In attempts to reverse the deficit in Complex I in the cell, in earlier experiments, we used a ketone body, D-beta- hydroxybutyrate (DBHB) in the presence of MPTP to increase oxidative phosphorylation. This change in phosphorylation state afforded protection to the SNpc TH+neurons. One drawback to the use of DBHB is that it is short- acting. In our present experiment, we used a DBHB analogue, glyceryl tris(3- hydroxybutyrate, G3HB) which is the basic DBHB structure that has been altered. Compared to DBHB which increased DBHB levels in plasma by almost 100%, G3HB increased plasma DBHB levels by less than 50%, Increasing the assay sample volume increases brain tissue DBHB levels . In the in vivo studies, the combination of MPTP and G3HB seemed to cause significant mortality in the two strains of mice that we used. This high mortality rate may be strain or breeding house dependent. More studies need to be done to sort this situation out.Personal Author S. Przedborski V. Jackson-Lewis
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Targeted Nanoparticles for Kidney Cancer Therapy

images[2]The objective of this proposal is to test targeted carbon nanotubes for their ability to thermally ablate kidney cancer. Carbon nanotubes (CNTs) are efficient transducers of near-infrared radiation (NIR) for laser-induced thermal therapy of kidney cancer in mouse models. Our goal is to improve the anti-tumor efficacy of CNTs by designing them to target cancer cells and surrounding endothelial cells following systemic administration. Specifically, we will develop carbon nanotubes that bind to uPAR, a surface receptor overexpressed in kidney cancers and supporting endothelium. We will use D5, a peptide designed in the laboratory, as the targeting ligand. In the past year, we developed a new chemical approach to conjugating the targeting peptide to nanotubes. We demonstrated that the peptide is cytotoxic to kidney cancer cells. We also showed that the combination of nanotubes and NIR is effective in inhibiting the clonogenic survival of cultured kidney cancer cells. Next year, we will assess the flow of nanotubes in the vasculature and their ability to accumulate and exert an anti-tumor effect in a mouse tumor model. This grant is a mentor/predoctoral award that also focuses on training of a predoctoral candidate. The predoctoral fellow carried out the experiments described in this progress report, attended the national AACR cancer meeting, presented his work in seminars, and was co-first author on an article on nanotubes as thermal ablation agents.
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Personal Author S. V. Torti