This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glioblastomas are a subtype of the most common and aggressive group of primary brain tumors. A major issue in treating lioblastoma is that most potential drugs cannot reach the entire tumor. The core tends to have a weakened blood brain barrier (BBB) where drugs can enter, but the extensions of the tumor are around intact BBB and cannot be treated. The BBB is a tight seal of cells that lines the blood vessels in the brain controlling cerebral homeostasis and preventing toxins and other chemicals, which ake it into the blood stream, from entering the brain. The purpose of this project is to examine a series of nanoparticles that have been shown to carry a drug to the brain for safety and toxicity, and to determine their distribution within the brain when administered systemically. Poly(butylcyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 and loaded with an anti-cancer agent doxorubicin) have been shown to treat a specific type of brain tumor in rats. It is suggested that these NPs cross the blood brain barrier by adsorbing apolipoprotein, enabling the NP to cross the BBB using LDL receptors. Layer by layer (LbL)-technology(r) will be used to create nanocapsules (containing doxorubicin) made of layers of polyelectrolyte and apolipoprotein. We hypothesize that the outer layer of apolipoprotein will enable the LbL nanocapsules to cross the BBB using LDL receptors, similar to the PBCA. While much research has been conducted on the above-mentioned PBCA NPs, issues of toxicity and tissue distribution have not been elucidated. Additionally, no known research has investigated the proposed LbL nanocapsules.
Specific aims of this proposal include: (1) testing the safety and toxicity of NPs using a two-cell culture model of the BBB and rat tissues;(2) characterizing physicochemical properties of NPs, and their interaction with lipid BBB models;and (3) testing the distribution of nanoparticles through the rat BBB. By locating markers for tight junction proteins, astrocytes and degenerating neurons in the brain, we will be able to narrow down NP location and gain an additional measure of toxicity.
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