INVESTIGATING NANOPARTICLE INTERACTIONS WITH MODELSOF THE BLOOD BRAIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 胶质母细胞瘤是最常见和最具侵袭性的原发脑肿瘤的一个亚型。治疗脂肪母细胞瘤的一个主要问题是，大多数潜在的药物不能覆盖整个肿瘤。核心往往有一个削弱的血脑屏障(BBB)，药物可以进入，但肿瘤的延伸部分是完整的BBB周围，无法治疗。血脑屏障是一种紧密的细胞密封，它排列在大脑中的血管上，控制着大脑的稳态，并防止毒素和其他化学物质进入大脑，使其进入血液流动。该项目的目的是检查一系列已被证明可将药物带入大脑的纳米颗粒的安全性和毒性，并确定系统给药时它们在大脑中的分布。聚氰基丙烯酸丁酯(PBCA)纳米粒子包被聚山梨酸酯80并负载抗癌剂阿霉素)已被证明可治疗一种特定类型的大鼠脑瘤。推测这些NPs通过吸附载脂蛋白而穿过血脑屏障，使其能够通过低密度脂蛋白受体穿过血脑屏障。逐层(LBL)-技术(R)将被用来创建由多层聚电解质和载脂蛋白层组成的纳米胶囊(包含阿霉素)。我们假设载脂蛋白的外层将使LBL纳米囊能够使用低密度脂蛋白受体穿过血脑屏障，类似于PBCA。虽然对上述PBCA纳米粒已经进行了大量的研究，但其毒性和组织分布的问题尚未阐明。 此外，还没有已知的研究对拟议的LBL进行调查 纳米胶囊。这项建议的具体目标包括：(1)测试 利用血脑屏障和大鼠组织的两细胞培养模型研究纳米粒子的安全性和毒性；(2)表征纳米粒子的物理化学性质，及其与脂质血脑屏障模型的相互作用；以及(3)测试 纳米颗粒在大鼠血脑屏障中的分布。通过在大脑中定位紧密连接蛋白、星形胶质细胞和退化神经元的标记，我们将能够缩小NP的位置，并获得另一种毒性措施。

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.