Dual responsive nanoparticle for brain targeted drug delivery

由于血脑屏障（blood brain barrier，BBB）的存在，超过98%的分子不能进入脑组织.因此，可用于中枢神经系统疾病的药物不能有效地到达它们的靶点，并且不能表现出可接受的治疗效果。拟议研究的目标是开发一种高度选择性和有效的系统，用于药物递送到大脑中，并将其应用于金属离子螯合剂，可以溶解AB聚集体并抑制与阿尔茨海默病相关的AB斑块形成。我们假设，通过将两个靶向部分并入pH和氧化还原电位双重响应纳米凝胶中，金属离子螯合剂D-青霉胺（PA）和氯碘羟喹（CQ）可以选择性地靶向脑组织并减弱AB聚集。目的一是制备pH和氧化还原电位双重响应的纳米凝胶，探讨聚合物结构与纳米凝胶性能的关系。在目标2中，我们将螯合剂或荧光染料负载到具有两个脑靶向部分（转铁蛋白和谷胱甘肽）的双靶向双响应纳米凝胶（DTDR）中，并使用Transwell模型在体外测量DTDR功效和BBB渗透。螯合剂负载DTDR的神经保护作用将与游离药物对应物进行比较，并通过调整转铁蛋白、谷胱甘肽和聚乙二醇的密度进行优化。目的3评价荧光染料或螯合剂负载的脑靶向DTDR的体内疗效和血脑屏障穿透性。脑靶向荧光DTDR的组成将通过IVIS成像进行优化，以实现对小鼠脑组织的高选择性。通过在Tg 2576小鼠中使用体内微透析（IVM）测量细胞外脑AB来量化脑靶向PA或CQ负载的DTDR的治疗功效，并与它们的游离药物对应物进行比较。将分析IVM获得的PA和CQ浓度、脑组织中的Zn和Cu残留、免疫组织化学获得的淀粉样斑块沉积以及脑组织中的残留AB之间的相关性。并对DTDR纳米凝胶的药代动力学特性和全身毒性进行评价。这项研究的成功将大大增加可用于中枢神经系统疾病的药物的范围。

More than 98% of existing molecules cannot access the brain tissue because ofthe blood brain barrier (BBB). As a result, drugs that could be useful for central nervous system diseases cannot reach their targets efficiently and fail to exhibit acceptable therapeutic effect. The goal of the proposed research is to develop a highly selective and efficient system for drug delivery into the brain and to apply it to metal ion chelators that can solubilize AB aggregates and inhibit AB plaque formation associated with Alzheimer's disease. We hypothesize that by incorporating two targeting moieties into a pH and redox potential dual responsive nanogel, metal ion chelators, D-penicillamine (PA) and clioquinol (CQ) can be selectively targeted to the brain tissue and attenuate AB aggregation. Aim 1 is to develop a pH and redox potential dual responsive nanogel and explore the relationship between polymer structure and nanogel properties. In aim 2, we will load chelators or fluorescent dyes into dual targeted dual responsive nanogel (DTDR) with two braintargeting moieties (transferrin and glutathione) and measure DTDR efficacy and BBB penetration in vitro using a Transwell model. The neuroprotective effect of chelator-loaded DTDR will be compared with free drug counterparts and optimized by adjusting the densities of transferrin, glutathione, and polyethylene glycol. Aim 3 will assess the efficacy and BBB penetration of fluorescent dye or chelator-loaded brain-targeting DTDR in vivo. The composition of brain-targeted fluorescent DTDR will be optimized with IVIS imaging to achieve high selectivity for brain tissue in mice. The therapeutic efficacy of the brain-targeted PA or CQ-loaded DTDR will be quantified by measuring extracellular brain AB using in vivo microdialysis (IVM) in Tg2576 mice and compared with their free drug counterparts. Correlations between PA and CQ concentrations obtained from IVM, Zn and Cu residual in the brain tissue, amyloid plaque deposition from immunohistochemistry, and the residual AB in the brain tissue will be analyzed. Pharmacokinetic properties and systemic toxicity ofthe DTDR nanogel will also be evaluated. The success of this study should drastically increase the spectrum of drugs that can be developed for central nervous system diseases.