Gene Delivery Nanoparticles to Treat Glioblastoma

描述（由申请人提供）：脑癌，特别是胶质母细胞瘤（GB），是一种致命的疾病，迫切需要新的治疗方法。我们建议开发可生物降解的聚合基因递送纳米颗粒来治疗脑癌患者。基于我们最近对用于基因传递的聚合纳米颗粒文库的评估研究，我们将合成10个先导结构，并将其用于向人类多形性胶质母细胞瘤（GB）癌细胞进行非病毒和安全的DNA传递。十种密切相关的生物材料类似物及其形成的纳米颗粒的结构-活性关系将在体外正常人类星形胶质细胞和神经球以及术中获得的GB细胞和GB肿瘤神经球中进行探讨。我们假设，通过生物材料和纳米颗粒的选择，纳米颗粒可以靶向脑癌细胞和癌症干细胞而不是健康细胞。一个纳米粒子系统将被创建并在体外和体内进行评估，以非病毒递送一种基因，该基因诱导人类脑癌细胞凋亡，对健康的人类细胞是良性的，并以旁分泌方式起作用。非病毒颗粒进入细胞并安全降解，释放DNA作为导致癌细胞死亡的治疗药物。在目标1中，纳米颗粒将被合成和表征，并开发细胞分析。在第二部分中，我们将在体外评估纳米颗粒的作用机制、细胞靶向特异性和功效。在Aim 3中，前三种纳米颗粒制剂将在原位人GB小鼠模型中进行体内评估。这项工作的长期目标是创造一种新的正交临床方法来治疗胶质母细胞瘤。

DESCRIPTION (provided by applicant): Brain cancer, and in particular Glioblastoma (GB), is a deadly disease that is in critical need of new therapies. We propose to develop biodegradable polymeric gene delivery nanoparticles to treat patients with brain cancer. Based on our recent research on evaluating a library of polymeric nanoparticles for gene delivery, ten lead structures will be synthesized and utilized to non-virally and safely deliver DNA to human Glioblastoma Multiforme (GB) cancer cells. Structure-activity relationships for ten closely related biomaterial analogs and the nanoparticles that they form will be probed in vitro in normal human astrocytes and neurospheres as well human intraoperatively obtained GB cells and GB tumor neurospheres. We hypothesize that through biomaterial and nanoparticle selection, nanoparticles can be targeted to brain cancer cells and cancer stem cells over healthy cells. A nanoparticle system will be created and evaluated in vitro and in vivo to non-virally delivery a gene that induces apoptosis in human brain cancer cells, is benign to healthy human cells, and acts in a paracrine fashion. The non-viral particles enter cells and degrade safely, releasing DNA as therapeutics that causes cancer cell death. In Aim 1, nanoparticles will be synthesized and characterized and cell assays developed. In Aim 2, mechanisms of action, cell targeting specificity, and efficacy of the nanoparticles will be evaluated in vitro. In Aim 3, the top three nanoparticle formulations will be evaluated in vivo in an orthotopic human GB mouse model. The long-term aim of this work is to create a new orthogonal clinical approach to treat Glioblastoma.