Gene Delivery Nanoparticles to Treat Glioblastoma

描述(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物基因传递纳米颗粒来治疗脑癌患者。根据我们最近对用于基因传递的聚合物纳米粒文库的评估研究，将合成10个铅结构，并利用它们将DNA非病毒且安全地传递到人类多形性胶质母细胞瘤(GB)癌细胞。10种密切相关的生物材料类似物和它们形成的纳米颗粒的构效关系将在体外在正常人星形胶质细胞和神经球以及人术中获得的GB细胞和GB肿瘤神经球中进行探索。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。将在体外和体内创建和评估纳米颗粒系统，以非病毒方式传递一种诱导人脑癌细胞凋亡的基因，该基因对健康的人类细胞是良性的，并以旁分泌方式发挥作用。非病毒颗粒进入细胞并安全降解，释放出DNA作为治疗药物，导致癌细胞死亡。在目标1中，将合成和表征纳米颗粒，并开发细胞分析。在目标2中，将在体外评估纳米粒的作用机制、细胞靶向性和有效性。在目标3中，排名前三的纳米颗粒配方将在原位人类GB小鼠模型中进行活体评估。这项工作的长期目标是创造一种新的治疗胶质母细胞瘤的正交临床方法。

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.