Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors

 产品说明：胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，并且在很大程度上由于其高度侵袭性的性质，其是快速且均匀致命的。积极的治疗包括切除术，然后是放疗和化疗，但即使是最积极的治疗，中位生存期仍然不到20个月。迫切需要新的办法。一种有效的GBM基因治疗是有吸引力的，因为许多强大的遗传靶点最近已经确定，但临床试验迄今未能提供有意义的好处。需要新的方法来克服在整个脑肿瘤中有效基因递送的长期障碍，包括无法完全切除的高度侵袭性肿瘤前沿和血脑屏障保持完整的地方。我们提出了一种新的方法，利用：（i）图像引导以将静脉内施用的可生物降解的装载DNA的纳米颗粒（DNA NP）的递送集中到肿瘤的所有区域，（ii）先进的图像引导聚焦超声技术以克服血脑屏障（BBB）并增强DNA NP递送到组织和细胞中，（iii）由在体内高度有效的可生物降解的聚合物制成的DNA NP，包括在脑组织内快速扩散的能力，这可以使它们更有效地到达肿瘤内的细胞，和（iv）消除脱靶组织中转基因表达的肿瘤特异性启动子。这种方法将允许以微创方式（仅静脉注射）重复给药到患者的大脑中，以帮助控制或潜在地治愈GBM。我们将检验以下假设的组合：使用聚焦超声技术，图像引导基因递送至整个肿瘤，包括侵袭性肿瘤前沿，小的（~50 nm）且高度稳定的DNA NP能够快速穿透脑肿瘤组织并提供高的体内转染，以及由肿瘤特异性基因表达启动子提供的额外程度的控制，将在动物中提供安全有效的GBM基因治疗，可以根据需要重新应用以治疗疾病。如果成功的话，所提出的方法可以使用广泛测试的自杀基因（如将在这里研究的）迅速转化为临床，同时进行额外的临床前研究以测试针对GBM中新的有希望的遗传靶点的疗法的有效性。这种方法在未来也可以应用于其他神经系统疾病，如帕金森病。

 DESCRIPTION: Glioblastoma (GBM) is the most common primary brain tumor and it is rapidly and uniformly fatal due in large part to its highly invasive nature. Aggressive therapy involves resection followed by radiation and chemotherapy, but median survival even with the most aggressive therapy is still less than 20 months. New approaches are desperately needed. An effective GBM gene therapy is attractive since numerous powerful genetic targets have been recently identified, yet clinical trials have failed to provide meaningful benefit thus far. New methods to overcome long-standing barriers to effective gene delivery throughout brain tumors are needed, including to the highly invasive tumor front that cannot be completely resected and where the blood brain barrier remains intact. We propose a new approach that takes advantage of: (i) image-guidance to focus the delivery of intravenously-administered biodegradable DNA-loaded nanoparticles (DNA NP) to all areas of the tumor, (ii) advanced image-guided focused ultrasound techniques to overcome the blood brain barrier (BBB) and enhance DNA NP delivery into the tissues and cells, (iii) DNA NP made of biodegradable polymers that are highly effective in vivo, including the capability to rapidly spread within the brain tissue that may allow them to more effectively reach cells within the tumors, and (iv) tumor-specific promoters that eliminate transgene expression in off-target tissues. This approach will allow repeated dosing in a minimally invasive manner (only i.v. injection) into the brains of patients to help control or potentially cure GBM. We will test the hypothesis that the combination of: image-guided gene delivery to the entire tumor, inclusive of the invasive tumor front, using focused ultrasound techniques, small (~50 nm) and highly stable DNA NP capable of rapidly penetrating brain tumor tissues and providing high in vivo transfection, and an additional degree of control provided by a tumor-specific gene expression promoter, will provide safe and effective GBM gene therapy in animals that can be reapplied as needed to treat the disease. If successful, the proposed approach could be translated to the clinic rapidly using widely-tested suicide genes (as will be studied here) while additional preclinical studies are performed to test the effectiveness of therapies directed to new promising genetic targets in GBM. The approach could also be applied to other neurological disorders in the future, such as Parkinson's disease.