Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors

 描述：胶质母细胞瘤(GBM)是最常见的原发脑肿瘤，由于其高度侵袭性，其致命性迅速而均匀。侵袭性治疗包括切除、放疗和化疗，但即使是最具侵略性的治疗，中位生存期也不到20个月。迫切需要新的方法。一种有效的GBM基因疗法很有吸引力，因为最近已经确定了许多强大的基因靶点，但临床试验到目前为止还没有提供有意义的好处。需要新的方法来克服长期存在的阻碍基因在整个脑肿瘤中有效传递的障碍，包括高侵袭性的肿瘤前沿，这些肿瘤无法完全切除，血脑屏障保持完好。我们提出了一种新的方法，该方法利用：(I)图像引导，将静脉注射的可生物降解DNA载药纳米粒(DNA NP)集中于肿瘤的所有区域，(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进入组织和细胞的输送，(Iii)DNA NP由体内高效的可生物降解聚合物制成，包括在脑组织内快速扩散的能力，使其能够更有效地到达肿瘤内的细胞，以及(Iv)肿瘤特异性启动子，消除非靶标组织中的转基因表达。这种方法将允许以微创的方式重复给药(仅静脉注射。注射)进入患者的大脑，以帮助控制或潜在地治愈GBM。我们将检验这样一种假设：使用聚焦超声技术，通过图像引导将基因递送到整个肿瘤(包括侵袭性肿瘤前沿)，小的(~50 nm)且高度稳定的DNA纳米粒能够快速穿透脑肿瘤组织并提供高体内转染率，加上肿瘤特异性基因表达启动子提供的额外程度的控制，将在动物身上提供安全有效的GBM基因治疗，并可根据治疗该疾病的需要重复应用。如果成功，建议的方法可以使用广泛测试的自杀基因迅速转化到临床上(正如这里将研究的那样)，同时进行更多的临床前研究，以测试针对GBM新的有希望的基因靶点的治疗的有效性。这种方法未来也可以应用于其他神经疾病，如帕金森氏症。

 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.