Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors

脑部穿透性 DNA 纳米颗粒靶向递送至脑肿瘤

• 批准号: 9260870
• 负责人: Justin S. Hanes
• 金额: $ 51.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-12 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260870
• 关键词: Adenovirus Vector; Adhesives; Animal Model; Animals; Area; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; Cells; Clinic; Clinical; Clinical Trials; Contrast Media; Cytomegalovirus; DNA; DNA delivery; Data; Disease; Dose; Effectiveness; Esters; Excision; Extracellular Matrix; FDA approved; Family; Focused Ultrasound; Formulation; Future; Gene Delivery; Gene Expression; Gene Transfer; Genes; Genetic; Glioblastoma; Human; In Vitro; Injection of therapeutic agent; Intravenous; Lead; Magnetic Resonance Imaging; Malignant neoplasm of brain; Methods; Microbubbles; Modeling; Nature; Nucleic Acids; Operating Rooms; Parkinson Disease; Patients; Penetration; Polyethylene Glycols; Polymers; Price; Primary Brain Neoplasms; Prodrugs; Radiation; Rattus; Resected; Rodent; Safety; Suicide; System; Techniques; Technology; Testing; Time; Tissues; Toxic effect; Transfection; Translating; Translations; Tumor Tissue; aggressive therapy; base; biodegradable polymer; brain parenchyma; brain tissue; chemotherapy; clinical translation; density; gene therapy; gene therapy clinical trial; image guided; in vivo; minimally invasive; nanoparticle; neoplastic cell; nervous system disorder; neuropathology; novel strategies; preclinical study; prevent; promoter; public health relevance; success; suicide gene; targeted delivery; therapeutic gene; transgene expression; transgenic suicide gene; tumor; uptake; vector

 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.

 描述：胶质母细胞瘤 (GBM) 是最常见的原发性脑肿瘤，由于其高度侵袭性，它会迅速致死。积极的治疗包括切除，然后进行放疗和化疗，但即使采用最积极的治疗，中位生存期仍不足 20 个月。迫切需要新的方法。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遗传靶标，但迄今为止的临床试验未能提供有意义的益处。需要新的方法来克服长期以来在整个脑肿瘤中有效基因传递的障碍，包括无法完全切除且血脑屏障保持完整的高度侵袭性肿瘤前沿。我们提出了一种新方法，该方法利用：（i）图像引导将静脉注射的可生物降解的 DNA 负载纳米颗粒（DNA NP）集中输送到肿瘤的所有区域，（ii）先进的图像引导聚焦超声技术克服血脑屏障（BBB）并增强 DNA NP 输送到组织和细胞中，（iii）由 可生物降解的聚合物在体内非常有效，包括能够在脑组织内快速扩散，从而可以更有效地到达肿瘤内的细胞，以及（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）向患者大脑重复给药，以帮助控制或潜在治愈 GBM。我们将测试以下假设：使用聚焦超声技术将图像引导的基因递送至整个肿瘤（包括侵袭性肿瘤前沿）、能够快速穿透脑肿瘤组织并提供高体内转染的小型（~50 nm）且高度稳定的 DNA NP，以及肿瘤特异性基因表达启动子提供的额外控制程度，将在以下领域提供安全有效的 GBM 基因治疗： 可以根据需要重新应用来治疗疾病的动物。如果成功，所提出的方法可以使用广泛测试的自杀基因（如本文将要研究的那样）快速转化为临床，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标的疗法的有效性。该方法将来还可以应用于其他神经系统疾病，例如帕金森病。