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

基本信息

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
项目类别：
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

项目摘要

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，由于其高度侵入性的性质，它在很大程度上迅速而统一致命。侵略性疗法涉及切除，然后进行放射疗法和化学疗法，但即使使用最具侵略性的治疗仍少于20个月。迫切需要新的方法。由于最近已经确定了许多强大的遗传靶标，因此有效的GBM基因疗法具有吸引力，但临床试验迄今未能提供有意义的好处。需要在整个脑肿瘤中克服有效基因递送的长期障碍的新方法，包括无法完全切除的高度侵入性肿瘤前沿以及血液脑屏障保持完整的位置。我们提出了一种利用以下优势的新方法：（i）将静脉内化的可生物降解的可生物降解的DNA纳米颗粒（DNA NP）集中到肿瘤的所有区域，（ii）先进的图像引导的超声超声处理以克服血液脑屏障（BBB）和（bbb bbb）的（ii npn np np npn np），（ii）高级图像引导的超声处理（II）在体内高效的可生物降解聚合物，包括在脑组织内迅速扩散的能力，这可能使它们可以更有效地到达肿瘤内的细胞，以及（iv）肿瘤特异性启动子，从而消除了脱离目标时机中转化的表达。这种方法将允许以微创方式（仅注射静脉注射）重复给予患者的大脑，以帮助控制或潜在地治愈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 timings and providing high in vivo translation, and an additional degree of control provided by a tumor-specific gene expression promoter, will provide safe and effective GBM gene therapy in animals可以根据需要重新申请治疗该疾病。如果成功，则可以使用广泛测试的自杀基因迅速将提出的方法转化为诊所（在此处研究），同时进行了其他临床前研究，以测试针对GBM中新承诺的遗传靶标的疗法的有效性。将来，该方法也可以应用于其他神经系统疾病，例如帕金森氏病。