Focused ultrasound pre-conditioning for augmented nanoparticle penetration in infiltrative gliomas

聚焦超声预处理增强纳米颗粒在浸润性神经胶质瘤中的渗透

• 批准号: 10375573
• 负责人: Justin S. Hanes
• 金额: $ 58.66万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375573
• 关键词: Absorbable Implants; Accounting; Acids; Acoustics; Address; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; Bypass; Cessation of life; Cisplatin; Clinic; Clinical; Clinical Trials; Convection; Couples; Development; Diagnosis; Diffusion; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Engineering; Environment; Excision; Exposure to; Feedback; Focused Ultrasound; Formulation; Foundations; Generations; Glioblastoma; Glioma; Growth; Histology; Human; Immunocompetent; Immunohistochemistry; Implant; Infiltration; Infrastructure; Investigational Therapies; Lead; Libraries; Life Expectancy; Magnetic Resonance Imaging; Malignant - descriptor; Maximum Tolerated Dose; Measures; Mediating; Microbubbles; Modeling; Modification; Mus; Nature; Operative Surgical Procedures; Paper; Patient Recruitments; Patients; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Physiologic pulse; Physiological; Positioning Attribute; Primary Brain Neoplasms; Property; Protocols documentation; Publishing; Radiation; Radiation therapy; Rattus; Reproducibility; Safety; Scheme; Site; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Translating; Translations; Treatment Efficacy; Tumor Tissue; Vision; astrogliosis; base; brain tissue; cancer cell; chemotherapy; clinical translation; contrast enhanced; controlled release; design; experience; image guided; image-guided drug delivery; improved; in vivo; innovation; interstitial; nanoparticle; nanoparticle delivery; next generation; novel; preconditioning; pressure; quantum; screening; stability testing; stem cells; success; targeted delivery; temozolomide; tumor; tumor growth; tumor microenvironment; ultrasound

Gliomas are the most common malignant human brain tumors. Even when treated with surgery, radiotherapy, and chemotherapy, patients with the most commonly diagnosed glioma, grade IV glioblastoma (GB), have a life expectancy of only 14 months. The primary challenge to treating GB is its highly invasive nature, as infiltrating cancer cells are “protected” from exposure to systemically administered chemotherapies by the blood brain barrier (BBB). Here, we propose the development of a therapeutic approach for GB that couples non-invasive BBB opening via the activation of intravascular microbubbles (MBs) with MRI-guided focused ultrasound (FUS) and biodegradable [polyaspartic acid-polyethyleneglycol (PAA-PEG)], cisplatin (CDDP)- loaded, “brain-penetrating nanoparticles”. We have previously demonstrated the efficacy of “first-generation” CDDP-BPN agents, the ability of FUS to precisely target the delivery of BPN across the BBB to MR image- selected targets in the brain, and the delivery of CDDP-BPN to gliomas. Here, we propose four specific aims designed to markedly improve the therapeutic efficacy of the approach and advance it to clinical trials. In Aim 1, we will engineer a “next-generation” CDDP-BPN for formulation specifically for systemic administration and FUS-targeted delivery. In parallel, Aims 2 and 3 will be to markedly augment BPN delivery to invasive gliomas via novel, clinically-operable, modifications to FUS application protocols. These will include extending treatment volumes based on MRI guidance, testing the concept of “site-selective” acoustic emissions feedback during BBB opening, and evaluating newly identified FUS “pre-conditioning” pulse sequences for their ability to increase BPN penetration. Of note, an innovative new MR image-guided transport analysis of tumor interstitial flow and diffusion will be employed in Aims 2 and 3 to directly ascertain how FUS modulates the tumor microenvironment to facilitate CDDP-BPN spread though the treatment volume. Aim 4 will then start by establishing the maximum tolerated dose (MTD) of CDDP-BPN and assessing cisplatin levels in gliomas after CDDP-BPN delivery using optimized FUS protocols. Next, we will test whether combining next-generation CDDP-BPN with novel FUS protocols for augmented BPN delivery will control tumor growth, block infiltration, and improve survival. Importantly, we are about to open a clinical trial at UVA wherein MR image-guided FUS (Insightec Exablate Neuro System) will be used with MBs to open the BBB and deliver chemotherapy on a weekly basis to GB patients after they have undergone surgical resection and radiation. Moreover, MPI Hanes has deep experience with advancing controlled-release formulations for drug delivery to clinical trials. Thus, a clear precedent has been set for translation. Given our infrastructure and expertise, we are exceptionally well-positioned to translate successful findings to the clinic.

神经胶质瘤是最常见的恶性人脑肿瘤。即使接受手术治疗 放疗和化学疗法，患有最常见的神经胶质瘤的患者IV级胶质母细胞瘤 （GB），只有14个月的预期寿命。治疗GB的主要挑战是其高度侵入性的性质， 由于浸润性癌细胞受到“保护”的“保护” 血脑屏障（BBB）。在这里，我们建议开发一种伴侣的GB治疗方法 通过血管内微泡（MB）激活MRI引导的非侵入性BBB开放 超声（FUS）和可生物降解[聚天冬氨酸多甲基二聚糖（PAA-PEG）]，顺铂（CDDP） - 加载，“脑穿透纳米颗粒”。我们以前已经证明了“第一代”的效率 CDDP-BPN药物，FUS精确靶向BPN跨BBB的能力到MR图像 - 大脑中选定的靶标，以及将CDDP-BPN传递到神经胶质瘤中。 在这里，我们提出了四个特定目标，旨在显着提高 接近并将其推进到临床试验。在AIM 1中，我们将设计一个“下一代” CDDP-BPN 专门用于全身管理和FUS靶向输送的公式。同时，目标2和3将是 通过新颖的临床操作，对FUS进行新颖的修饰，明显地增强了BPN的BPN输送到侵入性神经胶质瘤 应用程序协议。这些将包括根据MRI指导扩展治疗量，测试 BBB开放期间“现场选择性”声传输反馈的概念，并评估新鉴定 FUS“预处理”脉冲序列增加了BPN渗透的能力。值得注意的是，创新的新 MR图像引导的肿瘤间隙流和扩散的转运分析将在AIM 2和3中聘请 直接确定FUS如何调节肿瘤微环境以促进CDDP-BPN扩散 治疗量。然后，AIM 4将首先建立CDDP-BPN的最大耐受剂量（MTD）和 使用优化的FUS方案评估CDDP-BPN递送后神经胶质瘤中的顺铂水平。接下来，我们将测试 将下一代CDDP-BPN与新的FUS协议相结合以增加BPN的交付 控制肿瘤的生长，阻止浸润并改善生存率。重要的是，我们即将在 UVA其中MR图像引导的FUS（Insightec Exablate Neuro System）将与MB一起使用以打开BBB 并在GB患者进行手术切除和 辐射。此外，MPI Hanes在推进药物的受控释放配方方面具有丰富的经验 交付到临床试验。这是一个明确的先例进行翻译。考虑到我们的基础设施和 专业知识，我们非常适合将成功的发现转化为诊所。