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: 10541232
• 负责人: Justin S. Hanes
• 金额: $ 58.34万
• 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/10541232
• 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; Cytoprotection; Development; Diagnosis; Diffusion; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Engineering; Environment; Excision; Exposure to; Feedback; Focused Ultrasound; Formulation; Foundations; Generations; Glioblastoma; Glioma; Gliosis; 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; Polyethylene Glycols; 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; 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; tissue preparation; 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类脑肿瘤。即使接受手术治疗， 放疗和化疗，最常诊断的胶质瘤患者，IV 级胶质母细胞瘤 (GB)，预期寿命只有 14 个月。治疗 GB 的主要挑战是其高度侵袭性， 因为浸润的癌细胞受到“保护”，免受全身化疗的影响 血脑屏障（BBB）。在这里，我们建议开发一种 GB 治疗方法，该方法结合 通过 MRI 引导聚焦激活血管内微泡 (MB)，实现非侵入性血脑屏障开放 超声波 (FUS) 和可生物降解 [聚天冬氨酸-聚乙二醇 (PAA-PEG)]、顺铂 (CDDP)- 装载“大脑穿透纳米颗粒”。我们之前已经展示过“第一代”的功效 CDDP-BPN 制剂，FUS 能够精确地将 BPN 穿过 BBB 传递到 MR 图像- 大脑中选定的靶标，以及将 CDDP-BPN 递送至神经胶质瘤。 在这里，我们提出了四个具体目标，旨在显着提高治疗效果 方法并将其推进临床试验。在目标 1 中，我们将设计一个“下一代”CDDP-BPN 专门用于全身给药和 FUS 靶向递送的制剂。同时，目标 2 和 3 将 通过对 FUS 进行新颖的、临床上可操作的修改，显着增强 BPN 对侵袭性神经胶质瘤的递送 应用协议。这些措施包括根据 MRI 指导扩大治疗量、测试 BBB 打开期间“选址”声发射反馈的概念，并评估新确定的 FUS“预调节”脉冲序列能够提高 BPN 穿透力。值得注意的是，一个创新的新 目标 2 和 3 将采用 MR 图像引导的肿瘤间质流动和扩散传输分析 直接确定 FUS 如何调节肿瘤微环境以促进 CDDP-BPN 通过肿瘤细胞扩散 治疗量。然后目标 4 将首先确定 CDDP-BPN 的最大耐受剂量 (MTD) 和 使用优化的 FUS 方案评估 CDDP-BPN 递送后胶质瘤中的顺铂水平。接下来我们将进行测试 将下一代 CDDP-BPN 与新型 FUS 协议相结合以增强 BPN 传输是否会 控制肿瘤生长、阻止浸润并提高生存率。重要的是，我们即将在 UVA，其中 MR 图像引导 FUS（Insightec Exablate 神经系统）将与 MB 一起使用以打开 BBB 并在 GB 患者接受手术切除后每周进行化疗 辐射。此外，MPI Hanes 在推进药物控释制剂方面拥有丰富的经验 交付临床试验。由此，为翻译树立了明确的先例。鉴于我们的基础设施和 凭借专业知识，我们处于非常有利的位置，可以将成功的研究结果转化为临床。