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.

胶质瘤是人类最常见的恶性脑肿瘤。即使接受手术治疗，