Immunotherapeutic Nanoparticle Delivery to Melanoma With MR-Guided Focused Ultrasound

通过 MR 引导聚焦超声将免疫治疗纳米颗粒递送至黑色素瘤

• 批准号: 9267820
• 负责人: TIMOTHY N BULLOCK
• 金额: $ 51.93万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267820
• 关键词: Address; Agitation; Animals; Antigens; Artificial nanoparticles; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; Cancer Patient; Cell membrane; Cells; Charge; Clinical; Clinical Trials; Complex; Deep Cervical Lymph Node; Dendritic Cells; Diffusion; Drug Kinetics; Electrostatics; Endothelium; Engineering; Focused Ultrasound; Genes; Goals; Growth; HLA-A2 Antigen; Human; Immune; Immune response; Immunize; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Infiltration; Influenza; Investigational Therapies; Life Expectancy; Magnetic Resonance Imaging; Maximum Tolerated Dose; Mediating; Metastatic malignant neoplasm to brain; Methods; Microbubbles; Mus; Neoplasm Metastasis; Oncogenic; Pathway interactions; Patients; Penetration; Perfusion; Permeability; Pharmaceutical Preparations; Plasmids; Polymers; Population; Positioning Attribute; Price; Proteins; Protocols documentation; RNA Interference; Radiation therapy; Solid Neoplasm; Stat3 protein; Surface; System; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Transfection; Transgenes; Translating; Transmembrane Transport; Treatment Efficacy; Tumor Immunity; Ultrasonography; base; brain tissue; cancer cell; cancer immunotherapy; chemotherapy; cytotoxic; design; image guided; image-guided drug delivery; improved; in vivo; interstitial; melanoma; memory recall; mind control; nanomedicine; nanoparticle; neoplastic cell; outcome forecast; pressure; public health relevance; response; small hairpin RNA; targeted delivery; therapy outcome; transgene expression; tumor; tumor growth

 DESCRIPTION (provided by applicant): Many (20%-40%) cancer patients develop brain metastases, a condition with a typical life expectancy of only 3-6 months. Chemotherapy is seldom effective because systemically administered drugs reach brain metastases in very low concentrations due to (i) the "blood-tumor barrier" (BTB), which is created by heterogeneous vessel permeability and high interstitial pressure, (ii) the blood-brain barrier (BBB), which "protects" infiltrating cancer cells on tumor margins, and (iii) the nanoporous and electrostaticaly charged tissue space, which limits diffusion. Until effective strategies for overcoming these barriers emerge, brain metastasis patients will not benefit from immunotherapy. To address this problem, we have assembled a team of engineers, biologists, and clinicians with expertise in image-guided drug delivery, nanomedicine, and immunotherapy. Our goal is to engineer image-guided immunotherapies for brain metastases by combining technologies for targeted BTB/BBB opening (MRI-guided focused ultrasound and microbubbles) and improved brain-tissue penetration (nanoparticles with densely PEGylated bioinert surfaces) with strategies for enhancing T-cell infiltration and cytotoxic anti-tumor function. Our approach is supported by preliminary studies showing, for the first time, robust and sustained transgene expression in the brain via the delivery of non-viral nanoparticles with focused ultrasound. This proposal consists of 3 aims. In Aim 1, we will develop the therapeutic delivery platform, whereby intracerebral B16 melanoma is effectively transfected via the focused ultrasound-mediated delivery of brain- penetrating nanoparticles. Aim 1a will be to engineer nanoparticles that effectively penetrate and transfect B16 tumors, while Aims 1b and 1c will be to develop an MRI-guided approach for safe and effective. In Aim 2, we propose to inhibit immunosuppression and control tumor growth by the focused ultrasound-targeted delivery of signal transducer and activator of transcription 3 (STAT3)-interfering brain-penetrating nanoparticles. STAT3 is constitutively active in melanoma metastases and critical in many immunosuppressive pathways, thus STAT3 RNA interference (RNAi) should be amongst the most highly effective methods for boosting tumor immunity and inhibiting growth. Finally, in Aim 3, we propose to enhance anti-tumor immune cell infiltration and function and control tumor growth by the ultrasound-targeted delivery of brain-penetrating nanoparticles that encode an antigen recognized as foreign. In essence, our objective is to elicit an immunotherapeutic memory recall response against B16 via the high-efficiency transfection of tumor and dendritic cells with an antigen (M1 matrix protein) recognized as foreign by the host (influenza-immunized HLA-A2 mice, which recognize influenza through M1). We postulate that M1 transfection will synergize with enhanced intratumor immune cell infiltration during BBB opening to elicit a memory recall response, including the exponential expansion of potent M1-specific secondary effector T-cell populations within the tumor and deep cervical lymph nodes.

 描述（由适用提供）：许多（20％-40％）癌症患者发展出脑转移，这种疾病的预期寿命仅为3-6个月。 Chemotherapy is seldom effective because systemically administered drugs reach brain metastases in very low concentrations due to (i) the "blood-tumor barrier" (BTB), which is created by heterogeneous vessel permeability and high interstitial pressure, (ii) the blood-brain barrier (BBB), which "protects" infiltrating cancer cells on tumor margins, and (iii) the nanoporous and electrostatically带电的组织空间，这限制了扩散。在克服这些障碍出现的有效策略之前，脑转移患者将不会受益于免疫疗法。为了解决这个问题，我们将一组工程师，生物学家和临床医生组成了图像引导的药物输送，纳米医学和免疫疗法方面的专业知识。我们的目标是通过将针对目标BTB/BBB开放的技术（MRI引导的集中超声和微泡）和改进的脑部组织渗透（纳米粒子（Nanoparticles）与脱氧生物剂表面）与增强T-Cell Infloction的策略相结合，并改善了脑组织渗透（Nanoparticle（Nanopartice）的策略，来设计针对脑转移的图像引导的免疫治疗。我们的方法得到了初步研究的支持，首次通过递送具有聚焦超声的非病毒纳米颗粒在大脑中的稳健和持续转化表达。该提议包括3个目标。在AIM 1中，我们将开发治疗递送平台，通过该平台，脑内B16黑色素瘤通过聚焦超声介导的脑穿透性纳米颗粒的递送有效地翻译。 AIM 1A将是对有效穿透和翻译B16肿瘤的纳米颗粒的工程纳米颗粒，而AIMS 1B和1C将开发MRI引导的方法以进行安全有效。在AIM 2中，我们建议通过集中的信号传感器的超声输送和转录3（STAT3）的激活因子（STAT3）介入脑渗透纳米颗粒来抑制免疫抑制和控制肿瘤的生长。 STAT3在黑色素瘤转移中一直活跃，在许多免疫抑制途径中至关重要，因此STAT3 RNA干扰（RNAI）应该是提高肿瘤免疫和抑制生长的最有效的方法之一。最后，在AIM 3中，我们建议通过超声靶向脑穿透纳米颗粒的递送来增强抗肿瘤免疫细胞浸润，功能和控制肿瘤的生长，该纳米颗粒编码被识别为异物的抗原。从本质上讲，我们的目标是通过用宿主识别为外国的抗原（M1基质蛋白）对肿瘤和树突状细胞的高效率转染对B16的免疫疗法记忆反应（流感 - 免疫化的HLA-A2小鼠，通过M1识别出影响）。我们假设M1转化将随着BBB开放期间的增强的肿瘤内免疫球体渗透而协同作用，以引起记忆召回响应，包括肿瘤内潜在M1特异性二级效应T细胞群体和深宫颈淋巴结的指数扩展。