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（由申请人提供）：许多（20%-40%）癌症患者会出现脑转移，这种情况的典型预期寿命仅为 3-6 个月，因为全身给药的药物到达脑转移的浓度非常低。由于 (i) “血肿瘤屏障”(BTB)，它是由不均匀的血管通透性和高间质压力形成的，(ii) 血脑屏障（BBB），它“保护”肿瘤边缘的浸润癌细胞，以及（iii）限制扩散的纳米孔和带静电的组织空间，在克服这些障碍的有效策略出现之前，脑转移患者将不会从免疫治疗中受益。为了解决这个问题，我们组建了一支由工程师、生物学家和新人组成的团队，他们在图像引导药物输送、纳米医学和免疫疗法方面拥有专业知识，我们的目标是设计针对大脑的图像引导免疫疗法。我们的方法是将靶向 BTB/BBB 打开（MRI 引导的聚焦超声和微泡）和改善脑组织渗透（具有密集聚乙二醇化生物惰性表面的纳米颗粒）技术与增强 T 细胞浸润和细胞毒性抗肿瘤功能的策略相结合。初步研究表明，通过聚焦超声输送非病毒纳米粒子，可以在大脑中实现稳健且持续的转基因表达。该提案由 3 项组成。在目标 1 中，我们将开发治疗传递平台，通过聚焦超声介导的脑穿透纳米粒子的传递来有效地转染脑内 B16 黑色素瘤。目标 1a 将设计能够有效穿透和转染 B16 肿瘤的纳米粒子。目标 1b 和 1c 将开发一种安全有效的 MRI 引导方法。在目标 2 中，我们建议抑制免疫抑制并控制肿瘤。通过聚焦超声靶向传递信号传感器和转录激活剂 3 (STAT3) 干扰脑穿透纳米粒子来促进生长，STAT3 在黑色素瘤转移中具有持续活性，并且在许多免疫抑制途径中至关重要，因此 STAT3 RNA 干扰 (RNAi) 应该属于其中。最后，在目标3中，我们提出增强抗肿瘤免疫细胞。本质上，我们的目标是通过高效转染肿瘤和 B16 来引发针对 B16 的免疫治疗记忆回忆反应。具有被宿主（流感免疫的 HLA-A2 小鼠，通过 M1 识别流感）识别为外源的抗原（M1 基质蛋白）的树突状细胞。转染将在 BBB 打开期间与肿瘤内免疫细胞浸润协同作用，引发记忆回忆反应，包括肿瘤和颈深淋巴结内有效的 M1 特异性次级效应 T 细胞群的指数扩张。