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%）癌症患者发生脑转移，典型的预期寿命仅为3-6个月。化疗很少有效，因为全身施用的药物以非常低的浓度到达脑转移，这是由于（i）“血肿瘤屏障”（BTB），其由异质血管渗透性和高间质压产生，（ii）血脑屏障（BBB），其“保护”肿瘤边缘上的浸润癌细胞，和（iii）纳米多孔和带静电的组织空间，这限制了扩散。在克服这些障碍的有效策略出现之前，脑转移患者不会从免疫治疗中受益。为了解决这个问题，我们组建了一个由工程师、生物学家和临床医生组成的团队，他们在图像引导药物输送、纳米医学和免疫治疗方面具有专业知识。我们的目标是通过结合靶向BTB/BBB开放（MRI引导聚焦超声和微泡）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）的技术与增强T细胞浸润和细胞毒性抗肿瘤功能的策略，设计脑转移的图像引导免疫疗法。我们的方法得到了初步研究的支持，初步研究首次显示，通过使用聚焦超声递送非病毒纳米颗粒，在大脑中实现了稳健和持续的转基因表达。 该提案包括三个目标。在目标1中，我们将开发治疗递送平台，由此通过聚焦超声介导的脑穿透纳米颗粒的递送来有效地转染脑内B16黑色素瘤。目标1a将是设计有效穿透和切除B16肿瘤的纳米颗粒，而目标1b和1c将是开发一种安全有效的MRI引导方法。在目标2中，我们提出通过聚焦超声靶向递送信号转导子和转录激活子3（STAT 3）干扰脑穿透纳米颗粒来抑制免疫抑制并控制肿瘤生长。STAT 3在黑色素瘤转移中具有组成性活性，并且在许多免疫抑制途径中至关重要，因此STAT 3 RNA干扰（RNAi）应该是增强肿瘤免疫和抑制生长的最高效方法之一。最后，在目标3中，我们提出通过超声靶向递送编码被识别为外来抗原的脑穿透纳米颗粒来增强抗肿瘤免疫细胞浸润和功能并控制肿瘤生长。本质上，我们的目标是通过用宿主（流感免疫的HLA-A2小鼠，其通过M1识别流感）识别为外源性的抗原（M1基质蛋白）高效转染肿瘤和树突状细胞来引发针对B16的免疫性记忆回忆应答。我们假设，M1转染将协同增强肿瘤内的免疫细胞浸润，在血脑屏障开放引起记忆回忆反应，包括在肿瘤和颈深淋巴结内的有效M1特异性次级效应T细胞群的指数扩增。