A platform for image-guided, magneto-acoustic gene therapy of pancreatic cancer

图像引导胰腺癌磁声基因治疗平台

• 批准号: 8397980
• 负责人: Beata Chertok
• 金额: $ 5.19万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397980
• 关键词: Acoustics; Binding; Biological Assay; Cells; DNA; DNA Binding; Diagnosis; Disease; Dose; Engineering; Evaluation; Exhibits; Gene Delivery; Gene Expression; Genes; Genetic Materials; Goals; Head; Human; Image; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Interferon-alpha; Interferons; Kinetics; Lesion; Libraries; Library Materials; Lipids; Luciferases; Magnetism; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Microbubbles; Modality; Modeling; Molecular; Mus; Nucleotides; Outcome; Outcomes Research; Pancreas; Patients; Penetration; Pharmaceutical Preparations; Phase; Polymers; Procedures; Property; Reporter; Research; Safety; Screening procedure; Site; Solid Neoplasm; Stimulus; System; Tail; Testing; Therapeutic; Therapeutic Studies; Time; Transfection; Treatment Efficacy; Tumor Suppression; Ultrasonics; Ultrasonography; Viral; Viral Genes; Viral Vector; Xenograft procedure; base; combinatorial; design; dosage; gene therapy; imaging modality; in vivo; magnetic field; minimally invasive; mouse model; nanoparticle; neoplastic; neoplastic cell; novel; novel therapeutics; pancreatic neoplasm; plasmid DNA; post-doctoral training; response; selective expression; subcutaneous; therapeutic gene; tumor; tumor growth; vector

DESCRIPTION: Locally advanced pancreatic cancer currently has no cure and the patients die within 5-11 months of diagnosis. Localized gene therapy could offer an attractive treatment modality. Many genes able to intervene with the path of pancreatic malignancy have already been developed and viral gene therapy showed efficacy in pancreatic tumor suppression. Yet, severe safety concerns undermine therapeutic prospects of the viral vectors and have ignited the search for non-viral alternatives. The non-viral systemic gene delivery to the tumor site and into the tumor cells is hampered by several formidable barriers. To facilitate efficacious, safe and minimally-invasive gene delivery to solid tumors following systemic administration, the delivery platform has to (i) selectively accumulate within the tumor, (ii) extravasate and distribue deep into the tumor mass to reach all viable tumor cells and, finally, (iii) mediate target cell transfection. The goal of the proposed research is to engineer a novel delivery platform for image-guided targeting of genetic material into tumors. The platform is designed such that it is responsive to the remote ultrasonic and magnetic physical stimuli and visible to a clinically-viable ultrasound imaging modality. In addition, lipid-like amphiphilic materials, termed lipidoids will be integrated into the platform. A large combinatorial library of lipidoid materials will be constructed and screened for their ability to incorporate into the platform, entrap genetic material and successfully mediate transfection. The platform containing the best performing lipidoid will be loaded with the plasmid DNA and tested in tumor-bearing mice for selectivity of gene expression in the tumor and distribution of the expressed genes deep within the tumor mass. Once tumor-selectivity and deep-intratumoral penetration are confirmed, the system will be further tested for therapeutic efficacy in a mouse model of human pancreatic cancer using interferon alpha plasmid DNA as a model gene therapeutic. Successful outcomes of this research will allow harnessing the value of a potent class of nucleotide-based therapeutics and providing a clinically viable way to realize gene therapy for locally advanced pancreatic cancer. PUBLIC HEALTH RELEVANCE: Locally advanced pancreatic cancer currently has no cure and the patients die within 5-11 months of diagnosis. The goal of this project is to engineer a new therapeutic modality for the treatment of this devastating disease.

局部晚期胰腺癌目前无法治愈，患者在诊断后5-11个月内死亡。局部基因治疗可以提供一个有吸引力的治疗方式。许多能够干预胰腺恶性肿瘤的基因已经被开发出来，并且病毒基因治疗在胰腺肿瘤抑制中显示出有效性。然而，严重的安全性问题破坏了病毒载体的治疗前景，并引发了对非病毒替代品的研究。非病毒系统性基因递送到肿瘤部位和肿瘤细胞中受到几个强大障碍的阻碍。为了在全身施用后促进有效、安全和微创的基因递送至实体瘤，递送平台必须（i）选择性地在肿瘤内积聚，（ii）外渗并分布到肿瘤块深处以到达所有活的肿瘤细胞，以及最后，（iii）介导靶细胞转染。拟议研究的目标是设计一种新的递送平台，用于图像引导遗传物质靶向肿瘤。该平台被设计成使得其响应于远程超声和磁物理刺激并且对临床上可行的超声成像模态可见。此外，脂质样两亲性材料，称为类胡萝卜素将被整合到平台中。将构建一个大型的类胡萝卜素材料组合文库，并筛选它们掺入平台、捕获遗传物质并成功介导转染的能力。将质粒DNA加载到含有表现最好的类胡萝卜素的平台上，并在荷瘤小鼠中测试肿瘤中基因表达的选择性和肿瘤块深处表达基因的分布。一旦确认肿瘤选择性和肿瘤内深层渗透，将使用干扰素α质粒DNA作为模型基因治疗剂，在人类胰腺癌小鼠模型中进一步测试该系统的治疗功效。这项研究的成功结果将允许利用一类有效的基于核苷酸的治疗方法的价值，并提供一种临床可行的方法来实现局部晚期胰腺癌的基因治疗。 公共卫生相关性：局部晚期胰腺癌目前无法治愈，患者在诊断后5-11个月内死亡。该项目的目标是设计一种新的治疗方法来治疗这种毁灭性的疾病。