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

描述：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种有吸引力的治疗方式。许多能够干预胰腺恶性肿瘤通路的基因已经被发现，病毒基因治疗在抑制胰腺肿瘤方面显示出有效的效果。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。非病毒系统基因传递到肿瘤部位并进入肿瘤细胞受到几个强大障碍的阻碍。为了在系统给药后有效、安全和微创地将基因传递到实体肿瘤，传递平台必须(i)选择性地在肿瘤内积累，（ii）外渗并分布到肿瘤肿块深处以到达所有活的肿瘤细胞，最后（iii）介导靶细胞转染。提出的研究目标是设计一种新的传递平台，用于图像引导靶向遗传物质进入肿瘤。该平台的设计使其能够响应远程超声和磁性物理刺激，并对临床可行的超声成像模式可见。此外，类脂两亲性材料，称为类脂物质将被整合到平台中。一个大型的类脂物质组合文库将被构建并筛选它们整合到平台、捕获遗传物质和成功介导转染的能力。含有最佳表现的类脂质的平台将被装载质粒DNA，并在荷瘤小鼠中测试基因在肿瘤中的表达选择性和表达基因在肿瘤肿块深处的分布。一旦肿瘤选择性和肿瘤内深度渗透得到证实，该系统将在人类胰腺癌小鼠模型中进一步测试治疗效果，使用干扰素α质粒DNA作为模型基因治疗。这项研究的成功结果将使利用一类有效的基于核苷酸的治疗方法的价值，并为实现局部晚期胰腺癌的基因治疗提供临床可行的方法。

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.