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

描述：局部晚期胰腺癌目前还没有治愈方法，患者在确诊后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的基因已经被开发出来，病毒基因治疗在抑制胰腺肿瘤方面显示出了良好的效果。然而，严重的安全性问题破坏了病毒载体的治疗前景，并点燃了寻找非病毒替代品的热情。非病毒系统的基因传递到肿瘤部位和进入肿瘤细胞受到几个强大的障碍的阻碍。为了便于在全身给药后有效、安全和微创地将基因输送到实体肿瘤，输送平台必须(I)选择性地在肿瘤内蓄积，(Ii)渗出并深入肿瘤块以到达所有存活的肿瘤细胞，最后，(Iii)介导靶细胞的转染。这项拟议研究的目标是设计一种新的递送平台，用于图像引导将遗传物质靶向肿瘤。该平台被设计成对远程超声和磁物理刺激做出响应，并且对于临床可行的超声成像模式是可见的。此外，类脂两亲材料，称为类脂类，将被整合到平台中。将构建和筛选一个大型的类脂材料组合文库，以确定它们是否能够整合到平台中，捕获遗传物质，并成功地介导转染。含有表现最好的类脂的平台将被装载上质粒DNA，并在荷瘤小鼠身上测试肿瘤中基因表达的选择性和表达基因在肿瘤块深处的分布。一旦证实了肿瘤的选择性和对肿瘤的深层渗透，该系统将在使用干扰素α质粒DNA作为模型基因治疗的人类胰腺癌小鼠模型上进一步测试治疗效果。这项研究的成功结果将允许利用一类强有力的基于核苷酸的治疗方法的价值，并提供一种临床上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还没有治愈方法，患者在确诊后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。

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.