Lipidoid Nanoparticles with Simultaneous Multi-Gene Regulation for Cancer Therapy

描述（由申请人提供）：癌症疾病是美国的主要死亡原因。2012年，预计577,190美国人将死于癌症。基因突变，包括异常的上调和下调，是癌症发生的主要原因。基因治疗中，使用DNA作为药物制剂是特异性地上调某一基因，而小干扰RNA （small interfering RNA, siRNA）是特异性地下调某一基因。siRNA和pDNA治疗方法的优势包括高靶点选择性和特异性，以及靶向生物途径的潜力，目前没有治疗选择。目前的研究重点是通过siRNA或pDNA调节某些治疗靶点。然而，这并不是治疗癌症等复杂疾病的最佳策略。因为癌症涉及到细胞增殖和血管生成的多个靶点突变，我们认为简单调控一个突变并不能达到治愈癌症的目的。相反，我们认为，在不同的生物学途径中同时控制致病基因可能导致这些疾病的有效管理。目前，还没有一种药物能够同时选择性地上调和下调所需的治疗靶点。我们的目标是调节肿瘤细胞中的关键信号通路，从而抑制肿瘤细胞的增殖和诱导肿瘤细胞死亡。在这个

DESCRIPTION (provided by applicant): Cancer disease is a leading cause of death in U.S. In 2012, an estimated that 577,190 Americans are expected to die of cancer. Gene mutations, including abnormal up-regulation and down-regulation, are the major origins for cancer development. Gene therapy, the use of DNA as a pharmaceutical agent is specific to the up-regulation of one gene, while small interfering RNA (siRNA) is specific down-regulating one gene. The advantages of siRNA and pDNA therapeutics include high target selectivity and specificity, and the potential to target biological pathways currently not addressed with therapeutic options. Current studies focus on regulating certain therapeutic targets through either siRNA or pDNA. However, this is not the optimal strategy to treat complex diseases such as cancer. Because cancer involves multiple target mutations for cell proliferation and vascular generation, the simple regulation of one mutation cannot achieve the cure of cancer, in our opinion. Rather, it is the simultaneous control of pathogenic genes in different biological pathways that we believe could result in efficacious management of these diseases. At present, there are no medicines that are capable of selectively up-regulating and down-regulating desired therapeutic targets at the same time. Our goal is to regulate the key signaling pathways in tumor cells so that we can inhibit tumor cell proliferation and induce tumor cell death. In this study, we propose the regulation of multiple signaling pathways via simultaneous administration of anti-Bcl-2 siRNA and p53 pDNA in single nanoparticles. Bcl-2 plays a critical role in regulating cell apoptosis, the inhibition of which leads to pro-apoptotic effect and tumor cell death. p53 is tumor suppressor gene in humans. Over 50% of cancers show a mutation of the p53 gene. p53 was shown to activate cell cycle checkpoints, while Bcl-2 inhibited cell death. It is the combination of anti-Bcl-2 siRNA and p53 pDNA which we believe will induce a synergistic effect for tumor cell apoptosis. This novel approach combines the advantage of siRNA therapeutics and gene therapy and offers a new perspective on cancer treatment. Moreover, by using only one type of delivery vehicle, we can reduce the potential of toxicity from extra carriers, simplify the formulation method, transport the payloads to the same target location, and maximize the desired functions. By utilizing different combinations of siRNA and pDNA for diverse targets, this new platform could also facilitate our understanding of the interactions between different therapeutic targets. We will evaluate this platform in various cell assays and animal models and it will be applied for the treatment of lung cancer, the most common cancer in both women and men. It is my hope that this platform will enable scientists in the future to fine-tune the combination of siRNA and pDNA for specific disease treatment in specific individuals, thereby advancing the field of personalized medicine.