Lipidoid Nanoparticles with Simultaneous Multi-Gene Regulation for Cancer Therapy

描述（申请人提供）：癌症是美国的主要死因。2012年，估计有577，190名美国人死于癌症。基因突变，包括异常上调和下调，是癌症发生的主要原因。基因治疗，使用DNA作为药剂特异性地上调一个基因，而小干扰RNA（siRNA）特异性地下调一个基因。siRNA和pDNA治疗剂的优点包括高靶标选择性和特异性，以及靶向目前未用治疗选择解决的生物途径的潜力。目前的研究集中在通过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。由于癌症涉及细胞增殖和血管生成的多个靶点突变，因此我们认为，对一个突变的简单调控无法实现癌症的治愈。相反，我们认为，在不同的生物途径中同时控制致病基因可以有效地控制这些疾病。目前，还没有能够同时选择性上调和下调所需治疗靶点的药物。我们的目标是调节肿瘤细胞中的关键信号通路，从而抑制肿瘤细胞增殖并诱导肿瘤细胞死亡。在这 在这项研究中，我们提出了通过在单个纳米颗粒中同时施用抗Bcl-2 siRNA和p53 pDNA来调节多种信号传导途径。Bcl-2在调节细胞凋亡中起着关键作用。 细胞凋亡，其抑制导致促凋亡作用和肿瘤细胞死亡。p53是人类的肿瘤抑制基因。超过50%的癌症显示p53基因突变。p53被证明激活细胞周期检查点，而Bcl-2抑制细胞死亡。我们认为抗Bcl-2 siRNA和p53 pDNA的组合将诱导肿瘤细胞凋亡的协同效应。这种新方法结合了siRNA治疗和基因治疗的优势，为癌症治疗提供了新的视角。此外，通过仅使用一种类型的递送载体，我们可以减少来自额外载体的毒性的可能性，简化递送系统。 的制定方法，运输有效载荷到同一目标位置，并最大限度地提高所需的功能。通过利用siRNA和pDNA的不同组合用于不同的靶点，这个新平台还可以促进我们对不同治疗靶点之间相互作用的理解。我们将在各种细胞试验和动物模型中评估该平台，并将其应用于治疗肺癌，这是女性和男性最常见的癌症。我希望这个平台能够使科学家们在未来微调siRNA和pDNA的组合，用于特定个体的特定疾病治疗，从而推进个性化医疗领域。

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.