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.
Cancer a leading cause of death in U.S. involves multiple gene mutations in humans. My project is to develop nanomedicines to regulate these gene mutations simultaneously, which will prevent tumor growth and induce tumor cell death with greater efficacy than prior treatments. This new biotechnology platform will be a valuable asset for the treatment of cancer and other genetic disorders.
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|Dong, Yizhou; Love, Kevin T; Dorkin, J Robert et al. (2014) Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proc Natl Acad Sci U S A 111:3955-60|
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|Dong, Yizhou; Eltoukhy, Ahmed A; Alabi, Christopher A et al. (2014) Lipid-like nanomaterials for simultaneous gene expression and silencing in vivo. Adv Healthc Mater 3:1392-7|