Nanotherapeutics for Synergistic Targeting of Myc in Prostate Cancer

C-Myc(Myc)的去调控与多种癌症的发病机制有关，在许多情况下 助长了他们的攻击性。人们对开发新的癌症疗法有极大的兴趣 以Myc为目标。已经报道了几种小分子抑制剂。然而，中国的发展 这些化合物受到许多问题的限制，包括新陈代谢快，生物利用度差，或 药物不能在肿瘤部位达到有效浓度。最近我们也发现， 抑制Myc导致谷氨酰胺：果糖-6-磷酸氨基转移酶-1(GFAT-1)上调， 几种癌细胞系中氨基己糖生物合成途径(HBP)中的限速酶。同时进行 Myc和GFAT-1的抑制导致对肿瘤细胞增殖的抑制急剧增加， 提示GFAT-1的上调可能是限制Myc疗效的另一个障碍 以抑制为主的治疗。这项应用的重点是开发改进的治疗策略 这不仅提高了向肿瘤组织的输送效率，而且同时阻断了Myc和Myc GFAT-1活动。这将通过开发一种多功能纳米载体来实现，该载体高度 有效地共递送小分子Myc抑制剂10058-F4和GFAT-1siRNA。三个具体目标将 在本申请中被继续使用。目标1将重点放在发展和体外表征 能有效协同合成10058-F4和GFAT-1siRNA的多功能载体。Aim 2将检查 10058-F4和GFAT-1siRNA在荷瘤小鼠体内的药代动力学和生物分布。目标3 将通过优化的方法研究联合传递10058-F4和GFAT-1siRNA的体内治疗效果 纳米载体。人类和小鼠前列腺癌模型都将用于这一应用。成功 这项研究的完成不仅可能导致开发一种新的递送系统，还可能导致一种新的 基于机制的治疗。

Deregulation of c-Myc (Myc) is implicated in the pathogenesis of various types of cancers and in many cases contributes to their aggressiveness. There has been enormous interest in developing new cancer therapies that are targeted at Myc. Several small molecule inhibitors have been reported. However, development of these compounds has been limited by a number of issues including rapid metabolism, poor bioavailability, or inability of the drug to reach effective concentrations at tumor sites. Recently, we have also discovered that inhibition of Myc leads to upregulation of glutamine:fructose-6-phosphate amidotransferase-1 (GFAT-1), the rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP) in several cancer cell lines. Simultaneous inhibition of Myc and GFAT-1 results in a drastic increase in the inhibition of the proliferation of tumor cells, suggesting that upregulation of GFAT-1 may represent another barrier that limits the effectiveness of Myc inhibition-based therapy. This application is focused on the development of an improved therapeutic strategy that not only improves the efficiency of delivery to the tumor tissues but also simultaneously blocks Myc and GFAT-1 activities. This will be achieved via the development of a multifunctional nanocarrier that is highly effective in codelivery of a small molecule Myc inhibitor, 10058-F4 and GFAT-1 siRNA. Three specific aims will be pursued in this application. Aim 1 will focus on the development and in vitro characterization of multifunctional carriers that are effective in co-formulating 10058-F4 and GFAT-1 siRNA. Aim 2 will examine the pharmacokinetics and biodistribution of both 10058-F4 and GFAT-1 siRNA in tumor-bearing mice. Aim 3 will investigate the in vivo therapeutic effect of codelivery of 10058-F4 and GFAT-1 siRNA via an optimal nanocarrier. Both human and murine prostate cancer models will be used in this application. Successful completion of this study may lead to not only the development of a new delivery system but also a new mechanism-based therapy.