Combination Anticancer Nanopreparations of Novel Proapoptotic Drug and siRNA

新型促凋亡药物与siRNA联合抗癌纳米修复研究 目前的项目是我们CCNE计划的一个组成部分，该计划旨在开发、在体外表征、在动物模型中试验，并在工业环境中放大一套广泛的新型多功能 纳米载体用于将包括DNA、siRNA和诊断试剂在内的各种药物靶向输送到体内实体肿瘤，以用于癌症治疗和诊断，特别是对多药耐药(MDR)肿瘤。在一般计划中，这项建议将涵盖包含一种新型、强大的促凋亡剂siRNA[下调癌细胞防御机制(如Pgp)]和肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的纳米修复药物组合，TRAIL是一种新的有前景的选择性抗癌药物TNFa家族的细胞因子。这种组合胶束制剂将被肿瘤特异性靶向抗体(用于全身给药)或细胞穿透性TAT多肽(用于肿瘤内给药)进行额外修饰。我们的建议是基于几个相互关联的挑战。首先，对癌症的有效治疗，特别是在多药耐药肿瘤填充的情况下，是一项重要的医学需求。其次，许多新发现或合成的促凋亡抗癌药，通过上调癌细胞的凋亡机制，可以作为一种有效的手段结合试验来治疗癌症，但由于它们在体内的溶解性和低稳定性，现在不能作为实用药物。第三，siRNAs(下调肿瘤防御机制的siRNAs)在体内的稳定性非常低，并且存在多重传递问题。我们建议通过配制一种新的药物组合来克服这些挑战，这些药物是专门针对癌细胞和进入癌细胞的自组装药物纳米载体(脂核胶束)。这样的配方将允许对难溶的促凋亡药物进行有效的溶解，稳定药物或体内的siRNA，并将它们与靶向肿瘤试验一起有效地共传递。 因此，在总体组织框架内，这项提案将提供多功能 纳米修复胶束组合，以特异性地传递促凋亡药物，siRNA，和 试验对各种肿瘤，特别是对多药耐药肿瘤。

Combination anticancer nanopreparations of novel proapoptotic drug and siRNA The current project is an integral part of our CCNE proposal which aims to develop, characterize in vitro, test in animal models, and scale up in an industrial setting a broad set of novel multifuncfional nanocarriers for targeted delivery of various drugs including DNA, siRNA, and diagnostic agents to solid tumors in vivo for the purposes of cancer therapy and diagnostics, especially for multidrug resistant (MDR) tumors. Within the general program, this proposal will cover a combination nanopreparations containing a novel, powerful proapoptotic agent, siRNA [to downregulate cancer cell defense mechanisms (such as Pgp)], and Tumor necrosis factor-Related Apoptosis-inducing Ligand (TRAIL), a cytokine of the TNFa family, a novel promising, selective anti-cancer agent. This combination micellar preparation will be addifionally modified with a tumor-specific targeting antibody (for systemic administration) or with the cell-penetrating TAT peptide (TATp) for intratumoral administration). Our proposal is based on several interrelated challenges. First, effective therapy of a cancer, especially in the case of MDR tumors sfill represents an important medical need. Second, many newly discovered or synthesized proapoptofic anticancer agents, which could serve as an effective means to treat cancer in combination with TRIAL by upregulating apopototic mechanisms in cancer cells, cannot now serve as practical drugs because of their poor solubility and low stability in vivo. Third, siRNAs (that downregulate tumor defense mechanisms) have very low stability in the body and multiple delivery problems. We propose to overcome these challenges by formulafing a combination of new agents into self-assembling pharmaceutical nanocarriers (lipid-core micelles) specifically targeted to and into cancer cells. Such formulafions will allow for an efficient solubilizafion of a pooriy soluble proapoptofic drug, stabilization of the drug or a siRNA in the body, and their efficient co-delivery together with TRIAL into targeted tumors. Thus, within the overarching organizing framework, this proposal will provide multifunctional micellar combinations of nanopreparations to specifically deliver a proapoptotic drug, a siRNA, and TRIAL to various tumors, particularly, to MDR tumors.