Combination Anticancer Nanopreparations of Novel Proapoptotic Drug and siRNA

新型促凋亡药物和siRNA的组合抗癌纳米制剂 目前的项目是我们CCNE提案的一个组成部分，该提案旨在开发，体外表征，动物模型测试，并在工业环境中扩大广泛的新型多功能药物组合物。 纳米载体用于将各种药物（包括DNA、siRNA和诊断剂）靶向递送至体内实体瘤，用于癌症治疗和诊断的目的，特别是用于多药耐药（MDR）肿瘤。在一般计划中，该提案将涵盖一种组合纳米制剂，含有一种新型的，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凋亡诱导配体（TRAIL），一种TNFa家族的细胞因子，一种新的有前途的选择性抗癌剂。该组合胶束制剂将另外用肿瘤特异性靶向抗体（用于全身施用）或用细胞穿透达特肽（TATp）（用于肿瘤内施用）修饰。我们的建议是基于若干相互关联的挑战。首先，癌症的有效治疗，特别是在MDR肿瘤填充的情况下，代表了重要的医疗需求。第二，许多新发现或合成的多产抗癌剂，其可以通过上调癌细胞中的凋亡机制而作为与TRIAL组合治疗癌症的有效手段，现在不能作为实用药物，因为它们在体内的溶解度差和稳定性低。第三，siRNA（下调肿瘤防御机制）在体内的稳定性非常低，并且存在多次递送问题。我们建议通过将新药物组合配制成自组装药物纳米载体（脂质核心胶束）来克服这些挑战，这些药物纳米载体特异性地靶向并进入癌细胞。这样的制剂将允许难溶性多产药物的有效增溶，药物或siRNA在体内的稳定，以及它们与TRIAL一起有效共递送到靶向肿瘤中。 因此，在总体组织框架内，本提案将提供多功能的 纳米制剂的胶束组合，以特异性递送促凋亡药物、siRNA和 TRIAL用于多种肿瘤，特别是MDR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.