Combination Anticancer Nanopreparations of Novel Proapoptotic Drug and siRNA

新型促凋亡药物与 siRNA 联合抗癌纳米制剂

• 批准号: 7984269
• 负责人: Vladimir P Torchilin
• 金额: $ 85.39万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984269
• 关键词: Address; Animal Model; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Behavior; Biological; Biological Availability; Blood Circulation; CCNE1 gene; Cell Line; Cells; Chemicals; Clinical; Combined Modality Therapy; Critical Pathways; DNA; Defense Mechanisms; Development; Diagnosis; Diagnostic; Drug Carriers; Drug Combinations; Drug resistance; Family; Family member; Human; Image; In Vitro; Ligands; Lipids; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Medical; Micelles; Mind; Monoclonal Antibodies; Multi-Drug Resistance; New Agents; Nude Mice; Ovarian Carcinoma; Pancreatic Adenocarcinoma; Peptides; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phosphatidylethanolamine; Phosphotransferases; Physiological; Polyethylene Glycols; Polyethylenes; Preparation; Property; Research; Signal Transduction; Site; Small Interfering RNA; Solid Neoplasm; Solubility; Staging; Surface; Survival Rate; System; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Variant; Xenograft Model; base; cancer cell; cancer therapy; cell growth regulation; clinical application; cytokine; cytotoxicity; design; effective therapy; in vitro activity; in vitro testing; in vivo; inhibitor/antagonist; lung Carcinoma; manufacturing scale-up; mouse model; nanocarrier; nanoparticle; nanoparticulate; nanosystems; novel; overexpression; phosphatidylethanolamine; programs; scale up; survivin; targeted delivery; treatment strategy; tumor

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.

新型促凋亡药物与siRNA联合抗癌纳米制剂 当前的项目是我们 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一系列新型多功能 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的纳米载体，用于癌症治疗和诊断，特别是多药耐药 (MDR) 肿瘤。在总体计划中，该提案将涵盖一种组合纳米制剂，其中包含一种新型强效促凋亡剂、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，一种新型有前途的选择性抗癌剂）。这种组合胶束制剂将用肿瘤特异性靶向抗体（用于全身给药）或细胞穿透性 TAT 肽（TATp）进行额外修饰，用于瘤内给药）。我们的建议是基于几个相互关联的挑战。首先，癌症的有效治疗，特别是在耐多药肿瘤的情况下，代表着重要的医疗需求。其次，许多新发现或合成的促凋亡抗癌药物，与TRIAL联合使用，通过上调癌细胞的凋亡机制，可以作为治疗癌症的有效手段，但由于其溶解度差、体内稳定性差，目前无法作为实用药物。第三，siRNA（下调肿瘤防御机制）在体内的稳定性非常低，并且存在多种递送问题。我们建议通过将新药物组合配制到专门针对癌细胞的自组装药物纳米载体（脂质核心胶束）中来克服这些挑战。这样的制剂将允许难溶性促凋亡药物的有效溶解、药物或siRNA在体内的稳定、以及它们与TRIAL一起有效地共同递送至靶肿瘤中。 因此，在总体组织框架内，该提案将提供多功能 纳米制剂的胶束组合，可特异性递送促凋亡药物、siRNA 和 试验各种肿瘤，特别是耐多药肿瘤。