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.

新型促凋亡药物和siRNA的抗癌组合 当前的项目是我们CCNE提案不可或缺的一部分，旨在开发，表征体外特征，在动物模型中进行测试并在工业环境中扩展一套广泛的新型多孔。 用于癌症治疗和诊断的目的，纳米载体针对各种药物的靶向输送，包括DNA，siRNA和诊断剂到体内实体瘤，尤其是用于多药耐药（MDR）肿瘤。在一般计划中，该提案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（例如PGP）]和肿瘤坏死因子相关的细胞凋亡诱导的配体（TRAIL），TNFA家族的细胞因子，一个新颖的镇定者，选择性镇定者，选择性镇定剂。这种组合的胶束制剂将通过肿瘤特异性靶向抗体（用于全身给药）或细胞穿透性TAT肽（TATP）进行添加修饰，以用于肿瘤内给药）。我们的建议基于几个相互关联的挑战。首先，癌症的有效疗法，特别是在MDR肿瘤的情况下，SFILL代表了重要的医疗需求。其次，许多新发现或合成的促丙型抗癌药，这些药物可以通过上调癌细胞中的凋亡机制来治疗癌症与试验的有效手段，因为它们的溶解度不佳，并且体内稳定性低，因此无法用作实用药物。第三，siRNA（下调肿瘤防御机制）的体内稳定性非常低，并且多个输送问题。我们建议通过将新代理的组合组合为自组装的药物纳米载体（脂质核胶束）来克服这些挑战，这些挑战是针对癌细胞和靶向癌细胞的。这种配方将允许有效的溶解度可溶性可溶性药物，体内药物或siRNA的稳定性，以及它们有效的共透递送以及对靶向肿瘤的试验。 因此，在总体组织框架内，该建议将提供多功能 纳米置胶的胶束组合，以特异性递送促凋亡药物，siRNA和 尤其是对MDR肿瘤的各种肿瘤的试验。