Intracellular delivery of proapoptotic peptide drugs for the treatment of cancer

用于治疗癌症的促凋亡肽药物的细胞内递送

• 批准号: 8456142
• 负责人: Patrick S. Stayton
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-09 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456142
• 关键词: Abnormal Cell; Address; Advanced Malignant Neoplasm; Adverse effects; Animals; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Biodistribution; Biomimetics; Biotin; Blood Circulation; Cancer Model; Cancerous; Caspase; Cause of Death; Cell Death; Cells; Cessation of life; Cisplatin; Clinical; Collaborations; Cytoplasm; Data; Development; Disulfide Linkage; Drug Delivery Systems; Drug Design; Drug Formulations; Effectiveness; Electron Microscopy; Family; Fred Hutchinson Cancer Research Center; Future; Gene Proteins; Growth; Human; Image; Intracellular Membranes; Lead; Luciferases; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measurement; Micelles; Molecular Sieve Chromatography; Molecular Weight; Monitor; NMR Spectroscopy; Operative Surgical Procedures; Ovarian Carcinoma; Paclitaxel; Pathway Analysis; Pathway interactions; Patients; Peptide antibodies; Peptides; Pharmaceutical Preparations; Phase; Polymers; Property; Proteins; Radiation; Recurrence; Research Personnel; Research Proposals; Resistance; Roche brand of trastuzumab; Scintillation Counting; Signal Transduction; Small Interfering RNA; Subgroup; System; Technology; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; United States; Validation; Xenograft Model; base; bioluminescence imaging; cancer cell; cancer therapy; chemotherapy; clinical application; clinically relevant; design; di-block copolymer; experience; fluorophore; improved; in vivo; indexing; intraperitoneal; light scattering; member; mitochondrial membrane; mouse model; neoplastic cell; novel therapeutics; ovarian neoplasm; polymerization; screening; small molecule; tumor; tumor growth; zeta potential; Abnormal Cell; Address; Advanced Malignant Neoplasm; Adverse effects; Animals; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Biodistribution; Biomimetics; Biotin; Blood Circulation; Cancer Model; Cancerous; Caspase; Cause of Death; Cell Death; Cells; Cessation of life; Cisplatin; Clinical; Collaborations; Cytoplasm; Data; Development; Disulfide Linkage; Drug Delivery Systems; Drug Design; Drug Formulations; Effectiveness; Electron Microscopy; Family; Fred Hutchinson Cancer Research Center; Future; Gene Proteins; Growth; Human; Image; Intracellular Membranes; Lead; Luciferases; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measurement; Micelles; Molecular Sieve Chromatography; Molecular Weight; Monitor; NMR Spectroscopy; Operative Surgical Procedures; Ovarian Carcinoma; Paclitaxel; Pathway Analysis; Pathway interactions; Patients; Peptide antibodies; Peptides; Pharmaceutical Preparations; Phase; Polymers; Property; Proteins; Radiation; Recurrence; Research Personnel; Research Proposals; Resistance; Roche brand of trastuzumab; Scintillation Counting; Signal Transduction; Small Interfering RNA; Subgroup; System; Technology; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; United States; Validation; Xenograft Model; base; bioluminescence imaging; cancer cell; cancer therapy; chemotherapy; clinical application; clinically relevant; design; di-block copolymer; experience; fluorophore; improved; in vivo; indexing; intraperitoneal; light scattering; member; mitochondrial membrane; mouse model; neoplastic cell; novel therapeutics; ovarian neoplasm; polymerization; screening; small molecule; tumor; tumor growth; zeta potential

DESCRIPTION (provided by applicant): Many cancers are thought to be caused by survival and growth of abnormal cells with impaired apoptotic machinery that, under normal circumstances, would undergo programmed cell death. Short peptides containing pro-apoptotic subgroups that antagonize the anti-apoptotic members have been developed as a means of restoring normal apoptotic signaling. However, cell specific peptide-based drugs that trigger apoptosis in cancerous cells while avoiding toxicity to healthy tissues have not yet achieved clinical utility. Despite the enthusiasm for peptide-based therapeutics, formidable obstacles persist that hinder their clinical application in humans with advanced cancer. Maintaining peptide stability and bioactivity as well as achieving targeted, intracellular delivery remain as major hurdles that must be overcome before these and other therapeutic peptides can be applied to in vivo systems and thereby realize their full potential. This proposal will bring together the Stayton Lab's drug delivery systems with the Press' labs clinical cancer experience to develop preliminary animal validation of functional proapoptotic peptide delivery in an ovarian cancer model. The unifying hypothesis underlying this research proposal is that facilitating tumor targeting, circulation stability, and translocation of proapoptotic peptides across intracellular membranes will augment their anti- tumor potency and substantially enhance their effectiveness. In addition, the project will evaluate the potential of antibody targeting in a xenograft model to enhance tumor localization using a herceptin-targeted carrier system. This project will take advantage of a strong cross-institutional collaboration between the Stayton group at UW and the Press group at the FHCRC to build strong preliminary data to support a future multi-investigator proposal around new peptide-based therapies for ovarian cancer.

描述（由申请人提供）：许多癌症被认为是由凋亡机制受损的异常细胞的生存和生长引起的，在正常情况下，这些机制会经历编程的细胞死亡。已经开发了含有抗凋亡构件的促凋亡亚组的短肽，作为恢复正常凋亡信号传导的一种手段。然而，基于细胞的基于特异性的肽药物会引发癌细胞凋亡，同时避免对健康组织毒性毒性，尚未达到临床实用性。尽管对基于肽的治疗药充满热情，但强大的障碍仍然阻碍了他们在晚期癌症的人类中的临床应用。维持肽稳定性和生物活性以及实现目标，细胞内递送仍然是必须克服的主要障碍，这些障碍必须在这些障碍和其他治疗性肽之前可以应用于体内系统，从而实现其全部潜力。该提案将与媒体实验室的临床癌症经验一起将Stayton Lab的药物输送系统汇总在一起，以在卵巢癌模型中开发功能性促凋亡肽递送的初步动物验证。这项研究建议的统一假设是，促进肿瘤靶向，循环稳定性和促凋亡肽在细胞内膜中的易位将增强其抗肿瘤效能并大大提高其效率。此外，该项目将评估异种移植模型中抗体靶向的潜力，以增强使用赫赛素靶向的载体系统来增强肿瘤定位。该项目将利用UW的Stayton Group与FHCRC的新闻集团之间的强大跨机构合作，以建立强大的初步数据，以支持围绕基于肽癌的新肽治疗的未来的多投资人提案。