Tumor Penetrating Peptides for Cancer Targeting

用于癌症靶向的肿瘤穿透肽

• 批准号: 8085532
• 负责人: ERKKI RUOSLAHTI
• 金额: $ 39.63万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085532
• 关键词: Adjuvant; Adverse effects; Antineoplastic Agents; Bacteriophages; Biochemical Genetics; Blood Vessels; Cells; Coupled; Dose; Drug Combinations; Extravasation; Glioblastoma; Goals; Homing; Image; Indium; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Molecular; Neuropilin-1; Normal tissue morphology; Pathway interactions; Penetration; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Preparations; Process; Protocols documentation; Regimen; Resistance development; Signal Pathway; Site; Solid Neoplasm; Specificity; System; Testing; Therapeutic Intervention; Time; Tissues; Treatment Efficacy; Tumor Tissue; base; cancer diagnosis; cancer therapy; design; fluorophore; improved; nanoparticle; neoplastic cell; prototype; research study; response; stem; tumor; Adjuvant; Adverse effects; Antineoplastic Agents; Bacteriophages; Biochemical Genetics; Blood Vessels; Cells; Coupled; Dose; Drug Combinations; Extravasation; Glioblastoma; Goals; Homing; Image; Indium; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Molecular; Neuropilin-1; Normal tissue morphology; Pathway interactions; Penetration; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Preparations; Process; Protocols documentation; Regimen; Resistance development; Signal Pathway; Site; Solid Neoplasm; Specificity; System; Testing; Therapeutic Intervention; Time; Tissues; Treatment Efficacy; Tumor Tissue; base; cancer diagnosis; cancer therapy; design; fluorophore; improved; nanoparticle; neoplastic cell; prototype; research study; response; stem; tumor

DESCRIPTION (provided by applicant): A major problem in cancer therapy is that anti-cancer agents do not adequately penetrate into tumor tissue. This proposal is based on recently identified tumor-homing peptides that specifically penetrate into tumors. These peptides contain both a tumor-specific homing sequence and a tissue-penetrating and cell-internalizing C-end Rule (CendR) motif. The CendR element in the tumor-penetrating peptides is cryptic, and proteolytically activated at the target site. Drug, fluorophore, and nanoparticle cargos attached to these peptides accumulate in tumors and penetrate deep into extravascular tumor tissue. Recent evidence produced with the prototype tumor-penetrating peptide, iRGD, indicates that it is not necessary to couple a cargo to the peptide for tumor-selective delivery; free iRGD activates a bulk transport pathway in the tumor which carries a co-injected drug or nanoparticle through the vascular wall and deep into the tumor tissue. This application proposes studies to provide detailed understanding of the tumor penetration process. Specifically, we propose (i) to define the molecular pathway of the transport pathway, (ii) to identify protease(s) that activate cryptic CendR elements in the tumor-penetrating peptides, (iii) to optimize the ability of the peptides to selectively increase tissue permeability in tumors, and (iv) to test selected peptide-anti-cancer drug combinations in treatment studies. The ability to specifically increase the accumulation of anti-cancer drugs in tumors is an advance of broad ramifications. It promises to make it possible to deliver drugs to tumors at higher concentrations than permitted by standard therapies. According to our results, the increase can be as high as 40 fold. Because the increase in drug concentration only occurs in tumors and not in normal tissues, the efficacy of the treatment is increased while the side effects remain the same. Alternatively, the dose could be reduced without compromising the efficacy of the treatment. As the adjuvant peptide and anti-cancer drug are not coupled to one another, a validated and an approved tumor-penetrating peptide could be used to augment any cancer drug - a major advance in cancer therapy could ensue. PUBLIC HEALTH RELEVANCE: We have discovered peptides that specifically increase the accumulation of co-injected drugs in tumors, which enhances the anti-cancer activity of the drugs. The peptides activate an extravasation and tissue-penetration pathway. We propose to characterize this transport pathway and use the information to develop compounds that are optimal for the use of this system in tumor therapy.

描述（由申请人提供）： 癌症治疗的一个主要问题是，抗癌药不能充分渗透到肿瘤组织中。该提案基于最近鉴定出的肿瘤肽，这些肿瘤是特异性渗透到肿瘤中的肽。这些肽既包含肿瘤特异性的归巢序列，又包含组织渗透和细胞内部化的C端规则（CENDR）基序。肿瘤穿透肽中的CENDR元素是隐秘的，并且在靶位部位激活蛋白水解。附着在这些肽上的药物，荧光团和纳米颗粒肉肉积聚在肿瘤中，并深入血管外肿瘤组织。原型肿瘤穿透肽IRGD产生的最新证据表明，不必将货物与肽相结合以进行肿瘤选择性递送。自由IRGD激活肿瘤中的散装运输途径，该肿瘤将共同注射的药物或纳米颗粒穿过血管壁，并深入肿瘤组织。该应用建议的研究旨在提供对肿瘤穿透过程的详细了解。 Specifically, we propose (i) to define the molecular pathway of the transport pathway, (ii) to identify protease(s) that activate cryptic CendR elements in the tumor-penetrating peptides, (iii) to optimize the ability of the peptides to selectively increase tissue permeability in tumors, and (iv) to test selected peptide-anti-cancer drug combinations in treatment studies.特异性增加抗癌药物在肿瘤中的积累的能力是广泛分析的进步。它有望使与标准疗法允许的浓度更高的肿瘤输送药物。根据我们的结果，增加可以高达40倍。由于药物浓度的增加仅发生在肿瘤中，而在正常组织中不发生，因此治疗的功效增加，而副作用保持不变。另外，可以减少剂量而不会损害治疗的疗效。由于辅助肽和抗癌药物不相互偶联，因此可以使用经过验证和经批准的肿瘤渗透肽来增强任何癌症药物 - 可能会发生癌症治疗的重大进展。 公共卫生相关性： 我们发现肽特异性增加了共同注射药物在肿瘤中的积累，从而增强了药物的抗癌活性。肽激活渗出和组织渗透途径。我们建议表征该传输途径，并使用这些信息来开发用于在肿瘤治疗中使用该系统的最佳化合物。