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

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）： 癌症治疗中的主要问题是抗癌剂不能充分渗透到肿瘤组织中。这一提议是基于最近鉴定的特异性渗透到肿瘤中的肿瘤归巢肽。这些肽含有肿瘤特异性归巢序列和组织穿透和细胞内化C末端规则（CendR）基序。肿瘤穿透肽中的CendR元件是隐蔽的，并且在靶位点被蛋白水解激活。药物，荧光团，和纳米颗粒货物连接到这些肽积累在肿瘤和渗透到血管外肿瘤组织深处。用原型肿瘤穿透肽iRGD产生的最新证据表明，不必将货物与肽偶联用于肿瘤选择性递送;游离iRGD激活肿瘤中的大量转运途径，其携带共注射的药物或纳米颗粒穿过血管壁并深入肿瘤组织。该申请提出了研究以提供对肿瘤穿透过程的详细理解。具体而言，我们提出（i）定义转运途径的分子途径，（ii）鉴定激活肿瘤穿透肽中隐蔽CendR元件的蛋白酶，（iii）优化肽选择性增加肿瘤组织渗透性的能力，以及（iv）在治疗研究中测试选定的肽-抗癌药物组合。特异性增加抗癌药物在肿瘤中积累的能力是广泛分支的进步。它有望使以比标准疗法所允许的更高浓度向肿瘤输送药物成为可能。根据我们的研究结果，增长可能高达40倍。由于药物浓度的增加仅发生在肿瘤中而不发生在正常组织中，因此治疗的功效增加，而副作用保持不变。或者，可以在不损害治疗功效的情况下减少剂量。由于佐剂肽和抗癌药物彼此不偶联，因此经验证和批准的肿瘤穿透肽可用于增强任何癌症药物-癌症治疗的重大进展可能随之而来。 公共卫生关系： 我们已经发现了特异性增加共注射药物在肿瘤中积累的肽，这增强了药物的抗癌活性。肽激活外渗和组织渗透途径。我们建议表征这种转运途径，并使用这些信息来开发最适合用于肿瘤治疗的该系统的化合物。