Tumor Penetrating Peptides for Cancer Targeting

用于癌症靶向的肿瘤穿透肽

• 批准号: 8624663
• 负责人: ERKKI RUOSLAHTI
• 金额: $ 39.25万
• 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/8624663
• 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.

描述(由申请人提供)： 癌症治疗中的一个主要问题是抗癌剂不能充分渗透到肿瘤组织中。这一建议是基于最近发现的肿瘤归巢多肽，这种多肽可以特异性地穿透到肿瘤中。这些多肽既包含肿瘤特异的归巢序列，也包含组织穿透和细胞内化的C末端规则(CEDR)基序。肿瘤穿透性多肽中的cendR元件是隐蔽的，并且在靶部位被蛋白水解性激活。药物、荧光团和附着在这些多肽上的纳米颗粒在肿瘤中积聚，并深入血管外肿瘤组织。肿瘤穿透性多肽原型IRGD的最新证据表明，没有必要将货物偶联到多肽上以进行肿瘤选择性递送；游离的IRGD激活了肿瘤中的一条大宗运输途径，该途径携带联合注射的药物或纳米颗粒穿过血管壁并深入肿瘤组织。这项应用提出了一些研究，以提供对肿瘤渗透过程的详细了解。具体地说，我们建议(I)确定转运途径的分子途径，(Ii)确定激活肿瘤穿透肽中隐藏的cendR元件的蛋白酶(S)，(Iii)优化多肽选择性增加肿瘤组织通透性的能力，以及(Iv)在治疗研究中测试选定的多肽-抗癌药物组合。能够特别增加抗癌药物在肿瘤中的积累是一个广泛分支的进步。它承诺使以高于标准疗法允许的浓度向肿瘤输送药物成为可能。根据我们的结果，涨幅可以高达40倍。由于药物浓度的增加只发生在肿瘤中，而不发生在正常组织中，因此在副作用保持不变的情况下，治疗的有效性得到了提高。或者，可以在不影响治疗效果的情况下减少剂量。由于辅助肽和抗癌药物不是相互偶联的，经过验证和批准的肿瘤穿透肽可以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。