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Thermally Targeted Delivery of Therapeutic Peptides

治疗性肽的热靶向递送

基本信息

批准号：
7670923
负责人：
DRAZEN RAUCHER
金额：
$ 13.94万
依托单位：
THERMALLY TARGETED THERAPEUTICS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7670923
关键词：
Address Adenocarcinoma Cell Adverse effects Amino Acid Sequence Animal Model Antineoplastic Agents Biopolymers Blood Circulation Breast Adenocarcinoma Breast Cancer Model Cell Culture Techniques Cell Cycle Cell Cycle Inhibition Cell Cycle Progression Cell Proliferation Cells Clinical Trials Code Coupled Data Dose Drug usage Elastin Engineering Excision Fever Goals Heating Human In Vitro Injection of therapeutic agent Kinetics Local Hyperthermia Mammary Neoplasms Measures Mediating Modeling Normal tissue morphology Operative Surgical Procedures Outcome Peptides Pharmaceutical Preparations Physiological Plasma Quantitative Autoradiography Radiation Radiation therapy Radiolabeled Rattus Research Resistance Rest Site Solid Neoplasm Solutions Specificity Staging Technology Temperature Therapeutic Therapeutic Index Tissues Toxic effect Toxicity due to chemotherapy Transition Temperature Treatment Efficacy Tumor Volume aqueous bactenecin base cancer cell cancer therapy chemotherapeutic agent chemotherapy cytotoxicity design in vivo inhibitor/antagonist intravenous administration neoplastic neoplastic cell new technology oncoprotein p21 polypeptide public health relevance radiotracer targeted delivery therapeutic target tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): Current treatment of solid tumors is limited by normal tissue tolerance, inherent tumor resistance to radiation or chemotherapy, and toxicity from systemic administration of antineoplastic agents. The result is a narrow therapeutic index for most current chemotherapeutic agents. Our long term goal is to overcome these limitations by developing a targeted therapeutic approach for localized tumors that increases the specificity and efficacy of the therapy and reduces the cytotoxicity in normal tissues. We have developed a thermally responsive polypeptide which inhibits cell cycle progression and proliferation of cancer cells in cell culture. The objective of the proposed research is to demonstrate that after systemic administration, these genetically engineered polypeptides can be targeted to the tumor site by applying local hyperthermia. This will results in accumulation of the agent in the tumor with subsequent inhibition of tumor growth. The amino acid sequence of the thermally responsive polypeptides is based on elastin-like (ELP) biopolymers, which are soluble in aqueous solution below physiological temperature (37 oC), but aggregate when the temperature is raised above 41 oC. A cell-penetrating peptide, Bactenecin (Bac) is conjugated to the ELP to facilitate cell entry. To the Bac-ELP is added a peptide derived from the cyclin- dependent kinase inhibitor p21, which inhibits the cell cycle. Our preliminary in vitro results demonstrate a very significant effect of the Bac-ELP-p21 construct in Mat BIII rat mammary adenocarcinoma cells when compared to a non-thermally responsive control peptide. Our hypothesis is that intravenously delivered thermally responsive cell cycle inhibitory polypeptides are likely to be cleared under physiological conditions (37 oC). However, they will accumulate in breast tumors, where externally induced local heat (40-42 oC) will be applied. The accumulated polypeptides will inhibit the cell cycle and consequently inhibit proliferation of the cancer cells. In order to address this hypothesis, the following specific aims will be addressed: (1) measure the plasma kinetics and in vivo distribution of Bac-ELP-p21 in normal and neoplastic tissue and (2) evaluate the therapeutic efficacy of Bac-ELP-p21 in the treatment of breast tumor in rats through repeated administration of the agent coupled with and without local hyperthermia. The successful completion of the proposed research will provide the basis for a new technology that has a competitive advantage over existing/alternate technologies. These studies will provide the in vivo data necessary to move this therapy towards the translational stage of human therapeutics. Specific targeting of the proposed therapeutic polypeptides to solid tumors by local hyperthermia would increase efficacy of the cancer treatment and reduce the cytotoxicity in normal tissues, and it would provide an alternative means to substitute or augment present therapy for treatment of localized tumors. PUBLIC HEALTH RELEVANCE: Current treatment of solid tumors is limited because only a small fraction of the administered dose of drug reaches the tumor site while the rest of the drug is distributed throughout the body. This causes undesirable side effects to normal tissues when drugs are used in the doses required to eradicate cancer cells. Our long term goal is to overcome this limitation by developing an approach that allows the therapeutics to be delivered specifically to the tumor site. This will increase the specificity of the therapy and reduce the toxicity in normal tissues.

描述（由申请人提供）：目前实体瘤的治疗受到正常组织耐受性、肿瘤对放射或化疗的固有抗性以及全身施用抗肿瘤药物的毒性的限制。结果是大多数当前化疗药物的治疗指数很窄。我们的长期目标是通过开发针对局部肿瘤的靶向治疗方法来克服这些限制，从而提高治疗的特异性和疗效并降低正常组织的细胞毒性。我们开发了一种热响应多肽，可抑制细胞培养物中癌细胞的细胞周期进程和增殖。该研究的目的是证明，在全身给药后，这些基因工程多肽可以通过局部热疗靶向肿瘤部位。这将导致药物在肿瘤中积聚，随后抑制肿瘤生长。热响应多肽的氨基酸序列基于类弹性蛋白（ELP）生物聚合物，其在低于生理温度（37℃）的水溶液中可溶，但当温度升高到41℃以上时会聚集。 Bactenecin (Bac) 是一种细胞穿透肽，与 ELP 缀合以促进细胞进入。 Bac-ELP 中添加了源自细胞周期蛋白依赖性激酶抑制剂 p21 的肽，可抑制细胞周期。我们的初步体外结果表明，与非热响应对照肽相比，Bac-ELP-p21 构建体在 Mat BIII 大鼠乳腺癌细胞中具有非常显着的作用。我们的假设是，静脉内递送的热响应细胞周期抑制多肽可能在生理条件下（37 oC）被清除。然而，它们会积聚在乳腺肿瘤中，并施加外部诱导的局部热量（40-42 oC）。积累的多肽将抑制细胞周期，从而抑制癌细胞的增殖。为了解决这一假设，将解决以下具体目标：（1）测量正常组织和肿瘤组织中 Bac-ELP-p21 的血浆动力学和体内分布；（2）通过重复给药联合或不联合局部热疗来评估 Bac-ELP-p21 在治疗大鼠乳腺肿瘤中的治疗效果。拟议研究的成功完成将为新技术提供基础，该新技术比现有/替代技术具有竞争优势。这些研究将提供将该疗法推向人类治疗转化阶段所需的体内数据。通过局部热疗将所提出的治疗性多肽特异性靶向实体瘤将提高癌症治疗的功效并降低正常组织中的细胞毒性，并且它将提供替代或增强目前治疗局部肿瘤的疗法的替代方法。公共卫生相关性：目前实体瘤的治疗是有限的，因为只有一小部分给药剂量到达肿瘤部位，而其余药物分布在全身。当以根除癌细胞所需的剂量使用药物时，这会对正常组织产生不良副作用。我们的长期目标是通过开发一种允许将治疗药物特异性输送到肿瘤部位的方法来克服这一限制。这将增加治疗的特异性并减少正常组织的毒性。