Targeted Delivery of c-Myc Inhibitory Polypeptides

c-Myc 抑制性多肽的靶向递送

基本信息

批准号：
7267997
负责人：
DRAZEN RAUCHER
金额：
$ 13.65万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7267997
关键词：
Address Adverse effects Amino Acid Sequence Animal Model Antineoplastic Agents Biopolymers Cell Proliferation Cells Coupled Cultured Cells Data Development Elastin Engineering Excision Fever Goals HI peptide Heating Helix (Snails)Helix-Turn-Helix Motifs Human In Vitro Injection of therapeutic agent Intravenous Kinetics Local Hyperthermia Localized MCF7 cell Measures Mediating Methods Modeling Muscle Normal tissue morphology Nude Rats Oncogenes Operative Surgical Procedures Outcome Pathway interactions Peptides Physiological Plasma Play Protein Overexpression Quantitative Autoradiography Radiation Radiation therapy Radiolabeled Rattus Research Resistance Role Site Solid Neoplasm Solutions Specificity Staging System Temperature Testing Therapeutic Therapeutic Index Thigh structure Tissues Toxicity due to chemotherapy Treatment Efficacy Xenograft procedure aqueous base c-myc Genes c-myc Proto-Oncogenes cancer cell carcinogenesis cell growth regulation chemotherapy cytotoxicity design ear helix endozepine-like peptide ELP hyperthermia treatment implantation in vivo inhibitor/antagonist intraperitoneal mouse steroidogenic factor 1 neoplastic new technology polypeptide protein aminoacid sequence radiotracer size targeted delivery therapeutic target transcription factor tumor tumor growth tumor xenograft uptake

项目摘要

DESCRIPTION (provided by applicant): Current treatment of solid tumors is limited by inherent tumor resistance to radiation or chemotherapy and toxicity from systemic administration of antineoplastic 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. The c-Myc proto-oncogene is a transcription factor which plays a central role in the regulation of cell growth and differentiation, and its aberrant overexpression is associated with carcinogenesis. We have developed a thermally responsive polypeptide which inhibits c-Myc transcriptional activity and proliferation of cells in culture. Our hypothesis is that after systemic administration, 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 designed polypeptides is based on elastin-like (ELP) biopolymers which are soluble in aqueous solution below physiological temperature 37 degrees C, but aggregate when the temperature is raised above 41 degrees C. A cell-penetrating peptide (CPP) is conjugated to the ELP to facilitate cell entry. To the CPP-ELP is added a peptide from the helix-loop-helix region of c-Myc, called H1, which inhibits the c-Myc pathway. Our preliminary in vitro results demonstrate a very significant effect of the CPP- ELP-H1 construct in MCF7 cells when compared to a non-thermally responsive control peptide. In order to address the hypothesis, the following specific aims will be addressed: (1) Create a suitable animal model to test the hypothesis in vivo through implantation of the MCF7 cells in the thigh muscle of athymic rats, (2) Measure the plasma kinetics and in vivo distribution of CPP-ELP-H1 in normal and neoplastic tissue in an athymic rat model by determining the plasma concentration curve and determination of the tissue concentrations with quantitative autoradiography.and (3) Evaluate therapeutic efficacy of CPP-ELP-H1 in the treatment of neoplastic xenografts in the thigh of athymic rats with and without localized hyperthermia through repeated administration of the agent coupled with local hyperthermia. These studies will provide the basis for a new technology for targeted delivery of specific oncogene inhibitors. Specific targeting of the proposed therapeutic polypeptides to solid tumors by local hyperthermia would increase specificity and efficacy of treatment and reduce the cytotoxicity in normal tissues. Thus, development of the proposed polypeptide-mediated therapeutic delivery system would provide an alternative means to effectively substitute or augment present therapy for treatment of localized tumors. The successful completion of the proposed research will provide In vivo data to move this therapy towards the translational stage of human therapeutics.

描述（由申请人提供）：目前对实体瘤的治疗受到固有的肿瘤耐药性或化学疗法的抵抗力以及抗肿瘤剂的全身施用的毒性。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局限性，从而提高治疗的特异性和功效，并降低正常组织中的细胞毒性。 C-MYC原始癌基因是转录因子，在调节细胞生长和分化中起着核心作用，其异常过表达与癌变有关。我们已经开发了一种热响应的多肽，该多肽抑制了培养物中细胞的C-MYC转录活性和细胞的增殖。我们的假设是，在全身给药后，基因工程性多肽可以通过施加局部热疗来靶向肿瘤部位。这将导致肿瘤中该药物的积累，随后抑制肿瘤生长。设计的多肽的氨基酸序列基于弹性（ELP）生物聚合物，这些生物聚合物可在生理温度下方的水溶液中溶于37摄氏度以下的水溶液中，但是当温度升高到41摄氏度以上时，聚集在C.一个细胞渗透肽（CPP）以上时，可将细胞渗透肽（CPP）构成ELP，可构成细胞的细胞进入。向CPP-ELP添加来自C-MYC的螺旋环螺旋区的肽，称为H1，该肽抑制了C-MYC途径。我们的初步体外结果表明，与非热反应式对照肽相比，MCF7细胞中CPP-H1构建体的效果非常重要。 In order to address the hypothesis, the following specific aims will be addressed: (1) Create a suitable animal model to test the hypothesis in vivo through implantation of the MCF7 cells in the thigh muscle of athymic rats, (2) Measure the plasma kinetics and in vivo distribution of CPP-ELP-H1 in normal and neoplastic tissue in an athymic rat model by determining the plasma concentration curve and determination of the具有定量自显影的组织浓度。（3）评估CPP-ELP-H1在无局部大鼠大腿中的肿瘤异种移植物治疗和没有局部过度热的大腿中的治疗功效，通过反复给予局部过度疗法的药物与局部高温治疗。这些研究将为针对特定的癌基因抑制剂的新技术提供基础。通过局部高温对拟议的治疗多肽对实体瘤的特定靶向将提高治疗的特异性和功效，并降低正常组织中的细胞毒性。因此，提出的多肽介导的治疗递送系统的开发将提供有效替代或增强目前治疗局部肿瘤的替代方法。拟议的研究的成功完成将提供体内数据，以将这种疗法转移到人类疗法的转化阶段。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative.

DOI：
10.1016/j.ijpharm.2012.07.043
发表时间：
2012-10-15
期刊：
International journal of pharmaceutics
影响因子：
5.8
作者：
Walker L;Perkins E;Kratz F;Raucher D
通讯作者：
Raucher D

Inhibition of ovarian cancer cell proliferation by a cell cycle inhibitory peptide fused to a thermally responsive polypeptide carrier.

DOI：
10.1002/ijc.24725
发表时间：
2010-01-15
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Massodi, Iqbal;Moktan, Shama;Rawat, Aruna;Bidwell, Gene L., III;Raucher, Drazen
通讯作者：
Raucher, Drazen

Thermal targeting of an acid-sensitive doxorubicin conjugate of elastin-like polypeptide enhances the therapeutic efficacy compared with the parent compound in vivo.