Inhibition of metastasis-initiating cells by chimeric polypeptide nanoparticles

嵌合多肽纳米粒子对转移起始细胞的抑制

基本信息

批准号：
8704347
负责人：
Mingnan Chen
金额：
$ 24.08万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704347
关键词：
Achievement Address Advisory Committees Amino Acid Sequence Back Behavior Blood Circulation Blood Vessels Caliber Cancer Etiology Cells Cessation of life Characteristics Charge Deposition Development Dissociation Drug Carriers Drug Delivery Systems Drug Kinetics Enzymes Extracellular Matrix Foundations Funding Future Gelatinase A Goals Half-Life Invaded K-Series Research Career Programs Knowledge Lead Malignant Neoplasms Mentorship Molecular Weight Nanotechnology Neoplasm Metastasis Peptide Hydrolases Peptides Pharmaceutical Preparations Polymers Productivity Property Public Health Research Research Personnel Research Project Grants Research Training Scientist Site System Testing Therapeutic Training Work abstracting amphiphilicity base cancer therapy career chemical property clinical application cytotoxicity design improved in vivo inhibitor/antagonist innovation migration mortality nanocarrier nanoparticle nanoscale neoplastic cell novel particle polypeptide prevent salinomycin self assembly small molecule success treatment strategy tumor uptake

项目摘要

Abstract Less than 10% of metastatic tumors are curable by current therapies, a fact that warrants the need for more effective strategies to treat these tumors. The overall goal of this project is to develop a nanoscale drug carrier system to improve therapy of cancer metastases. The applicant of this K99/R00 proposal recently designed a novel polypeptide drug carrier, chimeric polypeptides (CP), which self-assembles into nanoparticles upon drug conjugation, and which displays a long circulation half-life and good accumulation in tumors, as compared to free drug. The candidate hypothesizes that the invasive behaviors of metastasis-initiating cells (MICs) can be utilized for drug delivery using CP-based nanoparticles loaded with an anti-MIC drug, salinomycin (Sali) base on the following observations: (a) nanoscale drug carriers accumulate in the perivasuclar region of tumors; (b) MICs migrate through the perivascular space and invade a blood vessel as their first step in metastasis, and (c) MICs rely on potent peptidase activities in the local extracellular matrix (ECM) to degrade the ECM facilitate their migration. We will leverage these three facts to design a nanoscale delivery system that specifically targets MICs via a CP nanoparticle that is loaded with Sali. The overall hypothesis of this proposal will be tested by the following three aims: (1) Sali will be conjugated with a range of CPs with varied composition, physico-chemical properties and molecular weights to systematically vary the in vivo stability of the CP-Sali conjugate; (2) the attachment triggered self-assembly of the CP-Sali conjugates into sub-100 nm diameter particles and their in vivo stability will be quantified; (3) a peptide substrate of an invasion-associated proteinase, matrix metalloproteinase 2 (MMP2), will be incorporated into the primary amino acid sequence of the CP, and the resulting MMP2-dependent cleavage, cellular uptake, cytotoxicity, and the metastasis- inhibitory activity of CP(MMP2)-sali conjugates will be studied. The proposed drug carrier system will be the first to exploit the mobility of MICs for drug delivery, and the study may lead to a novel therapy for cancer metastases. The overall career goal of the candidate is to become an independent investigator contributing at the interface of nanotechnology and cancer therapy. This goal is backed by candidate's excellent prior training and research productivity. Through this career development award, the candidate will: (1) acquire additional training under the mentorship of Dr. Ashutosh Chilkoti and Dr. Mark W. Dewhirst, who are well-known investigators in nanotechnology and cancer therapy, respectively; (2) closely interact with his career advisory committee and accomplish career transition under the guidance of the committee; (3) produce research results, which serve not only as a foundation for him to apply for future federal funding on cancer nanotechnology. This research is relevant to public health because it will lead to an innovative therapeutic strategy for the treatment of cancer metastasis.

抽象的不到 10% 的转移性肿瘤可以通过当前的疗法治愈，这一事实表明需要更多的治疗治疗这些肿瘤的有效策略。该项目的总体目标是开发纳米级药物载体改善癌症转移治疗的系统。该 K99/R00 提案的申请人最近设计了一个新型多肽药物载体，嵌合多肽（CP），在药物作用下自组装成纳米颗粒结合，与相比，它表现出较长的循环半衰期和在肿瘤中良好的积累免费药物。候选人假设转移起始细胞（MIC）的侵袭行为可以是用于使用负载抗 MIC 药物盐霉素 (Sali) 基的 CP 纳米颗粒进行药物输送根据以下观察结果：（a）纳米级药物载体在肿瘤的血管周围区域积聚； (二) MIC 通过血管周围空间迁移并侵入血管，这是其转移的第一步，并且 (c) MIC 依赖于局部细胞外基质 (ECM) 中有效的肽酶活性来降解 ECM 促进他们的迁徙。我们将利用这三个事实来设计一种纳米级输送系统，该系统专门用于通过负载 Sali 的 CP 纳米颗粒靶向 MIC。该提案的总体假设是通过以下三个目标进行测试：（1）Sali将与一系列具有不同成分的CP缀合，物理化学性质和分子量，系统地改变 CP-Sali 的体内稳定性共轭； (2) 连接触发 CP-Sali 缀合物自组装成直径小于 100 nm 颗粒及其体内稳定性将被量化； (3) 侵袭相关肽底物蛋白酶，基质金属蛋白酶 2 (MMP2)，将被整合到 CP，以及由此产生的 MMP2 依赖性切割、细胞摄取、细胞毒性和转移将研究 CP(MMP2)-sali 缀合物的抑制活性。拟议的药物载体系统将是首次利用 MIC 的移动性进行药物输送，该研究可能会带来一种新的癌症疗法转移。候选人的总体职业目标是成为一名独立调查员，为以下领域做出贡献纳米技术与癌症治疗的结合。这一目标得到了候选人之前出色的培训的支持和研究生产力。通过此职业发展奖，候选人将：(1) 获得额外的在著名的Ashutosh Chilkoti博士和Mark W. Dewhirst博士的指导下接受培训分别是纳米技术和癌症治疗领域的研究人员； (2)与他的职业咨询密切互动委员会并在委员会的指导下完成职业转型； (3) 生产研究结果不仅为他申请未来联邦癌症资助奠定了基础纳米技术。这项研究与公共卫生相关，因为它将带来创新的治疗方法治疗癌症转移的策略。