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

• 批准号: 8518265
• 负责人: Mingnan Chen
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518265
• 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

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％ 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 新型多肽药物载体，嵌合多肽（CP），它们会自组成在药物的纳米颗粒中 结合，并且显示出长长的循环半衰期和肿瘤中的良好积累 免费药物。候选人假设转移性细胞的侵入性行为（MIC）可以是 使用基于CP的纳米颗粒用于药物递送 在以下观察结果中：（a）纳米级药物载体积累在肿瘤的核酸果区域； （b） 麦克风迁移到血管周围空间，并入侵血管作为转移的第一步，并且 （c）MIC依靠局部细胞外基质（ECM）中有效的肽酶活性来降解ECM 他们的迁移。我们将利用这三个事实设计一个纳米级传递系统 通过装有sali的CP纳米颗粒靶向麦克风。该提议的总体假设将是 通过以下三个目的测试：（1）Sali将与一系列具有不同组成的CP结合， 物理化学特性和分子量，以系统地改变CP-SALI的体内稳定性 共轭； （2）触发CP-SALI偶联物的自组装成100 nm的自组装 颗粒及其体内稳定性将被量化； （3）侵入相关的肽底物 蛋白酶，基质金属蛋白酶2（MMP2）将掺入一级氨基酸序列中 CP以及所得的MMP2依赖性裂解，细胞摄取，细胞毒性和转移 将研究CP（MMP2）-Sali结合物的抑制活性。拟议的毒品载体系统将是 首先利用MIC的迁移率用于药物输送，这项研究可能导致新的癌症治疗 转移。候选人的总体职业目标是成为一名独立调查员 纳米技术和癌症治疗的界面。这个目标得到了候选人的出色培训的支持 和研究生产力。通过这个职业发展奖，候选人将：（1）获得额外 在Ashutosh Chilkoti博士和Mark W. Dewhirst博士的指导下进行培训，他们是著名的 纳米技术和癌症治疗的研究人员； （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过渡； （3）进行研究 结果，不仅为他申请未来联邦癌症资金的基础 纳米技术。这项研究与公共卫生有关，因为它将导致创新的治疗性 治疗癌症转移的策略。