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: 8009726
• 负责人: Mingnan Chen
• 金额: $ 8.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009726
• 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; 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; public health relevance; salinomycin; self assembly; small molecule; success; treatment strategy; tumor; uptake

DESCRIPTION (provided by applicant): 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 perivascular 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. PUBLIC HEALTH RELEVANCE: This research project is relevant to public health because the achievements of this project will lead to innovation of a better therapeutic strategy to prevent tumor metastasis, and the knowledge generated is valuable for future development of the anti-metastasis therapy. The research project also provides training opportunity for future scientists in cancer nanotechnology research.

描述（由申请人提供）：不到10％的转移性肿瘤可以通过当前的疗法治愈，这一事实值得需要更有效的策略来治疗这些肿瘤。该项目的总体目标是开发一种纳米级药物载体系统，以改善癌症转移的治疗。该K99/R00提案的申请人最近设计了一种新型多肽药物载体嵌合多肽（CP），与药物相比，在药物共轭后，它们会在药物共轭后自组合成纳米颗粒，并显示出长长的循环半寿命和良好的肿瘤积聚。候选者假设转移性细胞（MIC）的侵入性行为可用于使用基于CP的基于CP的纳米颗粒，这些纳米颗粒载有以下观察结果：（a）纳米级药物携带者在肿瘤周围的纳米级药物携带者基础上基于以下观察结果：（A） （b）MIC通过血管周空间迁移，并侵入血管作为转移的第一步，（c）MIC依赖于局部细胞外基质（ECM）中有效的肽酶活性，以降解ECM促进其迁移。我们将利用这三个事实设计一个纳米级传递系统，该系统专门针对麦克风通过装有sali的CP纳米颗粒。该提案的总体假设将通过以下三个目的测试：（1）SALI将与一系列具有多种组成，物理化学特性和分子量的CP偶联，以系统地改变CP-Sali结合物的体内稳定性； （2）触发CP-SALI偶联物在低100 nm直径颗粒中的自组装及其体内稳定性的自组装； (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.拟议的药物载体系统将是第一个利用麦克风用于药物递送的迁移率的人，该研究可能导致对癌症转移的新疗法。候选人的总体职业目标是成为纳米技术和癌症治疗界面的独立研究人员。这一目标得到了候选人的出色培训和研究生产力的支持。通过这项职业发展奖，候选人将：（1）在Ashutosh Chilkoti博士和Mark W. Dewhirst博士的指导下获得额外的培训，他们分别是纳米技术和癌症疗法的著名研究者； （2）与他的职业咨询委员会紧密互动，并在委员会的指导下完成职业过渡； （3）产生研究结果，不仅为他申请未来联邦纳米技术资金的基础。这项研究与公共卫生有关，因为它将为治疗癌症转移而制定创新的治疗策略。 公共卫生相关性：该研究项目与公共卫生有关，因为该项目的成就将导致创新更好的治疗策略来预防肿瘤转移，并且所产生的知识对于抗糖症治疗的未来发展是有价值的。该研究项目还为癌症纳米技术研究的未来科学家提供了培训机会。