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疗法治愈，这一事实表明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），与药物结合后可自组装成纳米颗粒，与传统药物相比，其在肿瘤中表现出较长的循环半衰期和良好的蓄积性。免费药物。候选者假设，基于以下观察，转移起始细胞 (MIC) 的侵袭行为可用于使用负载抗 MIC 药物盐霉素 (Sali) 的 CP 纳米颗粒进行药物输送：(a) 纳米级药物载体积聚在肿瘤的血管周围区域； (b) MIC 穿过血管周围空间迁移并侵入血管，作为其转移的第一步；(c) MIC 依靠局部细胞外基质 (ECM) 中有效的肽酶活性来降解 ECM，从而促进其迁移。我们将利用这三个事实来设计一种纳米级递送系统，通过负载 Sali 的 CP 纳米颗粒专门针对 MIC。该提案的总体假设将通过以下三个目标进行检验：（1）Sali将与一系列具有不同组成、物理化学性质和分子量的CP缀合，以系统地改变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 的颗粒，并量化其体内稳定性； (3) 侵袭相关蛋白酶、基质金属蛋白酶 2 (MMP2) 的肽底物将被整合到 CP 的一级氨基酸序列中，并产生 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。所提出的药物载体系统将是第一个利用 MIC 的移动性进行药物输送的系统，这项研究可能会带来一种治疗癌症转移的新疗法。候选人的总体职业目标是成为一名在纳米技术和癌症治疗领域做出贡献的独立研究者。这一目标得到了候选人之前出色的培训和研究生产力的支持。通过这个职业发展奖，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治疗领域的著名研究者； （二）与其职业顾问委员会密切互动，在委员会的指导下完成职业转型； （3）产生研究成果，这不仅可以作为他申请未来癌症纳米技术联邦资助的基础。这项研究与公共卫生相关，因为它将带来治疗癌症转移的创新治疗策略。 公共健康相关性：该研究项目与公共健康相关，因为该项目的成果将带来更好的预防肿瘤转移治疗策略的创新，并且所产生的知识对于抗转移治疗的未来发展很有价值。该研究项目还为癌症纳米技术研究的未来科学家提供培训机会。