Inhibition of metastasis-initiating cells by chimeric polypeptide nanoparticles

摘要 目前只有不到10%的转移性肿瘤可以通过现有疗法治愈，这一事实证明需要更多的治疗。 治疗这些肿瘤的有效策略。本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。K99/R 00提案的申请人最近设计了一个 一种新型多肽药物载体，嵌合多肽（CP），它在药物上自组装成纳米颗粒， 结合，并且其显示出较长的循环半衰期和在肿瘤中良好的积累，与 免费药物该候选人假设转移起始细胞（MIC）的侵袭行为可能是 用于使用装载有抗MIC药物盐霉素（Sali）碱的基于CP的纳米颗粒的药物递送 基于以下观察：（a）纳米级药物载体在肿瘤的血管周围区域中积累;（B） MIC通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依赖于局部细胞外基质（ECM）中的有效肽酶活性来降解ECM， 他们的迁徙。我们将利用这三个事实来设计一个纳米级的输送系统， 通过装载Sali的CP纳米颗粒靶向MIC。本提案的总体假设是 通过以下三个目的进行测试：（1）Sali将与具有不同组成的一系列CP缀合， 理化性质和分子量，以系统地改变CP-盐的体内稳定性 （2）连接触发了CP-Sali缀合物自组装成亚100 nm直径的 将量化颗粒及其体内稳定性;（3）侵袭相关的肽底物 蛋白酶，基质金属蛋白酶2（MMP 2），将被掺入到一级氨基酸序列中， CP和由此产生的MMP 2依赖性切割、细胞摄取、细胞毒性和转移- 将研究CP（MMP 2）-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，该研究可能导致癌症的新疗法 转移候选人的总体职业目标是成为一名独立的调查员， 纳米技术与癌症治疗的结合这一目标是由候选人的良好的事先培训支持 研究生产力。通过这个职业发展奖，候选人将：（1）获得额外的 在Ashutosh Chilkoti博士和Mark W. Dewhirst，谁是众所周知的 研究人员在纳米技术和癌症治疗，分别;（2）密切互动，他的职业顾问 委员会，并在委员会的指导下完成职业转型;（3）进行研究 这不仅是他申请未来联邦癌症基金的基础， 纳米技术这项研究与公共卫生有关，因为它将导致一种创新的治疗方法。 癌症转移的治疗策略。

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.