Decoy nanoparticles to disrupt cancer cell-stromal cell networks

诱饵纳米颗粒破坏癌细胞-基质细胞网络

• 批准号: 9102034
• 负责人: Zaver M. Bhujwalla
• 金额: $ 21.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102034
• 关键词: Attenuated; Binding; Biodistribution; Biomimetics; Blood Circulation; Breast Cancer Cell; Breast Cancer cell line; Breast cancer metastasis; CD44 Antigens; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cancer Survivor; Cell Communication; Cell Line; Cell Survival; Cell membrane; Cells; Characteristics; Collagen; Communication; Complementary DNA; Contrast Media; Detection; Development; Distant; Dose; ERBB2 gene; FDA approved; Fiber; Fibroblasts; Future; Glycolates; Health; Human; Image; Immune response; Injectable; Invaded; Label; Left; MDA MB 231; Malignant Neoplasms; Mediating; Membrane; Metastatic breast cancer; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Pattern; Peptides; Play; Positron-Emission Tomography; Primary Neoplasm; Radiolabeled; Radiosurgery; Reagent; Reporter; Role; Signal Transduction; Site; Small Interfering RNA; Source; Stromal Cells; Therapeutic; Toxic effect; Validation; Vesicle; base; biomaterial compatibility; cancer cell; chemotherapy; circulating cancer cell; distraction; effective therapy; high reward; high risk; in vivo; malignant breast neoplasm; migration; nanoparticle; novel; optical imaging; personalized medicine; prevent; radiotracer; receptor expression; stem; triple-negative invasive breast carcinoma; tumor; tumor growth

 DESCRIPTION (provided by applicant): Decoys are used in strategies to achieve distraction or misdirection. In this application we intend to develop biomimetic nanoparticles (NPs) that are covered with cancer cell membranes to act as decoys to misdirect or distract cancer cells, or cancer associated stromal cells. Stromal cells such as cancer associated fibroblasts (CAFs) mediate many of the aggressive characteristics of cancer but have reservoirs that are largely left intact by our current therapeutic strategies. Therefore following surgery or chemotherapy, a few surviving cancer cells that ordinarily would not survive on their own, continue to have a host of stromal cells to assist them in re- establishment, either at the primary site or at a distant site. Because of their important functional roles, destroying stromal cells that assist cancer cells is not a viable solution. Instead, disrupting communications between cancer cells and stromal cells may be a useful strategy. Once developed and characterized, the NPs will be evaluated for their ability to attach to cancer cells, and activated fibroblasts in circulation and at primary or distat tumor sites. These NPs will be decorated with an imaging reporter to characterize their biodistribution in vivo and ex vivo. Such NPs have not been previously developed for applications in cancer. Our ultimate purpose is to determine if these NPs attract circulating cancer cells, circulating stromal cells, or disrupt the spontaneous or experimental metastatic cascade in triple negative breast cancer. Since the CXCL12-CXCR4 axis has a wide spectrum of roles in facilitating breast cancer invasion and metastasis through breast cancer cell-CAF signaling, we will initially investigate the role of high and low CXCR4 expressing cancer cell membrane coated NPs in disrupting cancer cell-CAF interactions. CAFs also play a major role in the formation of collagen 1 (Col1) fibers in tumors. We can therefore evaluate the functional effects of these NPs on Col1 fiber patterns in primary and metastatic tumors. In the future, such NPs may be loaded with a therapeutic cargo for targeting the premetastatic niche or eliminating circulating cancer cells, or they may be used to assist in the activation of the immune response. These NPs can also, in the future, be labeled with MR contrast agents or radiolabeled for detection using human MR or PET scanners. These studies will potentially identify new, clinically translatable strategies to disrupt the metastatic cascade in breast cancer, and represent a new strategy in developing effective treatments to prevent metastatic breast cancer.

 描述（由申请人提供）：诱饵是用于战略，以实现分心或误导。在本申请中，我们打算开发覆盖有癌细胞膜的仿生纳米颗粒（NP），以作为诱饵来误导或分散癌细胞或癌症相关基质细胞。基质细胞如癌症相关成纤维细胞（CAF）介导癌症的许多侵袭性特征，但具有通过我们目前的治疗策略基本上保持完整的储库。因此，在手术或化疗后，一些通常不能自己存活的存活癌细胞继续具有基质细胞的宿主以帮助它们在原发部位或远处部位重建。 由于其重要的功能作用，破坏辅助癌细胞的基质细胞不是可行的解决方案。相反，破坏癌细胞和基质细胞之间的通讯可能是一种有用的策略。一旦开发和表征，将评估NP附着于癌细胞的能力，以及循环中和原发性或远端肿瘤部位的活化成纤维细胞。这些NP将用成像报告分子修饰以表征其体内和离体生物分布。这种纳米颗粒以前没有被开发用于癌症。我们的最终目的是确定这些NP是否吸引循环癌细胞、循环基质细胞，或破坏三阴性乳腺癌中的自发或实验性转移级联。由于CXCL 12-CXCR 4轴在通过乳腺癌细胞-CAF信号传导促进乳腺癌侵袭和转移中具有广泛的作用，我们将首先研究高和低CXCR 4表达的癌细胞膜包被的NP在破坏癌细胞-CAF相互作用中的作用。CAF还在肿瘤中胶原1（Col 1）纤维的形成中起主要作用。因此，我们可以评估这些NP对原发性和转移性肿瘤中Col 1纤维模式的功能影响。在未来，这样的纳米颗粒可以装载治疗性货物，用于靶向转移前小生境或消除循环癌细胞，或者它们可以用于帮助激活免疫应答。在未来，这些纳米颗粒也可以用MR造影剂标记或放射性标记，以便使用人类MR或PET扫描仪进行检测。这些研究将有可能确定新的、临床上可转化的策略来破坏乳腺癌的转移级联反应，并代表了开发有效治疗方法以预防转移性乳腺癌的新策略。