Decoy nanoparticles to disrupt cancer cell-stromal cell networks

 描述(由申请者提供)：在策略中使用诱饵来分散注意力或误导方向。在这项应用中，我们打算开发覆盖在癌细胞膜上的仿生纳米颗粒(NPs)，作为诱饵来误导或分散癌细胞或癌症相关基质细胞的注意力。基质细胞，如癌症相关成纤维细胞(CAF)，介导了癌症的许多侵袭性特征，但我们目前的治疗策略基本上保留了这些细胞的储存库。因此，在手术或化疗后，少数幸存的癌细胞通常无法自行存活，但仍有大量基质细胞帮助它们重建，无论是在原发部位还是在远处。 由于它们的重要功能，摧毁帮助癌细胞的基质细胞不是一个可行的解决方案。相反，干扰癌细胞和间质细胞之间的通讯可能是一个有用的策略。一旦开发和表征，将评估NPs附着于癌细胞和循环中激活的成纤维细胞以及原发或远端肿瘤部位的能力。这些NPs将被装饰上成像记者，以表征它们在体内和体外的生物分布。这种纳米粒子以前还没有被开发出来用于癌症。我们的最终目的是确定这些NPs是吸引循环癌细胞和循环基质细胞，还是干扰三阴性乳腺癌的自发或实验性转移级联。由于CXCL12-CXCR4轴具有广泛的作用，通过乳腺癌细胞-CAF信号促进乳腺癌的侵袭和转移，我们将初步研究高表达和低表达CXCR4的癌细胞膜包裹NPs在破坏癌细胞-CAF相互作用中的作用。CAF在肿瘤中胶原1(COL1)纤维的形成中也起着重要作用。因此，我们可以评估这些NPs对原发和转移性肿瘤中COL1纤维模式的功能影响。在未来，这种纳米粒子可能会被装载到治疗货物中，用于靶向转移前的利基或消除循环中的癌细胞，或者它们可能被用来帮助激活免疫反应。将来，还可以用磁共振造影剂标记这些NPs，或者用人类MR或PET扫描仪进行放射性标记。这些研究可能会发现新的、临床上可翻译的策略来阻断乳腺癌的转移级联反应，并代表着开发有效的治疗方法来预防转移性乳腺癌的新策略。

 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.