Targeting smaller populations of circulating tumor clusters (CTC) with tumor-initiating and colonization potentials at distant sites in circulation remains a challenge as clusters possess both epithelial and mesenchymal characteristics. Bullet shaped ellipsoidal nanostructures of size 600 ± 11.3 nm (major axis) and 281.9 ± 5.3 nm (minor axis) with 2.2 aspect ratio were self-assembled using inorganic and organic GRAS biomaterials to preferentially target tumor-causing CTCs. Negatively-charged chondroitin sulfate in presence of gelatin guides unidirectional growth of calcium carbonate mesocrystals to form nanobullets, mediates CD44 targeting of CTCs. Switchable multi-responsive drug release profiles (temperature and pH) were recorded for nanobullets promoting spontaneous and efficient cell-killing. CD44 and E-cadherin overexpressing 'seeding' cell clusters of 170 ± 22 µm were developed as in vitro CTC model. pH responsive release of Dox into lysosome stimulates calcium influx resulting in cell death. CD44-blocked CTCs showed significantly reduced internalization when compared to CD44-expressing CTCs thereby confirming CD44 specific internalization of nanobullets. Significantly retarded expansion of clusters when shifted to cell adhesive surfaces depicts the potential of nanobullets against colonization of CTCs. Hence, newer insights on developed anisotropic ECM-mimetic nanohybrids would enhance targeted capture of tumor-initiating clusters in systemic circulation that would potentially reduce the progression of tumor in breast cancer patients.

中文翻译：

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针对乳腺癌的转移性循环肿瘤集群的ECM模拟多反应纳米球。

由于肿瘤簇具有上皮和间充质特征，因此以较小的循环肿瘤簇（CTC）群体为靶标，使其在循环的远处具有启动和定植的潜力，这仍然是一个挑战。使用无机和有机GRAS生物材料自组装了尺寸为600±11.3 nm（长轴）和281.9±5.3 nm（短轴），直径为2.2的子弹形椭圆形纳米结构，以优先靶向引起肿瘤的CTC。在明胶存在下带负电的硫酸软骨素可指导碳酸钙中间晶体的单向生长以形成纳米弹，介导CTC的CD44靶向。记录了可促进自发和有效细胞杀伤的纳米弹的可切换多响应药物释放曲线（温度和pH）。CD44和E-钙粘着蛋白过表达“种子” 开发了170±22 µm的细胞簇作为体外CTC模型。pH响应性的Dox释放到溶酶体中会刺激钙内流，导致细胞死亡。与表达CD44的CTC相比，CD44阻断的CTC显着降低了内在化，从而证实了纳米粒的CD44特异性内在化。当转移到细胞粘附表面时，簇的显着延迟的扩张描述了纳米粒对抗CTC定居的潜力。因此，对已开发的各向异性ECM模拟纳米杂化物的新见识将增强系统性循环中肿瘤起始簇的靶向捕获，这有可能减少乳腺癌患者的肿瘤进展。pH响应性的Dox释放到溶酶体中会刺激钙内流，导致细胞死亡。与表达CD44的CTC相比，CD44阻断的CTC显着降低了内在化，从而证实了纳米粒的CD44特异性内在化。当转移到细胞粘附表面时，簇的显着延迟的扩张描述了纳米粒对抗CTC定居的潜力。因此，对已开发的各向异性ECM模拟纳米杂化物的新见解将增强系统性循环中肿瘤引发簇的靶向捕获，这有可能减少乳腺癌患者的肿瘤进展。pH响应性的Dox释放到溶酶体中会刺激钙内流，导致细胞死亡。与表达CD44的CTC相比，CD44阻断的CTC显着降低了内在化，从而证实了纳米粒的CD44特异性内在化。当转移到细胞粘附表面时，簇的显着延迟的扩张描述了纳米粒对抗CTC定居的潜力。因此，对已开发的各向异性ECM模拟纳米杂化物的新见解将增强系统性循环中肿瘤引发簇的靶向捕获，这有可能减少乳腺癌患者的肿瘤进展。当转移到细胞粘附表面时，簇的显着延迟的扩张描述了纳米粒对抗CTC定居的潜力。因此，对已开发的各向异性ECM模拟纳米杂化物的新见解将增强系统性循环中肿瘤引发簇的靶向捕获，这有可能减少乳腺癌患者的肿瘤进展。当转移到细胞粘附表面时，簇的显着延迟的扩张描述了纳米粒对抗CTC定居的潜力。因此，对已开发的各向异性ECM模拟纳米杂化物的新见解将增强系统性循环中肿瘤引发簇的靶向捕获，这有可能减少乳腺癌患者的肿瘤进展。