Molecular Imaging Program at Stanford (MIPS), and Bio-X Program, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94305-5427, USA.
Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94305-5427, USA.
J Nanobiotechnology. 2022 Jun 10;20(1):267. doi: 10.1186/s12951-022-01484-9.
Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancer subtype with poor prognosis. Although anatomical imaging figures prominently for breast lesion screening, TNBC is often misdiagnosed, thus hindering early medical care. Ultrasound (US) molecular imaging using nanobubbles (NBs) capable of targeting tumor cells holds great promise for improved diagnosis and therapy. However, the lack of conventional biomarkers in TNBC impairs the development of current targeted agents. Here, we exploited the homotypic recognition of cancer cells to synthesize the first NBs based on TNBC cancer cell membrane (i.e., NB) as a targeted diagnostic agent. We developed a microfluidic technology to synthesize NB based on the self-assembly property of cell membranes in aqueous solutions. In vitro, optimal NB had a hydrodynamic diameter of 683 ± 162 nm, showed long-lasting US contrast enhancements and homotypic affinity. In vivo, we demonstrated that NB showed increased extravasation and retention in a TNBC mouse model compared to non-targeted NBs by US molecular imaging. Peak intensities and areas under the curves from time-intensity plots showed a significantly enhanced signal from NB compared to non-targeted NBs (2.1-fold, P = 0.004, and, 3.6-fold, P = 0.0009, respectively). Immunofluorescence analysis further validated the presence of NB in the tumor microenvironment. Circumventing the challenge for universal cancer biomarker identification, our approach could enable TNBC targeting regardless of tumor tissue heterogeneity, thus improving diagnosis and potentially gene/drug targeted delivery. Ultimately, our approach could be used to image many cancer types using biomimetic NBs prepared from their respective cancer cell membranes.
三阴性乳腺癌（TNBC）是一种高度异质性的乳腺癌亚型，预后不良。尽管解剖影像学在乳腺病变筛查中起着重要作用，但 TNBC 经常被误诊，从而阻碍了早期医疗。使用能够靶向肿瘤细胞的纳米气泡（NBs）进行超声（US）分子成像，为改善诊断和治疗提供了很大的希望。然而，TNBC 中缺乏常规生物标志物，阻碍了当前靶向药物的开发。在这里，我们利用癌细胞的同型识别，合成了第一个基于 TNBC 癌细胞膜的纳米气泡（NB）作为靶向诊断剂。我们开发了一种微流控技术，基于细胞膜在水溶液中的自组装特性来合成 NB。在体外，最佳 NB 的水动力直径为 683 ± 162nm，表现出持久的超声对比增强和同型亲和力。在体内，我们通过 US 分子成像证明，与非靶向 NB 相比，NB 在 TNBC 小鼠模型中表现出增加的血管外渗和滞留。时间强度曲线的峰值强度和曲线下面积显示，NB 与非靶向 NB 相比，信号显著增强（2.1 倍，P=0.004 和 3.6 倍，P=0.0009）。免疫荧光分析进一步验证了 NB 存在于肿瘤微环境中。我们的方法规避了通用癌症生物标志物识别的挑战，可以实现 TNBC 的靶向治疗，而无需考虑肿瘤组织的异质性，从而改善诊断并可能实现基因/药物靶向递送。最终，我们的方法可以使用仿生 NB 对许多癌症类型进行成像，这些 NB 是从各自的癌细胞膜制备的。
