Bhagavatula Sharath, Thompson Devon, Ahn Sebastian W, Upadhyaya Kunj, Lammers Alex, Deans Kyle, Dominas Christine, Ferland Benjamin, Valvo Veronica, Liu Guigen, Jonas Oliver
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Cancers (Basel). 2021 Feb 6;13(4):653. doi: 10.3390/cancers13040653.
By observing the activity of anti-cancer agents directly in tumors, there is potential to greatly expand our understanding of drug response and develop more personalized cancer treatments. Implantable microdevices (IMD) have been recently developed to deliver microdoses of chemotherapeutic agents locally into confined regions of live tumors; the tissue can be subsequently removed and analyzed to evaluate drug response. This method has the potential to rapidly screen multiple drugs, but requires surgical tissue removal and only evaluates drug response at a single timepoint when the tissue is excised. Here, we describe a "lab-in-a-tumor" implantable microdevice (LIT-IMD) platform to image cell-death drug response within a live tumor, without requiring surgical resection or tissue processing. The LIT-IMD is inserted into a live tumor and delivers multiple drug microdoses into spatially discrete locations. In parallel, it locally delivers microdose levels of a fluorescent cell-death assay, which diffuses into drug-exposed tissues and accumulates at sites of cell death. An integrated miniaturized fluorescence imaging probe images each region to evaluate drug-induced cell death. We demonstrate ability to evaluate multi-drug response over 8 h using murine tumor models and show correlation with gold-standard conventional fluorescence microscopy and histopathology. This is the first demonstration of a fully integrated platform for evaluating multiple chemotherapy responses in situ. This approach could enable a more complete understanding of drug activity in live tumors, and could expand the utility of drug-response measurements to a wide range of settings where surgery is not feasible.
通过直接观察抗癌药物在肿瘤中的活性，有可能极大地扩展我们对药物反应的理解，并开发出更个性化的癌症治疗方法。可植入微型设备（IMD）最近已被开发出来，用于将微量化疗药物局部递送至活体肿瘤的受限区域；随后可以取出组织并进行分析，以评估药物反应。这种方法有快速筛选多种药物的潜力，但需要手术切除组织，并且仅在切除组织时的单个时间点评估药物反应。在这里，我们描述了一种“肿瘤内实验室”可植入微型设备（LIT-IMD）平台，用于在活体肿瘤内对细胞死亡药物反应进行成像，而无需手术切除或组织处理。LIT-IMD被插入活体肿瘤中，并将多种药物微剂量递送至空间上离散的位置。同时，它局部递送荧光细胞死亡检测的微剂量水平，该检测会扩散到药物暴露的组织中并在细胞死亡部位积累。一个集成的微型荧光成像探针会对每个区域进行成像，以评估药物诱导的细胞死亡。我们使用小鼠肿瘤模型证明了在8小时内评估多药反应的能力，并显示出与金标准传统荧光显微镜和组织病理学的相关性。这是首个用于原位评估多种化疗反应的完全集成平台的演示。这种方法可以使我们更全面地了解活体肿瘤中的药物活性，并可以将药物反应测量的效用扩展到手术不可行的广泛场景中。
