Abstract
Simple SummaryWe have developed an implantable microdevice that is placed into a live tumor, and can directly image how effective various chemotherapy drugs are at inducing cell death, without having to remove or process the tumor tissue. Currently drug optimization is performed by assessing tumor shrinkage after treating a patient with systemic doses of a chemotherapy agent; this only evaluates a single treatment at a time and typically takes weeks-months before an optimal treatment strategy is found (if found at all) for a specific patient. In contrast, using the technology presented here, a personalized cancer treatment strategy can potentially be optimized and tailored to a specific patient’s tumor characteristics within several hours, without requiring surgical tissue removal or prolonged trials of potentially ineffective chemotherapies.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.
Highlights
Understanding the effect of anti-cancer drugs on the tumor and its microenvironment is central to the design of effective single agent and combination regimens
Sections (r = 0.88, p < 0.001). n = 15 replicate drug sites from five tumors were used for this correlation. These findings indicate that in situ measurement of propidium iodide (PI) signal intensity using the LIT-implantable microdevice (IMD) is representative of overall cell death and nonviability within a drug exposed
This study demonstrates that localized drug-induced cell death can be assessed directly in a live tumor, and represents a unique approach compared to current histopathology methods that require tissue removal and processing
Summary
Sharath Bhagavatula 1,* , Devon Thompson 1, Sebastian W. Lyng Received: 7 January 2021 Accepted: 1 February 2021 Published: 6 February 2021. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Drug optimization is performed by assessing tumor shrinkage after treating a patient with systemic doses of a chemotherapy agent; this only evaluates a single treatment at a time and typically takes weeks-months before an optimal treatment strategy is found (if found at all) for a specific patient. Using the technology presented here, a personalized cancer treatment strategy can potentially be optimized and tailored to a specific patient’s tumor characteristics within several hours, without requiring surgical tissue removal or prolonged trials of potentially ineffective chemotherapies
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