Journal
ANALYTICAL CHEMISTRY
Volume 90, Issue 2, Pages 1423-1430Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.analchem.7b04969
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Funding
- National Institutes of Health [R01GM110406]
- National Science Foundation (CAREER Award) [CHE-1351595]
- National Science Foundation [1625944]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1625944] Funding Source: National Science Foundation
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For a patient with metastatic colorectal cancer there are limited clinical options aside from chemotherapy. Unfortunately, the development of new chemotherapeutics is a long and costly process. New methods are needed to identify promising drug candidates earlier in the drug development process. Most chemotherapies are administered to patients in combinations. Here, an in vitro platform is used to assess the penetration and metabolism of combination chemotherapies in three-dimensional colon cancer cell cultures, or spheroids. Colon carcinoma HCT 116 cells were cultured and grown into three-dimensional cell culture spheroids. These spheroids were then dosed with a common combination chemotherapy, FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) in a 3D printed fluidic device. This fluidic device allows for the dynamic treatment of spheroids across a semipermeable membrane. Following dosing, the spheroids were harvested for quantitative proteomic profiling to examine the effects of the combination chemotherapy on the colon cancer cells. Spheroids were also imaged to assess the spatial distribution of administered chemotherapeutics and metabolites with MALDI-imaging mass spectrometry. Following treatment, we observed penetration of folinic acid to the core of spheroids and metabolism of the drug in the outer proliferating region of the spheroid. Proteomic changes identified included an enrichment of several cancer-associated pathways. This innovative dosing device, along with the proteomic evaluation with iTRAQ-MS/MS, provides a robust platform that could have a transformative impact on the preclinical evaluation of drug candidates. This system is a high-throughput and cost-effective approach to examine novel drugs and drug combinations prior to animal testing.
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