Journal
ACS BIOMATERIALS SCIENCE & ENGINEERING
Volume 3, Issue 6, Pages 951-959Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.7b00023
Keywords
intestine-on-a-chip; 7-ethyl-10-hydroxycamptothecin (SN38); prodrugs; biomicrofluidic; intestinal drug transport
Categories
Funding
- Australian Research Council [LP150100032]
- Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology [CE140100036]
- Australian Government NHMRC Fellowship
- Australian Research Council [LP150100032] Funding Source: Australian Research Council
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Many highly effective chemotherapeutic agents can only be administered intravenously as their oral delivery is compromised by low gastro-intestinal solubility and permeability. SN-38 (7-ethyl-10-hydroxycamptothecin) is one such drug; however, recently synthesized lipophilic prodrugs offer a potential solution to the low oral bioavailability issue. Here we introduce a microfluidic-based intestine-on-a-chip (IOAC) model, which has the potential to provide new insight into the structure permeability relationship for lipophilic prodrugs. More specifically, the IOAC model utilizes external mechanical cues that induce specific differentiation of an epithelial cell monolayer to provide a barrier function that exhibits an undulating morphology with microvilli expression on the cell surface; this is more biologically relevant than conventional Caco-2 Transwell models. IOAC permeability data for SN38 modified with fatty acid esters of different chain lengths and at different molecular positions correlate excellently with water lipid partitioning data and have the potential to significantly advance their preclinical development. In addition to advancing mechanistic insight into the permeability of many challenging drug candidates, we envisage the IOAC model to also be applicable to nanoparticle and biological entities.
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