Intestine-on-a-Chip Microfluidic Model for Efficient in Vitro Screening of Oral Chemotherapeutic Uptake

Abstract

Many highly effective chemotherapeutic agents can only be administered intravenously as their oral delivery is compromised by low gastro-intestinal solubility and permeability. ) 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.

Dynamic in vitro intestinal barrier model coupled to chip-based liquid chromatography mass spectrometry for oral bioavailability studies

“…Several different geometries and designs have been developed for gut-on-a-chip devices, but two main types of designs are commonly found in the literature. The first one is based on the traditional Transwell system, where intestinal cells are grown on a circular porous membrane [9][10][11][12], and the second one is based on culturing cells on a porous membrane that separates two sides of a linear channel or tube [13][14][15][16][17]. Both types of systems contain an apical and basolateral flow of cell culture medium inducing shear forces on the cells and mimicking the luminal flow and blood flow.…”

Emerging Role of Organ‐on‐a‐Chip Technologies in Quantitative Clinical Pharmacology Evaluation

“…More recently, a similar system, including Caco-2 cells and microfluidic flow, was used to evaluate permeability of caffeine and atenolol together with irinotecan. 52 Surprisingly, the permeability values obtained from the microphysiological system with Caco-2 cells resulted in consistently higher apparent permeability values than those obtained from conventional 2-D Caco-2 transwell studies. This may be due to the spontaneous formation of microvilli in the microphysiological system, which increases the effective surface area or other differences in the monolayer formed, or the presence of the unstirred water layer in the two systems.…”

“…Using the microfluidic system, the authors determined the low passive permeability of curcumin and measured an efflux ratio of 0.68. More recently, a similar system, including Caco‐2 cells and microfluidic flow, was used to evaluate permeability of caffeine and atenolol together with irinotecan . Surprisingly, the permeability values obtained from the microphysiological system with Caco‐2 cells resulted in consistently higher apparent permeability values than those obtained from conventional 2‐D Caco‐2 transwell studies.…”

Organoids, organs-on-chips and other systems, and microbiota

“…The integration of microfluidics with living biological systems has paved the way for new techniques such as the exciting 'organ-on-a-chip' concepts, which aims at developing advanced in vitro models that replicate the key features of human tissues and organs [80]. The culturing methods outlined below are discussed in increasing order of their ability to represent the in vivo environment and its suitability to study host-microbe interactions.…”

“…The applications of gut-on-a-chip systems are still at the early stages of development [80]; however, they hold great promise for studying the interactions between host and microbiome. Initial studies involved culturing a monolayer of human epithelial Caco-2 cells inside a microfluidic device [127].…”