Tumour-on-chip microfluidic platform for assessment of drug pharmacokinetics and treatment response
Microphysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. However, existing microfluidic devices are not yet able to deliver compounds to cell models in a way that reproduces the real physiological drug exposure. Here, we introduce a novel tumour-on-chip microfluidic system that mimics the pharmacokinetic profile of compounds on 3D tumour spheroids to evaluate their response to the treatments. We used this platform to test the response of SW620 colorectal cancer spheroids to irinotecan (SN38) alone and in combination with the ATM inhibitor AZD0156, using concentrations mimicking mouse plasma exposure profiles of both agents. We explored spheroid volume and viability as a measure of cancer cells response and changes in mechanistically relevant pharmacodynamic biomarkers (γH2AX, cleaved-caspase 3 and Ki67). We demonstrate here that our microfluidic tumour-on-chip platform can successfully predict the efficacy from in vivo studies and therefore represents an innovative tool to guide drug dose and schedules for optimal efficacy and pharmacodynamic assessment, while reducing the need for animal studies.
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Treatment efficacy study
Male immunocompromised Hsd:Athymic Nude-Foxn1nu mice (Envigo) were used for xenograft tumour implantation. SW620 (ATCC® CCL-227™) xenograft was established by implanting 100 µL of a cell suspension (1 × 106 cells in 50% Matrigel (BD Bioscience)) subcutaneously into the dorsal left flank of the animals. Animals were randomised into groups of 9–15 when tumours reached a volume of ~0.30 cm3 and 4 weekly cycles of treatment commenced.
AZD0156 was formulated in a 10% DMSO/90% Captisol (30%w/v) solution (Cydex Pharmaceuticals) and orally dosed. Irinotecan was formulated in a 7.5% DMSO/92.5% water for injection solution and administered once a week via the intra peritoneal (IP) route (50 mg/kg). In the combination group animals were treated with irinotecan (50 mg/kg IP) followed 24 or 72 h by three consecutive daily oral doses of AZD0156 (10 mg/kg)). This was repeated for four consecutive weeks. Control animals were treated IP once weekly with 0.85% Physiological saline and PO with 10% DMSO/90% Captisol (30% w/v) once daily for 3 days per week 24 h after the IP weekly dose.
Tumours were measured twice weekly (length × width) by bilateral Vernier calliper measurements and tumour volume calculated using Mousetrap software. Tumour growth inhibition from start of treatment was assessed by comparison of the mean change in tumour volume for the control and treated groups using the Mousetrap application and represented as TGI.
All in vivo studies complied with all relevant ethical regulations for animal testing and research, followed AstraZeneca’s global bioethics policy and received ethical approval from the AstraZeneca ethical committee. All studies were conducted in the UK in accordance with UK Home Office legislation, the Animal Scientific Procedures Act 1986 and under Home Office project licence 40/8894.
Petreus, T., Cadogan, E., Hughes, G. et al. Tumour-on-chip microfluidic platform for assessment of drug pharmacokinetics and treatment response. Commun Biol 4, 1001 (2021). https://doi.org/10.1038/s42003-021-02526-y