Probing prodrug metabolism and reciprocal toxicity with an integrated and humanized multi-tissue organ-on-a-chip platform

Rajan, Shiny Amala Priya; Aleman, Julio; Wan, Meimei; Zarandi, Nima Pourhabibi; Nzou, Goodwell; Murphy, Sean V.; Bishop, Colin E.; Sadri‐Ardekani, Hooman; Shupe, Tom; Atala, Anthony; Hall, Adam R.; Skardal, Aleksander

doi:10.1016/j.actbio.2020.02.015

Cited by 133 publications

(114 citation statements)

References 64 publications

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“…[24] Such multiorgan devices have been used to simultaneously evaluate drug efficacy and safety aspects on a systemic level. [24][25][26][27] Probing off-target toxicity of compounds in multiorgan systems has proven to be particularly useful for prodrugs that are inactive without hepatic metabolism. [26][27][28][29][30][31] Multiorgan systems represent a potential solution to capture the full extent of complex DDI eventsranging from metabolizing organs to drug target organs-and to predict the safety of critical drug combinations.…”

Section: Introductionmentioning

confidence: 99%

Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

et al. 2020

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Pharmacokinetic DDIs arise upon modulation of the absorption, distribution, and metabolism or excretion (ADME) properties of one drug by co-administration of another drug and can lead to massive changes of drug plasma concentrations with potentially life-threatening consequences. [6] Most commonly, a perpetrator drug modulates the metabolism of a victim drug by chemical inhibition or transcriptional induction of drug-metabolizing enzymes. In both cases, such an interaction leads to an altered metabolic fate of the victim drug. [7] The clinical implications of such interactions can result in a lack of efficacy, especially in the context of so-called prodrugs. Prodrugs are drug variants with enhanced solubility or lifetime, which rely on in vivo bioconversion to exert their pharmacological activity. [8] Positive treatment outcomes in prodrug therapies strongly depend on the ability of the patient to endogenously bioactivate the prodrug compound to its pharmacologically active metabolite(s). [9] Drug metabolism predominantly occurs in the liver and is mainly catalyzed by enzymes of the cytochrome P450 (CYP) family. These enzymes oxidize, reduce, and hydrolyze a wide range of drugs or chemical entities. Therefore, it does not come as a surprise that inhibition or induction of CYP enzymes is largely involved in clinical DDIs and has led to severe ADRs and the withdrawal of multiple drugs from the market. [10] In many cases, DDIs manifest themselves in secondary organs, to which liver-generated metabolites are transported through systemic circulation. Such tissues include kidney, heart, brain, gut, and lungs, and drug target tissues, such as tumors. [11] Oncology patients are considered especially prone to toxic DDI events owing to i) the wide use of anticancer prodrugs, [12,13] ii) the inherent toxicity of anticancer agents and their very narrow therapeutic index, iii) the likelihood of cancer patients to receive many different medications for the management of other illnesses, [14] and iv) the increasing use of combination therapies with more than one anticancer medication. [15] Hence, clinicians are confronted with the growing risk of prescribing drug combinations that can inadvertently lead to severe clinical implications. [16] Additionally, genetic polymorphisms in the liver can lead to individual patterns of CYP-enzyme-mediated metabolism for different patients. [17] Management of DDIs is, therefore, crucial in oncology therapy, where the altered Drug-drug interactions (DDIs) occur when the pharmacological activity of one drug is altered by a second drug. As multimorbidity and polypharmacotherapy are becoming more common due to the increasing age of the population, the risk of DDIs is massively increasing. Therefore, in vitro testing methods are needed to capture such multiorgan events. Here, a scalable, gravity-driven microfluidic system featuring 3D microtissues (MTs) that represent different organs for the prediction of drug-drug interactions is used. Human liver microtissues (hLiMTs) are combined with tumor m...

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Section: Introductionmentioning

confidence: 99%

Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

et al. 2020

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“…The resemblance to human organs reached with these novel strategies allows a more complete comprehension of pathogenic mechanisms and provides a more efficient tool for drug discovery. Furthermore, the recent concept of body-on-a-chip aims to reflect the interaction among organs in vivo, combining multiple OOC in a unique integrated system for various potential biomedical applications, such as disease modeling, drug discovery, biomarker detection [135][136][137]. In this way, it could be possible to observe the role of other organs, such as nervous or respiratory systems, which are closely interconnected with heart and vessel physiology, and sometimes participate to pathogenesis of specific CVDs.…”

Section: Discussionmentioning

confidence: 99%

Human Cell Modeling for Cardiovascular Diseases

Lippi

Stadiotti

Pompilio

et al. 2020

IJMS

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The availability of appropriate and reliable in vitro cell models recapitulating human cardiovascular diseases has been the aim of numerous researchers, in order to retrace pathologic phenotypes, elucidate molecular mechanisms, and discover therapies using simple and reproducible techniques. In the past years, several human cell types have been utilized for these goals, including heterologous systems, cardiovascular and non-cardiovascular primary cells, and embryonic stem cells. The introduction of induced pluripotent stem cells and their differentiation potential brought new prospects for large-scale cardiovascular experiments, bypassing ethical concerns of embryonic stem cells and providing an advanced tool for disease modeling, diagnosis, and therapy. Each model has its advantages and disadvantages in terms of accessibility, maintenance, throughput, physiological relevance, recapitulation of the disease. A higher level of complexity in diseases modeling has been achieved with multicellular co-cultures. Furthermore, the important progresses reached by bioengineering during the last years, together with the opportunities given by pluripotent stem cells, have allowed the generation of increasingly advanced in vitro three-dimensional tissue-like constructs mimicking in vivo physiology. This review provides an overview of the main cell models used in cardiovascular research, highlighting the pros and cons of each, and describing examples of practical applications in disease modeling.

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“…These operating volumes will not support high-throughput analysis such as microfluidics (Tumarkin et al, 2011). Micro-bioreactors, and those operating in the milliliter scale, have been suitable platforms for drugscreening, stem cell differentiation protocols or organ-on-a-chip devices as they enable expensive processes to be conducted in a cost-effective way, a consequence of the small operating volumes, otherwise prohibitive at larger scales (Kane et al, 2019;Rajan et al, 2020;Zhao et al, 2020). However, the sFBB system offers an appropriate scale, operating in perfusion mode, for the intermediate stage of testing methods in a more physiologically relevant volume or expanding optimized protocols.…”

Section: Discussionmentioning

confidence: 99%

Small-Scale Fluidized Bed Bioreactor for Long-Term Dynamic Culture of 3D Cell Constructs and in vitro Testing

Silva

Erro

Awan

et al. 2020

Front. Bioeng. Biotechnol.

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With the increasing interest in three-dimensional (3D) cell constructs that better represent native tissues, comes the need to also invest in devices, i.e., bioreactors, that provide a controlled dynamic environment similar to the perfusion mechanism observed in vivo. Here a laboratory-scale fluidized bed bioreactor (sFBB) was designed for hydrogel (i.e., alginate) encapsulated cells to generate a dynamic culture system that produced a homogenous milieu and host substantial biomass for long-term evolution of tissue-like structures and "per cell" performance analysis. The bioreactor design, conceptualized through scale-down empirical similarity rules, was initially validated through computational fluid dynamics analysis for the distributor capacity of homogenously dispersing the flow with an average fluid velocity of 4.596 × 10 −4 m/s. Experimental tests then demonstrated a consistent fluidization of hydrogel spheres, while maintaining shape and integrity (606.9 ± 99.3 µm diameter and 0.96 shape factor). It also induced mass transfer in and out of the hydrogel at a faster rate than static conditions. Finally, the sFBB sustained culture of alginate encapsulated hepatoblastoma cells for 12 days promoting proliferation into highly viable (>97%) cell spheroids at a high final density of 27.3 ± 0.78 million cells/mL beads. This was reproducible across multiple units set up in parallel and operating simultaneously. The sFBB prototype constitutes a simple and robust tool to generate 3D cell constructs, expandable into a multi-unit setup for simultaneous observations and for future development and biological evaluation of in vitro tissue models and their responses to different agents, increasing the complexity and speed of R&D processes.

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Probing prodrug metabolism and reciprocal toxicity with an integrated and humanized multi-tissue organ-on-a-chip platform

Cited by 133 publications

References 64 publications

Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

Human Cell Modeling for Cardiovascular Diseases

Small-Scale Fluidized Bed Bioreactor for Long-Term Dynamic Culture of 3D Cell Constructs and in vitro Testing

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