Array-Based Cell Sensing for Chemical Screening: Comparison
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Please note this is a comparison between Version 3 by Mingdi Jiang and Version 4 by Amina Yu.

Synthetic chemicals are widely used in the daily life, making chemical safety assessments necessary for environmental exposure. Additionally, the rapid determination of chemical drug efficacy and safety is a key step in therapeutic discoveries. Cell-based screening methods are non-invasive, and cellular phenotypic changes can also provide more sensitive indicators of chemical effects than conventional cell viability. Array-based cell sensors can be engineered to maximize sensitivity to changes in cell phenotypes, lowering the threshold for detecting cellular responses under external stimuli. Therefore, array-based sensing can provide a robust strategy for both cell-based chemical risk assessments and therapeutics discovery.

  • cellular phenotypic response
  • array-based sensor
  • multichannel
  • chemical risk assessment
  • therapeutics discovery

1. Introduction

Synthetic chemicals are used in almost every aspect of daily life, making it critical to know their acute and long-term health effects [1][2][3]. Additionally, new synthetic chemicals are being developed regularly by the pharmaceutical [4], agricultural [5], cosmetics, [6] and other related industries. Each of these new chemicals needs to be evaluated for toxicity, and it is very important to assess the efficacy and off-target effects of these new drugs [7][8].
Cell-based screening assays are important tools in drug discovery and risk assessments, providing a less expensive alternative to animal models [9]. Additionally, the use of cell models provides the ethical benefit of minimizing animal use and suffering [10]. The most common cell-based approach for chemical safety assessments is cell viability [11]. These approaches are effective for predicting cell death or major cellular dysfunctions arising from acute chemical exposure [12]. Long-term exposure to low doses of synthetic chemicals, however, can induce more subtle cellular responses which are responsible for chronic diseases, including metabolic [13], autoimmune [14], neurocognitive [15] and cardiovascular diseases [16]. Intracellular and extracellular biomarkers provide useful indicators for detecting cellular abnormality, with limits of detection at the range of micromolar to nanomolar levels [17][18]. However, recent studies have shown that chronic exposure to far lower levels of chemicals can induce cellular phenotypic responses [19]. Additionally, biomarker-based strategies are generally expensive and require the multi-step processing of cells, limiting their application in high-throughput detection [20].
Cellular phenotypic signatures have the potential to be more sensitive indicators of chemical effects than conventional cell viability and biomarker-based measurements [21]. Hypothesis-free array-based sensing platforms can be engineered to maximize sensitivity to early and subtle cellular phenotypic changes [22]. This design capability makes hypothesis-free sensor arrays potential tools for both high-throughput chemical safety assessments and as important tools for probing both efficacy and off-target effects for drug discovery [23].

2. Array-Based Cell Sensing for Chemical Safety Assessment

2.1. Environmental Safety Assessment

Living cells produce a large variety of metabolites including volatile organic compounds (VOCs), which can provide valuable information about the physiological and metabolic state of cells [24][25][26]. Therefore, early studies using array-based sensing explored cellular VOCs. Aldo et al. designed a metal–oxide semiconductor gas-sensor array to detect the changes in cell VOC profiles in response to the presence of chemical compounds [27]. This sensing was achieved through changes in electrical resistance resulting from the redox interactions of volatile compounds with sensor-surface-absorbed oxygen.
Pesticides are one of the most prevalent sources of chemical exposure due to their wide use in the food and agriculture industries [28]. It was developed a multi-channel array-based sensing platform capable of detecting the effects of femtomolar levels of common pesticides on macrophages [29]. This system used a polymer–protein supramolecular assembly to generate a scalable sensor array platform. The sensor array was composed of a cationic benzylammonium-functionalized cationic poly(oxanorborneneimide) random copolymer conjugated with pyrene dye (PONI-C3-Bz-Py), electrostatically bound to anionic enhanced green fluorescent protein (EGFP). The benzyl group provides differential interactions with cell surface functionalities, resulting in changes in Förster resonance energy transfer (FRET) upon interactions of the sensor with cells. Additionally, the pyrene moiety displays an ensemble of monomeric fluorescence emission peaks and an excimer peak. Therefore, five fluorescent channels are generated in a single well. The FRET-based nanosensor array detected and discriminated phenotypic changes in macrophages after 24 h exposure to femtomolar concentrations (10−14 M) of two common pesticides, chlorpyrifos and methoxychlor, with 96% correct classification and 96% accurate unknown identificatio. In addition, this system was able to differentiate between different pesticide-induced phenotypes to classify pesticide class, which confirmed the high sensitivity of array-based sensing for observing the effects of environmental chemicals on human health. Moreover, it was also performed two widely used cytotoxicity assays (Alamar Blue assay and Trypan Blue exclusion assay) and a reactive oxygen species (ROS) detection assay to determine the effects of pesticides on RAW 267.4 cells at the 10−14 M concentration. No significant cell response was detected from these methods, further indicating that cellular phenotypic changes provide a more sensitive indicator of chemical effects than conventional cell viability, as well as the high promise of array-based sensing in drug discovery and diagnostics.
Nanomaterials are widely used in drug delivery [30], cell imaging [31], and consumer product development [32], leading to increased human contact. There are several cell-based approaches to study nanotoxicity using simple outputs [33]. Li et al. presented a microelectromechanical-system-based sensor array system to highlight the cell kinetics behavior of small-cell colonies of PC12 cells under exposure to NPs with different compositions [34]. The sensor array was fabricated using different sizes of microwells to hold different numbers of cells, and the cell responses under different NPs exposure were measured with a microelectromechanical system (MEMS). The MEMS was fabricated with two different electrodes, an indium tin oxide (ITO) electrode and gold electrode, to generate dielectrophoresis (DEP) from a non-uniform dielectric field. DEP can manipulate the movement of particles by a trapping force when the particles and surrounding medium have different polarizabilities, offering a rapid and label-free toxicity detection method with high reproducibility. In this system, the cell impedance response to NPs was dependent on major changes in cell morphology and cell attachment.
The lab created a hypothesis-free nanosensor through the electrostatic complexation of cationic gold nanoparticles (AuNPs) with anionic enhanced green fluorescent protein (EGFP). The fluorescence of EGFP can be quenched by AuNP and restored by the competitive interactions of AuNPs and biomacromolecular analytes. The multivalency of the nanoparticle provides high sensitivity, and fluorogenesis of the EGFP generates a robust fluorescent pattern. This sensor was initially used to discriminate metastatic cells and tissues [35]. The sensitivity displayed in these studies suggested that this platform could be used for the detection of cell phenotypes arising from nanoparticle exposure [36]. It was determined the effects of ultra-low concentrations of a library of cationic nanoparticles with varying degrees of hydrophobicity (C2, C4, C6 and C10) on the non-malignant human mammary epithelial cell line MCF10A. In addition, it was compared the sensing results with three commonly used cytotoxicity assays, Trypan Blue exclusion assay, Alamar Blue assay and DNA-staining Hoechst dye, which were respectively used to evaluate cell membrane integrity, mitochondrial metabolism and cell proliferation. The nanosensor was readily able to detect phenotypic changes, whereas no response was observed using traditional cytotoxicity assays. Similarly, the AuNP-EGFP nanosensor was used to detect the estrogenic activity of low doses of endocrine-disrupting chemicals (EDCs) and their mixtures on MCF-7 cells [37].

2.2. Therapeutics Safety Assessment

Toxicology plays an important role in drug development for evaluating the risk of potential drug candidates on human health [38]. For example, medications can cause acute kidney injury [39]. However, the complexity and diversity of various nephrotoxic mechanisms make risk assessments of nephrotoxic drugs challenging. Recently, Tian et al. constructed an array-based sensor using cationic polydopamine-polyethyleneimine (PDA-PEI) and three anionic quantum dots (QD515: CdSe/ZnS QD modified with 3-mercaptopropionic acid; QD580: CdSe/ZnS QD modified with PEG-COOH; QD640: CdSe/ZnS QD modified with l-cysteine) to classify nephrotoxic drug mechanisms based on the fluorescence changes arising from changes in cell surface phenotypes induced by multiple nephrotoxic drugs [40]. PDA-PEI is an effective quencher, and the QDs have a wide absorption and narrow emission, allowing multiple emission channels with a single excitation wavelength [41]. A total of 50 nephrotoxic drug from 7 classes were incubated with HK-2 cells at a concentration of IC50 for 24 h. The array-based sensor generated a unique fluorescent fingerprint for each class of drug-induced cell injury, and 50 drugs were separated into 7 clusters using both PCA and LDA, corresponding to 7 classes of drugs. These clusters were classified with 100% accuracy, and each cluster had an individual fluorescence signature trend over time.

3. Array-Based Cell Sensing for Therapeutics Discovery

The high-throughput screening of therapeutic efficacy and mechanism of drug candidates accelerates the discovery of new therapeutics [42]. Conventional screening methods, including screening genomic [43], transcriptional [44] and metabonomic [45] signatures, are time-consuming and require specialized equipment. The array-based sensing of cell surface phenotype signatures provides new directions for high-throughput and high-content screening (HT-HCS) methods for drug discovery.
The lab developed a multichannel sensor platform capable of rapidly profiling the mechanism of chemotherapeutic drugs in minutes [46]. This sensor uses a three-channel fluorescent protein (FP) platform analogous to the previously discussed EGFP systems [36][37]. In this study, the authors complexed a cationic AuNP with three different anionic FPs, EGFP, enhanced blue fluorescent protein (EBFP) and tandem dimer Tomato (tdTomato). The nanosensor was used to screen 15 chemotherapeutics with different known molecular mechanisms to generate a training set of fluorescence fingerprints using linear discriminant analysis (LDA). The overlap of drugs with similar mechanisms and the separation of apoptotic and necrotic groups demonstrates the ability of the sensor to detect broader classes of cell death mechanisms. Significantly, the nanosensor can also predict unknown mechanisms and determine mechanistic correlations between individual drugs and their combinations. This identification was quantifiable through the use of Mahalanobis distances, a key advantage of LDA-based clustering [47]. Recently, this hypothesis-free AuNP-FPs sensor platform was used to identify nanoparticles capable of efficiently differentiating cancer stem cells (CSCs) into new phenotypes that are more susceptible towards traditional chemotherapeutics [48]. The susceptible phenotype had increased ROS levels and had synergistic effects with a metabolic inhibitor, 2DG on CSCs.
Single-stranded DNA (ssDNA) can be readily chemically synthesized to generate a large library, making these materials attractive motifs for sensing [49]. Agasti et al. complexed three cationic surface-functionalized AuNPs with different fluorophore-labeled ssDNA strands to form a robust multichannel array-based sensing platform [50]. Cells with different states were lysed to extract the total protein components. Proteins vary in size and possess their own signature of surface amino acid residues; therefore, they generate unique interactions with cationic AuNPs. The fluorescence of ssDNA was quenched by AuNPs via surface binding, but regenerated the fluorescence response when the lysate competitively interacted with AuNP, achieving the discrimination of cells based on their entire proteome signatures. The ability of this DNA-based multichannel sensor array to rapidly identify cell states encouraged authors to determine small-molecule autophagy modulator-induced global cellular state alterations, using LDA to assess the fluorescence signatures. The high accuracy of discrimination between inducers, inhibitors and control (98%) further demonstrated the excellent capability of the multichannel sensing system for high-throughput drug screening.

4. Conclusions and Future perspectives

The increase in synthetic chemical production and drug diversification greatly increases the need for new tools for chemical risk assessment. The high sensitivity of array-based sensing enables the detection of more subtle cellular phenotypic changes under ultra-low doses of chemical exposure, facilitating the safer use of synthetic chemicals and the discovery of new therapeutic chemicals. In the near future, it will be important to combine the opportunities provided by hypothesis-free array-based sensing with the mechanistic understanding that biomarkers offer. These 'hybrid' platforms will allow array-based sensing to be a more robust and efficient tool for chemical risk assessments and drug candidate screening.

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