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Long-Term Toxicity and Regulations for Bioactive-Loaded Nanomedicines
Published in Mahfoozur Rahman, Sarwar Beg, Mazin A. Zamzami, Hani Choudhry, Aftab Ahmad, Khalid S. Alharbi, Biomarkers as Targeted Herbal Drug Discovery, 2022
Iqbal Ahmad, Sobiya Zafar, Shakeeb Ahmad, Suma Saad, S. M. Kawish, Sanjay Agarwal, Farhan Jalees Ahmad
High throughput screening (HTS) and high content screening (HCS) are the automated tools used for the estimation of in vitro toxicity related to NMs. HTS is mainly a type of automated assay and usually focuses on a separate biological mechanism or biochemical alteration. HTS-based screening of test NMs do not observe the whole phenotypical changes in cell. HCS is also an automated screening tool and mainly uses fluorescence and microscopic images for the toxicity analysis. Contrary to HTS, it is used to estimate multiple changes in the phenotype of similar cell population (Godwin et al., 2015) The HTS based in vitro assays are comparatively simple, less time consuming and less expensive than complicated animal model experiments. However, it cannot be used solely for the in vitro toxicity study due to the poor in vitro-in vivo correlation (IVIC); as a small cell cannot be a representative of an animal with complex body structure.
Key Concepts in Assay Development, Screening and the Properties of Lead and Candidate Compounds
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
High Content Screening (HCS) has become a firmly established technology that can aid the reduction in the high attrition rates in drug discovery (Mandavilli et al. 2018, Smith et al. 2018, Xia and Wong 2012). Too often, the identification of compounds that exhibit the ability to modulate the activity of a therapeutically relevant target in isolation fails to translate their behaviour when evaluated in a cellular context. Compounds identified from screening activities against libraries carried out in a HCS setting may be better starting points for drug discovery efforts. This has been possible as a result of the fusion of the outcomes of the advances in microscopy, image acquisition and analysis software, computer processing power, integration into automated platforms, and molecular biological techniques to construct tagged target proteins with suitable labels, e.g., Green Fluorescent Protein (GFP). HCS also offers the possibility of evaluating the effect of compounds on both phenotypic end-points as well as on individual cellular events (Kain 1999).
Applications for Drug Development
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Jessica Kalra, Donald T. Yapp, Murray Webb, Marcel B. Bally
Animal models have been pivotal in determining the function of the many compounds discovered or synthesized de novo by chemists for over eight decades. In many cases, such studies led to the discovery and development of compounds that are now used clinically. Examples include lithium as an anticonvulsant and treatment for bipolar disease, and halothane as a general anesthetic. Animal testing has made treatments possible for serious illness such as hypertension, cancer, and AIDS, and the eradication of diseases such as diphtheria. Despite the clear societal benefits of testing drugs in animals, the use of animals for research remains controversial. There are those who believe that testing in animals is simply unethical. Those who accept the necessity of preclinical testing are trying to better regulate the humane use of animals for research by defining guidelines to balance the procedures against the information obtained. In Canada, the Canadian Council of Animal Care is “responsible for setting and maintaining the standards for the ethical use and care of animals in science” (Canadian Council of Animal Care 2014). Comparable organizations in the United States (e.g., Association for Assessment and Accreditation of Laboratory Animal Care International), Europe (e.g., ETS 123), and Asia (e.g., Japanese Association for Laboratory Animal Science), emphasize the three “Rs” of animal research: Replace, Reduce, and Refine. Each of the aforementioned organizations recognizes that animal models are an essential tool in the development of new pharmaceutical products. Further, the data from such studies are required by various regulatory bodies that must assess the safety of new products prior to initiation of human clinical trials and prior to final approval. It is argued here that small animal imaging has the potential to refine how animals are used in the context of drug development programs, and that noninvasive imaging methods will result in a net reduction in the number of animals used in preclinical studies. Over the next decade, imaging will form the basis of a high content screening (HCS) platform for animal research in drug discovery.
The latest advances in high content screening in microfluidic devices
Published in Expert Opinion on Drug Discovery, 2023
Weiyu Liu, Jingyu Wang, Huibo Qi, Qisen Jiao, Lei Wu, Yu Wang, Qionglin Liang
High content screening (HCS) was introduced in the late 1990s to facilitate integrated disease-relevant cell screening at the early stages of the drug discovery process [139]. However, the traditional culture platform that uses multi-well plates suffers from several limitations, such as low throughput and complicated processing, which restrict the potential of HCS in the field of drug screening. In recent years, microfluidic devices, including droplet, microarray and organs-on-chip platforms, have been widely applied for HCS assays to improve the efficiency of drug discovery. Droplet-based microfluidics allow for a high-throughput screening of drug candidates with minimal reagent consumption, leading to a more cost-effective and efficient process. This approach is particularly useful for rare or expensive sample, such as primary cells or patient-derived samples. Microarray-based microfluidics allows for parallelized screening of a large number of samples using an array of discrete locations, and is particularly suitable for imaging-based assays. The small-scale reactions provide high sensitivity, enabling the detection of rare events, and enabling imaging in real-time. Organs-on-chip microfluidics enables the creation of microenvironments that mimic physiological conditions, allowing for more biologically relevant drug screening. This approach can provide insights into drug effects on tissues, such as toxicity, and can help identify compounds with a higher chance of clinical success.
Harnessing the power of microscopy images to accelerate drug discovery: what are the possibilities?
Published in Expert Opinion on Drug Discovery, 2020
Justin Boyd, Myles Fennell, Anne Carpenter
High-content screening combines automated microscopy with automated image analysis and is a common phenotypic drug discovery strategy. Discrete cellular features, defined by the researcher, are quantified through measuring segmented cellular features and used to characterize disease-associated phenotypes [4]. HCS takes a pre-defined approach to identify features that differentiate cellular systems in a predictive way based upon specific feature changes. In other words, HCS focuses on quantifying single cellular processes or functions in the context of a disease. Historically, only a few user-defined features – fewer than 6, and in most cases 1–2 – have been used to differentiate treatment conditions [5]. Robust phenotypes associated with perturbations (e.g. nuclear translocation) can be quantified with few measurements, making screening tractable. By limiting the measurements to discrete features proximal to the biology of interest, researchers can quickly and effectively identify conditions (e.g. compounds or genetic perturbations) which provide the desired effect. Moreover, this approach is amenable to determining the potency and efficacy of compounds for structure-activity relationship (SAR) determination.
The impact of chemoinformatics on drug discovery in the pharmaceutical industry
Published in Expert Opinion on Drug Discovery, 2020
Karina Martinez-Mayorga, Abraham Madariaga-Mazon, José L. Medina-Franco, Gerald Maggiora
High content screening [109] is an important technology for facilitating phenotype-based drug discovery efforts [110]. Focusing on cellular, organ, and organism phenotypes in addition to enzyme and receptor information is becoming recognized as an important aspect on drug discovery. There are compounds that have similar activities in both enzyme and cell-based assays, but there also are compounds that are active in enzyme assays that are inactive in cell-based assays, and vice-versa. Although molecules that do not follow either of the trends tend to be more challenging to deal with, they may nevertheless provide important information that bears on a drug’s mechanism of action as well as its effectiveness – if it works in a cell but not on an isolated enzyme, it might be working by other mechanisms. If it works for the enzyme but not for the cell, there might be solubility, permeability or other issues. Nevertheless, in some cases it could be a useful hit.