3D Cell Culture and Drug Discovery

Drug discovery remains difficult research, as success rates in clinical trials are relatively low. According to Frontiers in Pharmacology, more than half of all new drugs fail in the second or third phase of clinical trials because of lack of efficacy, and another 30 percent fail because of safety issues.

There is a significant need for new technologies that increase precision in drug discovery. Enter 3D cell culture.

2D vs. 3D in Drug Research

Two-dimensional culture has been the fundamental cell culture technique used in drug research for decades. But in recent years, 3D cell culture models have been increasingly utilized in multiple phases of the process, from target validation to lead identification to preclinical optimization.

3D cell culture models were initially developed for oncology research, and many existing 3D cell tumor models are often grown as 3D spheroids on plates. But dish-based organoids are a newer development, and they show great potential as a tool for drug discovery, according to Drug Discovery World.

3D cell culture can also be used to grow patient-specific cells, which leads to the possibility of testing drugs on lab-grown organoids to predict response before giving drugs directly to patients.

The Advantages of the Extracellular Matrix

3D cell culture often utilizes an extracellular matrix, a solid scaffold upon which cells can grow. Naturally derived ECMs, such as Corning® Matrigel matrix and other so-called basement membrane hydrogels, are widely used in 3D cell culture. Matrigel matrix is an optimized version of an extracellular matrix.

In the early days, it was thought that the ECM mostly provided structural support, but researchers now know that the ECM actively affects cell behavior, according to Frontiers in Pharmacology. Dynamic changes in the various components of the ECM regulate cell growth, cell signaling, and cytoskeletal organization. The composition of the ECM can influence the cell's response to drugs, promoting drug resistance, enhancing drug efficacy, or even altering a drug's mechanism of action.

Cell Migration and Invasion with Transwell Permeable Supports

In vitro cell migration and invasion assays are frequently used as model systems to quantify the directed movement of cells towards a chemoattractant stimulus or to measure how a particular drug, antibody or extracellular matrix (ECM) coating affects movement of cells.

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Matrigel matrix, like natural collagen, promotes cell attachment via integrin receptors. This leads to the "activation of cell signaling pathways that control cell survival, growth, and differentiation," Frontiers in Psychology notes, "and can modulate the response to therapeutic approaches, including chemotherapy, immunotherapy, and radiation." Matrigel matrix can also facilitate streamlined workflow for organoid culture due to its reproducibility and consistency.

The Role of Cellular Spheroids

Cellular spheroids grown on microplates, such as Corning® Spheroid microplates, and embedded in ECMs can be generated from many types of cells, and they can be used in screening assays for compounds that modulate tumor growth, invasion, and angiogenesis.

In a recent study published in Anticancer Research, hanging drop spheroids were generated from head and neck squamous cell carcinoma cell lines and primary human cells. The preliminary study was conducted with cells from fresh tumor biopsies and confirmed the feasibility of this approach to develop an assay that can be used to assess individual patients' susceptibilities to common chemotherapy and experimental drugs.

However, it can be difficult to create uniform spheroids, and controlling size to prevent necrosis and lack of nutrient supply is also challenging, according to Frontiers in Pharmacology. Microwell arrays such as Corning® Elplasia plates feature microcavity technology that allows thousands of spheroids to be created under one culture condition in one plate, and also facilitate producing uniformly sized spheroids in a high-throughput manner.

What Does the Future Hold?

Authentic 3D cell culture models are enhancing the drug discovery process by modeling in vivo conditions and microenvironments far more precisely, yielding results with better clinical outcomes.

Research methods and models will need to consider that the response to drugs varies not only with the tumor type and cell line but the surrounding ECM, their interaction with stromal cells, and immunomodulatory molecules.

A cancer drug discovery that combines 3D cell culture with tumoroids (patient-derived tumor cells) and organoid banks of tumor cells of different subtypes is possible. Such a discovery could lead to the development of personalized drug therapies that improve treatment outcomes and come with less intense side effects.

3D Cell Culture and Drug Discovery | Corning