Advancing Drug Discovery through 3D Biology

For every successful drug that gets approved for use, nine other drug candidates don't make it. A 2016 study identified four possible reasons for this huge drug development failure rate. Between 40 percent and 50 percent of drug failures are caused by a lack of clinical efficacy. Another 30 percent are due to unmanageable side effects or toxicity, and 10 percent-15 percent result from inadequate pharmacokinetic properties, which refer to how well a drug is absorbed by and excreted from the body. Finally, lack of commercial interest and poor strategic planning is responsible for 10 percent of failures.

The low success rate in drug development indicates that current animal models and two-dimensional (2D) cell culture methods fail to replicate the complexities of human biology or capture the side effects of drugs, which remain the primary reasons for drug failure. 

Over the past decade, researchers have tried to create in vitro cell culture models that are more representative of the in vivo environment. This has led to the development of three-dimensional (3D) cell cultures, which aim to replicate tissue physiology more accurately than traditional 2D cultures. Using 3D cultures in drug discovery improves the accuracy of predicting how patients will respond to new medicines, ultimately increasing efficiency and reducing the cost of drug development. 

In this article, we explore the role of 3D biology in advancing research across various stages of the drug development pipeline.

Enhancing early-stage target identification 

Target identification and validation is a crucial phase in pre-clinical drug discovery. By culturing cells in 3D structures that resemble native tissues, scientists can gain deeper insights into the behavior of potential drug targets, including their interactions with neighboring cells, extracellular matrix, and effects on signaling pathways. Such enhanced comprehension helps researchers determine which targets are most promising for further investigation.

In particular, 3D models have gained popularity in elucidating tumor biology, as standard 2D models are inadequate to address questions about indolent disease, metastatic colonization, dormancy, relapse, and drug resistance.

Models focused on enhanced cell motility, induction of cell dormancy, and promotion of cell differentiation enable the possibility of more specifically targeting certain cell behavior in drug discovery. Moreover, the support of stem cell-like properties or a desired microenvironment like that of a metastatic niche introduces a novel potential for precision-driven target identification.

Using 3D cell cultures to model diseases and identify potential targets for therapy is still in its infancy but shows promise in translational research. For example, researchers have begun culturing cancer cells and cancer-associated fibroblasts in 3D structures that recapitulate biological and mechanical features of bladder cancer. These 3D models allow scientists to better understand the dynamic interactions between cancer cells and cancer-associated fibroblasts, as well as their effects on the surrounding extracellular matrix. This improved understanding has led to the identification of specific signaling pathways activated in the presence of cancer-associated fibroblasts, making them plausible targets for therapeutic intervention.

Optimizing compound screening 

Once potential targets are identified and validated, the next crucial step in drug discovery is screening various compounds to select potential drug candidates. Integrating 3D cell culture systems into high-throughput screening workflows adds a new dimension to this process. 

Many companies provide scaffold-based 3D culture systems in a high-throughput screening format for cell-based assay. Moreover, 3D spheroid culture techniques are today adapted and applicable for both basic research and high-throughput screening. While there is still room for optimization in the automated image acquisition and analysis process, combining high throughput screening and 3D cell culture appears to represent the most likely way forward.

By cultivating patient-derived organoids or disease-specific 3D models, researchers can also evaluate the nuances of disease mechanisms and gain insights into how drug candidates may counteract them. Notably, this approach has proven effective in deciphering complex aspects of cancer biology, such as drug resistance and the impact of combination therapies. 

As a result, 3D cell cultures are not only optimizing compound screening but also playing a pivotal role in shaping innovative strategies to address some of the most pressing and unmet therapeutic needs in recent years.

Elevating toxicity assessment

Drug-induced toxicity in the liver, heart, kidney, and brain accounts for more than 70 percent of drug attrition and withdrawal from the market. These adverse drug reactions are often due to off-target interactions or excessive drug molecules binding to toxicity-prone cells. 

An innovative approach to assess drug-induced toxicity involves the culture of organ buds representing critical structures like the brain, liver, heart, and kidney. 

In an exemplary breakthrough, scientists created a brain organoid by combining human embryonic stem cell-derived neural progenitor cells, endothelial cells, mesenchymal stem cells, and microglia/macrophage precursors on polyethylene glycol. They then used machine learning to predict the developmental neurotoxicity of different chemicals. Other studies also used lung-on-chip and heart-on-a-chip devices to evaluate drug-induced toxicity.

3D biology represents a paradigm shift in toxicity evaluation, and recent research highlights the benefits of combining advanced biological techniques with computational methods. This combination can revolutionize drug development, leading to a substantial decrease in the failure rate and enhancing the safety profile for novel compounds. 

Improving pharmacokinetics and pharmacodynamics screening 

A deep understanding of a drug candidate's pharmacokinetics and pharmacodynamics is crucial to optimize its use in patients and bolstering the drug development program. 

Researchers have found that 3D cell culture models, such as liver spheroids and liver organoids, are particularly effective to investigate the pharmacokinetic profiles of drug molecules. In addition, several versions of liver-on-a-chip systems have been used to measure rates of metabolic drug clearance, exhibiting significant correlation with human in vivo data.

The gut-on-a-chip system is another example of how 3D biology can improve pharmacokinetics and pharmacodynamics screening. This microfluidic platform replicates the absorptive properties and barrier function of the human intestine, making it a helpful tool for conducting permeability assays during early drug development.

Integrating multiple organ types into one chip, referred to as body-on-a-chip, can be another powerful tool for understanding the pharmacokinetics and pharmacodynamics of drug molecules. This method closely mimics human physiology and allows researchers to evaluate not only the impact of drugs on individual organs but also their overall effects on the body. By combining specific cell types and observing how they interact with each other, scientists can gain valuable insights into potential adverse reactions or synergistic effects of drugs.

Challenges and perspectives of 3D cell cultures

While several 3D assays have been validated for high-throughput screening and high-content screening, a notable gap remains in the comprehensive use of 3D screens with extensive compound libraries. Other areas of concern include labor intensiveness, material cost, scalability to 384 and 1,536-well plates, reproducibility, and compatibility with currently available assay and detection methods. 

Despite these challenges, the potential that 3D biology adds to the well-established 2D cell culture is undoubted. 3D models offer a more faithful representation of the human body's complexities, foster a deeper understanding of disease biology, optimize compound screening, and enhance pre-clinical testing. 

As 3D cell culture becomes more popular, the technique will be better understood, and more advanced methods will arise for its integration into drug discovery. Researchers using 2D cell culture models should consider exploring 3D cell culturing, as this technology has the potential to reduce the high attrition rate of drug discovery and improve treatments for patients.