Precision medicine, in the current excitement of drug discovery, is now on the agenda. This is a question that scientists and clinicians must ask: how do the therapeutic drugs work on the body – at the cellular and tissue level? We measure biomarkers in tissues through advanced imaging – our ability to test novel drugs for efficacy, safety and mechanism of action. We discuss how imaging is used to map biomarkers in tissues to identify drugs, why it is important to do so, imaging techniques, and limitations and opportunities in the technologies in this paper.

BIOMARKS and Drug Discovery: What's Going On?

Biomarkers are molecules, cells or biochemical markers that can tell us useful things about the pathogenesis of disease, the response to drugs and treatment. For the purpose of drug design, biomarkers define the biology of biological response to a drug, the disease burden and efficacy. Especially for patient stratification, drug-drug combination and side-effect monitoring before clinical trials.

Figure 1. Overview of the imaging biomarker roadmap. (O'Connor JP, et al.; 2017)

So let's separate biomarkers into diagnostic, prognostic, predictive and pharmacodynamic. Especially useful for drug development are pharmacodynamic biomarkers, which immediately reveal how a drug will affect its target and how the body responds to treatment. Imagery biomarkers, a type of pharmacodynamic biomarker, allow us to observe the tissue reaction to drugs at any point, across space and time, in real-time, as biochemical analysis simply isn't.

Imaging Modalities for Monitoring Biomarkers

We look for biomarkers in tissues with imaging tools of every type to help us design drugs. Whether it's non-invasive methods with real-time data capture, or spatially resolved tissue profiling. The main imaging techniques used here are as follows:

1. Magnetic Resonance Imaging (MRI)

MRI is an excellent non-invasive imaging method in drug discovery for evaluation of soft tissue. MRI has the ability to measure very spatial detail and even images of the anatomy. Combining it with contrast agents or MRI sequences can show abnormal tissue, or track changes in biomarkers of disease and response to therapy.

In drug development, the use of functional MRI (fMRI) and MRI molecular imaging is on the rise. fMRI monitors fluctuations in blood flow and oxygenation, and can tell us about how tissues react to medications. Molecular MRI, however, involves focusing contrast agents on individual biomarkers so that precise molecular pathways in disease and drug action can be visualized.

2. Positron Emission Tomography (PET)

PET scans are also invaluable for monitoring molecular biomarkers. PET works by injecting radiolabeled compounds (radiotracers) that attach to certain biomarkers or biological targets in the body. By picking up the positrons that bounce back, PET can track the drug's delivery, binding and action in real time.

The greatest benefit of PET is that it gives you anatomical and functional data. - Used to investigate drug pharmacokinetics, biodistribution and receptor-ligand interactions. PET is now most useful in oncology to follow the treatment response of tumours through modifications in metabolism, tumour size and proliferation.

3. Computed Tomography (CT) Imaging

The other modality, often combined with PET (PET/CT), is CT imaging. The better the soft tissue contrast with MRI, the better the CT can give you super-high-resolution images of bone, and the more useful it is for checking changes in tissue density. On CT, we can also measure tumour size, morphology and vascularisation changes, biomarkers for oncology.

CT is used in drug development to evaluate efficacy of treatments, especially with solid tumours, and to observe how drugs alter the anatomy and function of tissues. The availability of dual-modality imaging, like PET/CT, means that scientists can receive synaptic data on the function and structure of tissues – making biomarker detection more sensitive and precise.

4. Fluorescence Imaging

As a way to track biomarkers within tissues, especially cells, fluorescence imaging is on the rise. Fluorescence-based methods such as confocal microscopy and intravital imaging enable scientists to see with ultra-sensitivity the active unfolding of biomolecules in living tissues. Using fluorescent probes to identify particular biomarkers, scientists can then monitor tissue-specific interactions, drug delivery and cellular capture as they happen.

Fluorescence molecular tomography (FMT) is a promising imaging technology that fuses fluorescence and tomography to give 3D tissues pictures. FMT can be applied especially to preclinical studies, to track the spread of drug candidates, receptor-ligand interactions and tissue responses to drugs.

5. Optical Coherence Tomography (OCT)

OCT is a non-invasive imaging technology that gives you high-resolution cross-sectional images of tissue, which can be used to track biomarker expression and tissue changes in time. The most common use is in ophthalmology, but oncology, cardiology and neurology are joining the ranks.

For drug development, OCT tracks the effect of treatment on the morphology of tissues – tumour shrinkage, vascular changes, and extracellular matrix integrity. A real-time, high resolution image of tissues in real time without the use of contrast is a powerful feature of OCT for drug detection, especially in the clinic.

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Imaging Monitoring of Biomarkers in Tissues

Problems of Imaging Biomarkers for Drug Development?

Even with all the improvements made in imaging technologies, there are some problems with imaging for biomarker monitoring in drug development.

1. Resolution and Sensitivity

Imaging imaging with MRI, PET and fluorescence has improved tremendously in resolution and sensitivity, but we still need better spatial and temporal resolution to see how biomarkers may change, even slightly, at the cellular or molecular level. This constraint is most obvious when it comes to tracking biomarkers that are present in low levels or in heterogeneous tissues (tumours).

2. Tissue Penetration

Most imaging methods can still only penetrate tissues and get good images. Fluorescence imaging, for instance, is very sensitive but doesn't penetrate deep tissue, so you have to use special probes or close-infrared fluorescence to get deeper tissues.

3. Quantification and Standardization

The most difficult aspect of imaging biomarker tracking is that there are no consistent protocols for estimating biomarker expression in various imaging modalities. Variation in imaging, contrast material and experiment can result in ambiguous findings that could complicate the analysis of data and derail successful biomarker-based drug therapies.

4. Cost and Accessibility

Advanced imaging like PET and MRI are more expensive and more skilled, making them less common, especially in resource-constrained environments. They also can be prohibitively expensive in the context of preclinical and clinical drug development, particularly in early-stage trials, where funding may be limited.

Opportunities and Future Directions

All this said, imaging biomarker tracking in drug development has the future bright. Nanotechnology, molecular imaging agents and hybrid imaging techniques promise better, more sensitive and less invasive biomarker surveillance.

Nanoparticle Imaging Agents: The research of nanoparticle imaging agents can significantly improve image quality and penetration into tissues. They can be highly sensitive for the cellular and molecular expression of biomarkers as these agents are directed at individual biomarkers.

Integration of Artificial Intelligence (AI): AI and machine learning algorithms are being built more frequently into imaging workflows to better manage large datasets. AI can help identify, measure and interpret biomarkers automatically – without having to invest time and expertise to interpret data.

Personalised Drug Monitoring: As personalized medicine evolves, biomarker monitoring in real time using the new imaging technologies will be essential for personalizing therapies for individual patients. This way, the therapy can be designed to be more effective, less toxic and better for the patients.

Conclusion

Tissue-level biomarkers are monitored with imaging and have become a tool that drug developers must use. Imaging technology is enabling non-invasive monitoring of drug activity, biomarker expression and tissue responses in real time, changing the way new therapies are trialled and developed. Resolution, sensitivity and standardisation will be difficult to achieve, but developments in imaging methods, nanoparticles and AI could make it happen, and precision medicine would become real.

1. O'Connor JP, et al.; Imaging biomarker roadmap for cancer studies. Nat Rev Clin Oncol. 2017, 14(3):169-186.

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