Diagnosis and treatment of diseases at the nano-level

Despite rapid progress, modern medicine remains largely reactive, addressing patients’ needs only after they visit their doctor with recognizable symptoms such as pain or function loss. By this time, many diseases have already progressed to the point where radical intervention – for example, surgery, radiation or potent drug therapies such as chemotherapy – are required to combat them. These late-stage interventions often require hospitalization and frequently have side effects that result in a significant level of patient discomfort, stress and anxiety.

The biochemistry of disease, however, starts well before symptoms become apparent. The new paradigm of ‘molecular medicine’ aims to detect the molecular hallmarks (typically biomarkers) of disease before patients experience symptoms, allowing much earlier diagnosis and far less traumatic therapies that employ highly targeted drugs. Early diagnosis and personalized treatment is widely regarded as one of the best ways of meeting the demand for effective healthcare while also controlling costs.

Molecular medicine itself is not new. Its origins lie in the first understanding of metabolic pathways within the human body, and the subsequent realization that specific genetic defects lead to enzyme deficiencies that disturb these pathways. Today’s knowledge of metabolic processes and the ways in which gene expression can affect them is vastly more detailed. Researchers have deciphered the human genome and are now getting an increasingly deeper insight into the protein networks and signal transduction pathways involved in body homeostasis and pathological processes. Yet even today, relatively little of this knowledge has been translated into clinical practice for the diagnosis and treatment of disease, largely because of the very high costs associated with developing and approving new forms of therapy.

Enabling medical technologies
Technology has consistently been a valuable tool in translating medical knowledge into patient care, and this will be no less true for molecular medicine. In order to detect the molecular biomarkers of disease, the enablers of molecular medicine will be technological developments such as ultra-sensitive diagnostic tests and molecular imaging that can identify and pinpoint molecular abnormalities at cellular and sub-cellular level.

The increased sensitivity of new biosensor technologies will make in-vitro tests a very powerful tool for patient stratification and diagnosis. In addition to new and more sensitive laboratory-based tests, there will be an ever-increasing need to move these tests out of the laboratory and into the field, through the use of highly integrated handheld or desktop in-vitro testing equipment. This is an area where disposable biosensors based on magnetic nanoparticles and magneto-resistive sensors are already showing promise.

At the same time, medical imaging modalities are rapidly improving by achieving unprecedented performance in terms of resolution, sensitivity and speed. For example, the latest 256-slice CT scanner can capture a detailed image of the entire heart in just two beats. Moreover, medical imaging modalities are evolving into extremely powerful tools for molecular imaging. Molecular imaging visualizes contrast agents with the help of imaging systems such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), molecular magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), optical bioluminescence and fluorescence, and ultrasound (US).

In addition to the development of improved imaging modalities and novel targeted imaging agents, molecular imaging will be further enabled by dedicated software for the quantification and analysis of imaging data. For example, dynamic PET imaging provides information on physiological processes in the human body. Algorithms based on the known time-related behavior of PET tracers allow the extraction of additional quantitative data about physiological processes in the target structures through a technique known as pharmacokinetic modeling (the absorption, distribution, metabolism and excretion, or ‘ADME’ of the tracer). Computer aided diagnosis (CADx) software tools are also emerging for the interpretation of imaging data. For example, a CADx system is under development that automatically interprets PET brain scans of patients suspected of having a neurodegenerative disease that leads to dementia, and combines them with MRI scans for differential diagnosis.

Applications
In addition to enabling the early diagnosis of disease, these developments will also allow drug therapies to be tailored to an individual patient’s genotype and phenotype. The potential for molecular imaging to track the pharmacodynamics (e.g. mode of action) and pharmacokinetics of drugs will also make it a valuable tool for drug development (in particular, in pre-clinical and clinical trials) as well as providing better and faster feedback on the therapeutic efficacy of drugs in individual patients.

Molecular imaging has already proved its value in pre-clinical trials. The current challenge is to extend its use into phase-I and phase-II clinical trials, where its ability to follow the pharmacodynamics and pharmacokinetics (ADME) of drugs at cellular and sub-cellular level will open up the possibility of micro-dosing studies of drug efficacy in clinical studies (administering a drug to healthy individuals at dose rates well below toxicity levels, often referred to as clinical phase-0 studies). The detection limit for PET is in the picomolar region. SPECT is less sensitive by one to two orders of magnitude (nanomolar). Such techniques will allow pharmaceutical companies to halt the development of problematic candidate drugs at an earlier stage in the evaluation process, significantly reducing the soaring cost of drug development.

Similar imaging techniques could even be of value in regenerative medicine, by tracking the delivery and homing of stem cells. In clinical practice, ultrasound imaging using microbubble contrast agents has been employed in the diagnosis of heart failure and liver disease, and in other important applications. In addition to improving the sensitivity of ultrasound imaging, specifically synthesized microbubbles can also carry defined quantities of drugs or synthetic genetic material, either in their interior or coated onto their surface. Carried via the bloodstream to diseased tissue within the body, they can be locally detected, quantified and their payload released by ultrasound pulses.

Outlook
The result of early diagnosis and treatment with better drugs and therapies will be that patients enter the care cycle much earlier and receive much more of their after care in the community. This will leave hospitals free to focus their resources on dealing with acute and complex cases. High-end diagnostic and treatment procedures such as molecular imaging and radiotherapy, where expensive equipment is required, will remain concentrated in specialist units. In contrast, however, much of in-vitro diagnostics will become far less centralized, moving from the laboratory to the doctor’s office and patient’s bedside.

Where hospitalization is required, it will be for much shorter periods, helping to reduce the incidence of hospital-borne infections and allowing people to return to the comfort of their own homes sooner. Based on an understanding of how each individual patient’s genotype and phenotype affects the way their body deals with disease, patient treatments will become far more personalized. All of these developments will create a much more holistic view of healthcare in which the entire care cycle for a particular patient becomes a single, highly patient-centered and coordinated exercise.