Targeted Molecular Imaging

The developing field of molecular imaging spans all biomedical imaging modalities including nuclear medicine, MRI, X-ray, CT, ultrasound, and optics; Molecular imaging is possible with the use of targeted contrast agents or probes that are detectable with the imaging modalities and localize to known receptors or targets on cells or in tissue. The resulting images therefore represent the three-dimensional spatial distribution of the targeted molecules within the tissue and can provide diagnostic information at the molecular level, or for revealing the functional properties of the cells. The figure shown here metaphorically illustrates the whole spectrum of molecular optical contrast agents based on the origin of contrast and their functionality.

Molecular imaging is defined as the characterization and observation of biological processes at a cellular level or molecular level using in vivo methods. Tremendous developments in the field of biomedical imaging in the past two decades have resulted in the transformation of anatomical imaging to molecular-specific imaging. The developments in the field of nano and biotechnology have created a profound impact on the biomedical imaging research community allowing scientists to identify, follow and quantify subcellular biological processes and pathways within a living organism. Molecular imaging is expected to play an important role in oncology, for example, by aiding the early detection of malignancies, locating metastatic disease, staging tumors, evaluating the availability of therapeutic targets, and monitoring the efficacy of treatment.

Molecular contrast agents

Novel molecularly-targeted contrast agents are being developed which enhance the diagnostic imaging capabilities of OCT and other non-fluorescent or non-bioluminescent imaging techniques. These include scattering microspheres as contrast and drug-delivery agents, magnetomotive nanoparticles, plasmon-resonant nanoparticles, and absorbing near-infrared dyes. In addition, there are a large number of optical properties and characteristics from contrast agents that can be leveraged to enable optical molecular imaging of cells and tissues. Strategies to generate molecular contrast in images have evolved dramatically in the past two decades from traditional dyes to highly sophisticated molecular agents that are generally sized in the range of hundreds of microns down to a few nanometers (figure) Illustrated below

Magnetomotive imaging

Principle of magnetomotion

Magnetomotion of contrast agents through an externally modulating magnetic field is an excellent mechanism for achieving dynamic contrast. This can be realized by using paramagnetic particles as contrast agents. Human tissue exhibits an extremely weak magnetic susceptibility (< |10-5|). Hence the employment of magnetic probes with ~1 provides a large potential dynamic range of magnetic contrast. Iron oxide, such as magnetite, with paramagnetic properties and ~1 is a good candidate with known biocompatibility after coating with biocompatible polymers such as dextran. Paramagnetic iron oxide magnetic nanoparticles (MNPs) have been already approved as contrast agents in MRI. These micron and nano-sized MNPs can be actuated externally using a modulating magnetic field. In the presence of a high magnetic field gradient, particles with high magnetic susceptibility embedded in tissue experience a gradient force, and ferromagnetic particles rotate to align their internal magnetization along the field. The resulting magnetomotion of the MNPs and the perturbation of the surrounding cells and extracellular matrix result in a change in the scattering properties of the local tissue microenvironment under observation In an elastic medium, the particle returns to its original position and orientation after removal of the magnetic field. This permits modulation of its position by repetitively modulating the magnetic field. The resulting increase in contrast due to magnetomotion can be effectively detected by an OCT system. The magnetomotive response of the tissue phantom to different magnetic field excitations can easily be demonstrated by performing M-mode imaging at one point on a tissue phantom. A step excitation or a sweep of frequencies applied to the sample under study is used to extract information about the mechanical and viscoelastic properties of the biological tissue. Doing this, one can find the resonant mechanical frequency of the biological sample as well.

Magnetomotive Optical Coherence Tomography (MM-OCT) is an important tool for the visualization and quantitative assessment of nanoparticles in tissues. This technology has many potential diagnostic and therapeutic applications.

Magnetomoive contrast agents

The magnetic nanoparticles can be used with magnetic resonance imaging (MRI) as well as OCT and, potentially, other imaging technologies, enabling biomechanical tissue measurements, contrast, and therapy through hyperthermia. This represents an entirely new class of imaging agents that we can use to tell more about the tissue, for diagnostic purposes and for therapeutic techniques.

MM-OCT imaging of chicken skin topically administered with Iron Oxide nanoparticles is illustrated in figure. The green channel shows the MM-Oct signal superposed on the structural OCT image ( red channel).

In vivo magnetomotive OCT of magnetic nanoparticles in a Xenopus (African frog) tadpole model.

Magnetomotive OCT of single cells dispersed in a 3-D gel. Cells containing magnetite are clearly identified.

MM-OCT can be effectively for quantitative measurement of magnetic iron-oxide nanoparticle transport and concentration in biological tissues like muscle, lung and liver. The effect of temperature on the dynamics of these nanoparticles is also analyzed. We observe that the rate of transport of nanoparticles in tissues is directly related to the elasticity of tissues, and describe how the origin of the MM-OCT signal is associated with nanoparticle binding. These results improve our understanding of how iron-oxide nanoparticles behave dynamically in biological tissues, which has direct implications for medical and biological applications of targeted nanoparticles for contrast enhancement and therapy.