In this review an overview about biological applications of magnetic colloidal nanoparticles will be given, which comprises their synthesis, characterization, and in vitro and in vivo applications. The potential future role of magnetic nanoparticles compared to other functional nanoparticles will be discussed by highlighting the possibility of integration with other nanostructures and with existing biotechnology as well as by pointing out the specific properties of magnetic colloids. Current limitations in the fabrication process and issues related with the outcome of the particles in the body will be also pointed out in order to address the remaining challenges for an extended application of magnetic nanoparticles in medicine.

Biological applications of magnetic nanoparticles

Lanthanide Nanoparticles: From Design toward Bioimaging and Therapy

X-ray computed tomography (CT) is a well-established tissue imaging technique employed in a variety of research and clinical settings.1 Specifically, CT is a non-invasive clinical diagnostic tool that allows for 3D visual reconstruction and segmentation of tissues of interest. High resolution CT systems can be used to perform non-destructive 3D imaging of a variety of tissue types and organ systems, such as: the gastrointestinal tract, cardiovascular system, renal tract, liver, lungs, bone, cartilage, tumorous tissue, etc. CT is one of the most prevalent diagnostic tools in terms of frequency-of-use and hospital availability.2 The use of CT is on the rise and the number of clinical CT scanners in operation worldwide is estimated at over 45,000.1b Today, over 70 million clinical CT scans are performed yearly in the U.S. alone. For a recent detailed analysis of the use of clinical CT imaging and data regarding the number of regular and contrast-enhanced CT scans performed annually in the U.S. we refer the reader to the “Nationwide Evaluation of X-ray Trends” survey published by the Conference for Radiation Control Program Directors (CRCPD).3

The idea of using tomography (Greek: tomos = slice, graphein = draw) as a diagnostic tool in medicine was adopted soon after the discovery of X-rays by W. C. Roentgen in 1895. However, several more decades passed before the technology advanced sufficiently to bring those ideas to fruition. The first successful CT imaging device was built in 1972 by G. N. Hounsfield, at Electric and Musical Industries Ltd. In 1979, G. N. Hounsfield and South African physicist A. M. Cormack shared a Nobel Prize in medicine for their contributions to the field of X-ray CT imaging and diagnostics.4

X-rays are a form of electromagnetic radiation with wavelengths roughly between 0.01 nm and 10 nm. Traditionally, X-rays are generated by a vacuum tube using high voltage to accelerate electrons from a cathode to a (usually) tungsten-alloy anode. In the process, the accelerated electrons release electromagnetic radiation in the form of X-rays and the maximum energy of the radiation is limited by the energy of the incident electron. Operating voltages of modern clinical CT scanners differ among instrument models and manufacturers, but generally fall between 80 kVp to 150 kVp.

As a rule, materials possessing higher density (ρ) or high atomic number (Z) tend to better absorb X-rays. The relationship is best expressed in the formula for X-ray absorption coefficient (μ): 


μ≈ρZ4AE3

(1)


where “A” is the atomic mass and “E” is the X-ray energy. The strong relationship between absorption and atomic number is of significant importance in clinical applications. The Z4 factor allows for contrast levels of several orders of magnitude between different tissues and types of contrast agents.

When an incident X-ray has energy equal or slightly greater than the binding energy of the K-shell electron of the atom, a large sudden increase in absorption coefficient is observed. This energy value is known as absorption edge (k), and the k value increases with atomic number of the element. Consequently, X-ray attenuating contrast media containing atoms of high atomic number (most commonly iodine or barium), are frequently used in clinical settings to obtain images of soft tissues. To generate images with the highest contrast to the surrounding tissue, the energy of the X-ray source can be adjusted to closely match the absorption edge value (k) of the relevant imaging-agent atoms (i.e., iodine, barium, gold, etc.). Thus, it is also possible to do selective X-ray imaging and to differentiate between attenuating materials by fine tuning the energy source to the appropriate absorption edge value.

A CT image is obtained by rotating an X-ray source around an object, with a detector positioned directly opposite the radiation source. Alternatively, in many preclinical CT scanners the object sometimes is rotated around its own axis. Such preclinical scanners are often being used for small animal in vivo imaging. Generally, X-ray scans are taken at small angular increments during rotation around the object over 360°. A series of attenuation profiles or projections is thus obtained. The projections are then processed mathematically to create a 3D rendition of the scanned object. An in depth description of the engineering principles underlying modern CT imaging instruments is beyond the scope of this manuscript, and the reader is referred to other published works.1c,5

A diagnostic imaging method related to CT is X-ray fluoroscopy. Fluoroscopy allows for the acquisition of real-time, continuous images of the internal organs. Like in CT, imaging agents are often used in fluoroscopy for better contrast resolution. Small iodinated agents are commonly injected into blood vessels for use in fluoroscopic angiography, allowing for the evaluation of blood flow and visualization of the vasculature system, while barium contrast media are introduced orally or with an enema to investigate the anatomy (and pathology) of the gastrointestinal tract.

The introduction of magnetic resonance imaging (MRI) resulted in a loss of interest and reduction in CT contrast agent development throughout the 1980s. However, advances in computer technology, and the introduction and widespread adoption of spiral-CT in the mid-1990s have sparked a revival of interest in CT imaging and CT contrast media. Current clinical CT scanners are capable of acquiring high resolution 3D isotropic images of the body within several minutes. CT imaging today is less time consuming, less expensive, and more readily available than other medical imaging technologies such as MRI and positron emission tomography (PET). In the last several years, the emergence of novel technologies such as dual-source CT, and multi-detector CT has advanced the field of CT imaging even further. As a comparison to X-ray imaging diagnostic methods, PET imaging employs gamma-ray emitting radioactive nuclei “tracers” as contrast agents while MRI takes advantage of nuclear magnetic resonance principles by applying high magnetic fields to align magnetization of certain atomic nuclei. In contrast to CT and PET imaging, MRI uses no ionizing radiation and it is therefore often deemed safer than the other two.

X-ray-Computed Tomography Contrast Agents

Glutathione-coated luminescent gold nanoparticles (GS-AuNPs) with diameters of ∼2.5 nm behave like small dye molecules (IRDye 800CW) in physiological stability and renal clearance but exhibit a much longer tumor retention time and faster normal tissue clearance, indicating that the well-known enhanced permeability and retention effect, a unique strength of conventional NPs in tumor targeting, still exists in such small NPs. These merits enable the AuNPs to detect tumor more rapidly than the dye molecules without severe accumulation in reticuloendothelial system organs, making them very promising for cancer diagnosis and therapy.

/pdf/passive-tumor-targeting-of-renal-clearable-luminescent-gold-6emxenl3z5.pdf

Passive tumor targeting of renal-clearable luminescent gold nanoparticles: long tumor retention and fast normal tissue clearance.

Computed tomography (CT) is one of the most widely used clinical imaging modalities. In order to increase the sensitivity of CT, small iodinated compounds are used as injectable contrast agents. However, the iodinated contrast agents are excreted through the kidney and have short circulation times. This rapid renal clearance not only restricts in vivo applications that require long circulation times but also sometimes induces serious adverse effects related to the excretion pathway. In addition, the X-ray attenuation of iodine is not efficient for clinical CT that uses high-energy X-ray. Due to these limitations, nano-sized iodinated CT contrast agents have been developed that can increase the circulation time and decrease the adverse effects. In addition to iodine, nanoparticles based on heavy atoms such as gold, lanthanides, and tantalum are used as more efficient CT contrast agents. In this review, we summarize the recent progresses made in nano-sized CT contrast agents.

Nano‐Sized CT Contrast Agents

The water-solvable FePt nanoparticles of 3, 6, and 12 nm in diameter (3 nm-, 6 nm-, and 12 nm-FePt) were synthesized and applied as a dual modality contrast agent for CT/MRI molecular imaging. These nanoparticles present excellent biocompatibility and hemocompatibility in all test concentrations for the imaging contrast. The biodistribution analysis revealed the highest serum concentration and circulation half-life for 12 nm-FePt, followed by 6 nm-FePt then 3 nm-FePt. Thus, the 3 nm-FePt showed higher brain concentrations. Anti-Her2 antibody conjugated FePt nanoparticles demonstrated molecular expression dependent CT/MRI dual imaging contrast effect in MBT2 cell line and its Her2/neu gene knock out counterpart. Selective contrast enhancement of Her2/neu overexpression cancer lesions in both CT and MRI was found in tumor bearing animal after tail vein injection of the nanoparticles. The 12 nm-FePt outperformed 3 nm-FePt in both imaging modalities. These results indicate the potential of FePt nanoparticles to serve as novel multimodal molecular imaging contrast agents in clinical settings.

/pdf/in-vitro-and-in-vivo-studies-of-fept-nanoparticles-for-dual-1es7fm36o1.pdf

Yu Sang Yang

Papers

In Vitro and in Vivo Studies of FePt Nanoparticles for Dual Modal CT/MRI Molecular Imaging