Current Topics in Medicinal Chemistry - Volume 13, Issue 4, 2013

As we move towards an era of personalized medicine, molecular imaging contrast agents are likely to see an increasing presence in routine clinical practice. Magnetic resonance (MR) imaging has garnered particular interest as a platform for molecular imaging applications due its ability to monitor anatomical changes concomitant with physiologic and molecular changes. One promising new direction in the development of MR contrast agents involves the labeling and/or loading of nanoparticles with gadolinium (Gd). These nanoplatforms are capable of carrying large payloads of Gd, thus providing the requisite sensitivity to detect molecular signatures within disease pathologies. In this review, we discuss some of the progress that has recently been made in the development of Gd-based macromolecules and nanoparticles and outline some of the physical and chemical properties that will be important to incorporate into the next generation of contrast agents, including high Gd chelate stability, high “relaxivity per particle” and “relaxivity density”, and biodegradability.

Potentials of hydrophilic and biocompatible ligand coated gadolinium oxide nanoparticles as multimodal imaging agents, drug carriers, and therapeutic agents are reviewed. First of all, they can be used as advanced T1 magnetic resonance imaging (MRI) contrast agents because they have r1 larger than those of Gd(III)-chelates due to a high density of Gd(III) per nanoparticle. They can be further functionalized by conjugating other imaging agents such as fluorescent imaging (FI), X-ray computed tomography (CT), positron emission tomography (PET), and single photon emission tomography (SPECT) agents. They can be also useful for drug carriers through morphology modifications. They themselves are also potential CT and ultrasound imaging (USI) contrast and thermal neutron capture therapeutic (NCT) agents, which are superior to commercial iodine compounds, air-filled albumin microspheres, and boron (10B) compounds, respectively. They, when conjugated with targeting agents such as antibodies and peptides, will provide enhanced images and be also very useful for diagnosis and therapy of diseases (so called theragnosis).

Magnetic resonance imaging (MRI) contrast agents have been used routinely for more than 20 years in order to increase sensitivity and specificity of lesion detection. MRI contrast agents (CAs) are usually categorized according to their magnetic behavior, biodistribution, and effect on the MR image. Typically, small molecular-weight gadolinium based CAs are examples of T1 agents, while magnetic nanoparticle (MNP) based CAs are examples of T2 agents. In addition to differences in magnetic relaxation behavior, small molecular-weight gadolinium based CAs and MNP based CAs show significantly different toxicity profiles. In the case of small molecular-weight gadolinium based CAs, many previous toxicological studies have reported favorable safety profiles of gadolinium based CAs. However, recently, a delayed serious adverse reaction known as nephrogenic systemic fibrosis (NSF) has been reported in patients, with a marked reduction in renal function after administration of certain types of gadolinium based CAs. For MNP based CAs, in addition to a wide spectrum of nanotoxicity common in nanomaterials, the emerging unexpected cytotoxicity of MNPs has become a new concern. Specifically, the combination of MNPs and strong static magnetic field (SMF) within MRI may give rise to potential adverse effects of MNPs in clinical application.

Positron emission tomography with 89Zr can be used to follow the behaviour of therapeutic monoclonal antibodies (mAbs) and other biologicals in vivo. The favourable radiophysical characteristics of 89Zr allow multiple days PET scanning after injection. For the coupling of 89Zr to proteins six desferrioxamine (DFO)-based bifunctional chelators have been described, five of which forming stable complexes in vivo. Of the methods that give stable complexes three are based on random lysine modification of mAbs and two on site-specific engineering. Up to now only two methods, random lysine modification with N-suc-DFO or DFO-Bz-NCS, have been used in clinical studies. In this review firstly aspects of the physicochemical properties and production of 89Zr are emphasized as well as important items that have to be taken into account for current good manufacturing practice (cGMP) compliant production of 89Zr-labeled proteins. Next, the different DFO-based conjugation strategies will be discussed with respect to synthesis, and their (pre)clinical evaluation particularly in the field of oncology.

Theranostic medicine is relatively a new term that describes integration of diagnostic and therapeutic functions within the same platform of pharmaceuticals. Such a design may in principle permit the molecular diagnosis, targeted therapy, and simultaneous monitoring and treatment necessary to achieve personalized medicine for cancer. Theranostic radiopharmaceuticals, for instance, carry the properties of both diagnostic radioimaging and radioimmunotherapy (RIT). As nuclear imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) have excellent sensitivity and can provide biochemical information on pathological conditions, much effort has been made in order to accomplish a more effective and powerful theranostic combination. Some recent examples include SPECT-therapy, PET-therapy, and therapy-therapy. In particular, the combined therapy-therapy method is the result of realization that RIT relying on a single radioisotope has an inherent limitation for practical cancer treatment. Thus the success of theranostic nuclear medicine depends on a proper choice of different radioisotopes that will lead to a perfect couple. This pair of radioisotopes is called matched-pair radioisotopes. The structural motif for radiopharmaceuticals based on matched-pair consists of a bifunctional chelator (BFCA) and a biologically active molecule (BAM). This review will focus on recent advances in radiopharmaceutical application of matched-pair radiometals in clinics as well as preclinics.

Labeling nanoparticles with radionuclides has been widely used to form multifunctional and multivalency agents for various biomedical applications. A variety of nanostructures including inorganic, organic and lipid nanoparticles have been labeled with positron or gamma emitting radioisotopes through versatile radiochemistry in a number of disease models to track their in vivo fate, image biomarkers, and monitor treatment response. This review briefly summarizes the recent applications of nanoparticles labeled with radionuclides for oncological, cardiovascular, and pulmonary theranostics.

At present, a limited number of strategies exist for diagnostic imaging of patients with bacterial infection. While radiolabeled probes and white blood cells provide robust solutions to detect bacteria in humans, they also give false positives in cases of sterile inflammation. With the onset of bacterial drug resistance, and a clinical trend toward reducing the prescription of antibiotics, the need for highly specific infection detection protocols has been renewed. The preclinical research community has recently utilized new optical imaging strategies, alongside traditional radioimaging research, to develop novel infection probes with translational potential. Here we review the current clinical methods for imaging bacteria in humans, and discuss the efforts within the preclinical community to validate new strategies. The review of preclinical infection imaging probes is limited to those probes that could be feasibly adapted for use in humans with currently available clinical modalities.

In this review, we are going to demonstrate the recent progresses in inorganic nanomaterial-based nanomedicines and their labeling for effective biological imaging. Nanomaterials which are classified according to their dimensionality, from zero- to three-dimensions can be utilized as nanomedicines including drug delivery, therapy and diagnosis. In the following section, the labeling of nanomaterials with various contrasting agents are introduced. Various labeling agents like fluorescence, quantum dots, upconversion nanoparticles, magnetic particles and radioisotopes can be tagged on nanomaterials for effective imaging such as optical, magnetic resonance, computed tomography, positron emission tomography and etc. The labeling of contrasting agent on nanomedicine can be summarized into intercalation, surface modification, embedment and combination depending on how and where the label is tagged. Through these approaches, multimodal biological imaging and multifunctional nanomedicine could be suggested.

The development of imaging probes based on advances in nanotechnology aims to substantially improve specificity and sensitivity of diagnostic imaging through non-invasive and quantitative detection of specific biomolecules in living subjects. A promising class of molecular imaging probes consists of nanoparticles (NPs) functionalized with a certain targeting agent. Such targeting agents can, for instance, be selected to recognize disease-related biomarkers located on the cell surface. Among the possible agents that direct the NPs to the target site, aptamers, being single-stranded DNA or RNA molecules that can be designed to bind preselected targets such as proteins and peptides with high affinity and specificity, play an increasingly important role. Indeed, aptamers selected against proteins or whole cells have been conjugated to a variety of nanomaterials (NMs) such as Au NPs, quantum dots (QD), and superparamagnetic iron oxide NPs (SPIONs). These probes have successfully been used for cell imaging, both in vitro and in vivo, by optical imaging, magnetic resonance imaging (MRI), computed tomography (CT), and positron-emission tomography (PET). This review presents an overview of the commonly used techniques involved in conjugating aptamer to NPs and their application as probes in cellular or in vivo imaging.

X-ray computed tomography (CT), an efficient non-invasive clinical technique, usually provides highresolution 3D structure details of tissues in early disease diagnosis. Here, we report a high-performance CT imaging platform based on a monodispersed Yb-based nanoparticulate contrast agent. The well-prepared nanoprobes presented excellent in vitro and in vivo performances in the CT imaging, very low cytotoxicity and no detectable tissue damage in one month. More significantly, compared with routinely used Iobitridol in clinic, our Yb-based CT contrast agents provided much more enhanced contrast at a clinical 120 kVp voltage. Additionally, these nanoparticulate contrast agent could be excreted mainly via feces and urine, indicating the total elimination from the animal bodies and more potential for further biomedical applications.

The preparation of a synthetic receptor for multivalent protein binding by a directed immobilization of bifunctional ligands was demonstrated using pentameric C-reactive protein (CRP) and a thiolated phosphocholine-containing ligand on a gold surface. CRP consisting of five identical, noncovalently linked subunits and having five phosphocholinebinding sites on the same face was complexed with 12-mercaptododecylphosphocholine. The complexes were reacted with a gold surface, which was blocked with BSA or 2-mercaptoethanol to avoid non-specific binding. CRP binding to the molecularly imprinted monolayer was investigated by surface plasmon resonance, exhibiting high sensitivity with a detection limit as low as 1 pM (0.12 ng/mL) and binding affinity (KA ~ 10-7-10-9 M-1) comparable to that of immobilized anti- CRP.