Current Protein and Peptide Science - Volume 17, Issue 6, 2016

Prostate cancer is the most common cancer for man with a high mortality rate due to a lack of non-invasive accurate and sensitive molecular diagnostic methods. The molecular imaging of cancer biomarkers using MRI with its spatial and temporal resolution, however, is largely limited by the lack of contrast agents with high sensitivity, targeting specificity and deep tumor penetration. In this review, we will first overview the current stage of prostate cancer diagnosis and then review prostate cancer biomarkers and related imaging techniques. Since biomarker targeting moieties are essential for molecular imaging, we will use prostate-specific membrane antigen (PSMA) as an example to discuss different methods to characterize the interaction between biomarker and targeting moieties. At the end, we will review current progress of the development of targeted protein-based MRI contrast agents (ProCAs) for prostate cancer biomarkers with improved relaxivity and targeting capability.

The epidermal growth factor receptor (EGFR) plays important roles in cell proliferation, suppression of apoptosis, increased motility, and recruitment of neovasculature. Overexpressed or mutated EGFR has been an important biomarker for cancer diagnosis and molecular target for many anticancer drugs because it frequently occurs in many common human cancers. Localizing and estimating the expression of EGFR can potentially identify patients who have tumors that overexpress EGFR and would, therefore, most likely benefit from a targeted treatment to avoid overtreatment and undertreatment. Traditional biopsy methods are invasive, and analysis of the specimens is not sufficient for real-time detection of the lesions or for monitoring the therapeutic efficacy of anticancer drugs. Molecular imaging, a technology of in vivo characterization and measurement of biological processes at the cellular and molecular level, can fulfill these goals. In this review, we summarize current molecular imaging techniques including optical imaging, magnetic resonance imaging, single photon emission computed tomography, and positron emission tomography for in vivo EGFR visualization and discuss their advantages and disadvantages. Special emphasis is placed on noninvasive imaging mutant EGFR with emerging new agents and new imaging technologies to distinguish the maximum benefit to cancer patients for molecular targeted therapy.

Neurologic disorders are prevalent diseases in the population and represent a major cause of death and disability. Despite the advances made during recent decades, the early diagnosis of these diseases remains a challenge. Determining the pathophysiology of such disorders is also challenging and is a requirement for the development of new drugs and treatments. Molecular neuroimaging studies can help fill these gaps in knowledge by providing clinicians with the tools necessary to diagnose and monitor treatment response and by providing data to help researchers understand the mechanisms of disease. Molecular imaging is a fast-growing field of research, and the development of imaging probes is crucial to molecular imaging research. Imaging based on peptide and small protein molecular probes provides many advantages over traditional neuroimaging for the identification of many pathological aspects of nervous diseases, especially gliomas, for which this type of imaging is gradually being moved to clinical settings. Nonetheless, peptide and small protein imaging also has potential applications in other neurologic diseases such as stroke, Parkinson’s disease and Alzheimer’s disease. This review is focused on the main peptide and small protein probes used for molecular imaging in neurologic disease.

Chronic pain is thought to be a brain disease, but the mechanisms are not well-known. In recent years, brain imaging has become an indispensable tool for pain research. For example, nuclear molecular imaging is a safe and noninvasive technology that allows researchers to probe potential brain regions of interest with suitable biomarkers. These studies help us to understand the central mechanisms of chronic pain states in humans. Brain receptors, such as the opioid receptors, dopamine receptors, NK-1 receptors, 5-HT receptors, NMDA receptors and CGRP receptors, are effector sites of neurotransmission and have prominent roles in pain generation and modulation. With nuclear molecular imaging, density, activity and distribution of such brain receptors can be visualized in vivo. Many PET and SPECT studies have shown that there is a disturbance in the function of these receptors in chronic pain states and other neurologic and/or psychiatric pathologies. Thus, these technologies have the potential to provide us with substantial and useful information of neurochemical and neurocircuit basis for pain. In recent studies, the development of nuclear molecular imaging of these receptors in the brain is summarized.

Integrins have an important impact on the regulation of normal and tumor cell migration and survival, especially the integrin αvβ3 and its role in angiogenesis and tumor metastasis. Owing to the role of integrins, non-invasive imaging of αvβ3 expression in diseased tissue will be of great benefit in directing adjuvant therapy for cancer patients. To this end, RGD peptide based probes for optical imaging have emerged as a real-time, sensitive, and noninvasive approach for visualization, localization, and measurement of cancer in vivo. With the advantages of optical imaging such as sensitivity, cost effectiveness, and non-invasion, the past decades have witnessed the rapid development of integrin- targeted optical probes and its wide applications in cancer research. In this review, we present and introduce numerous approaches by the term “RGD motif based optical imaging probes” with respect to their probe design strategies and applications. Additionally, a variety of labels such as QDs, UCLs and near-infrared fluorochrome used in these optical imaging probes are also discussed.

Molecular imaging is able to directly visualize targets and characterize cellular pathways with a high signal/background ratio, which requires a sufficient amount of agents to uptake and accumulate in the imaging area. The design and development of peptide based agents for imaging and diagnosis as a hot and promising research topic that is booming in the field of molecular imaging. To date, selected peptides have been increasingly developed as agents by coupling with different imaging moieties (such as radiometals and fluorophore) with the help of sophisticated chemical techniques. Although a few successes have been achieved, most of them have failed mainly caused by their fast renal clearance and therefore low tumor uptakes, which may limit the effectively tumor retention effect. Besides, several peptide agents based on nanoparticles have also been developed for medical diagnostics. However, a great majority of those agents shown long circulation times and accumulation over time into the reticuloendothelial system (RES; including spleen, liver, lymph nodes and bone marrow) after systematic administration, such long-term severe accumulation probably results in the possible likelihood of toxicity and potentially induces health hazards. Recently reported design criteria have been proposed not only to enhance binding affinity in tumor region with long retention, but also to improve clearance from the body in a reasonable amount of time. PEGylation has been considered as one of the most successful modification methods to prolong tumor retention and improve the pharmacokinetic and pharmacodynamic properties for peptide-based imaging agents. This review summarizes an overview of PEGylated peptides imaging agents based on different imaging moieties including radioisotopes, fluorophores, and nanoparticles. The unique concepts and applications of various PEGylated peptide-based imaging agents are introduced for each of several imaging moieties. Effects of PEGylation on their target capability, clearance kinetics and metabolic stability are depicted. Problems and issues relating to the pharmacokinetic and optimization design of peptide-based imaging agents are also discussed.

Hydroxyproline is a non-essential amino acid found in collagen and few other extracellular animal proteins. It’s two isomeric forms trans-4-hydroxy-L-proline and trans-3-hydroxy-L-proline play a crucial role in collagen synthesis and thermodynamic stability of the triple-helical conformation of collagen and associated tissues. Various abnormalities in hydroxyproline metabolism have been shown to play key roles in the pathophysiology and pathogenesis of different diseases. The elevated level of hydroxyproline is observed in several disorders, e.g., graft versus host disease, keloids, and vitiligo while its decreased level is a marker of poor wound-healing. This review explores the potential of using hydroxyproline as a biochemical marker to understand the pathogenesis, molecular pathophysiology and treatment of these diseases. The review concludes with an outlook on the scope and challenges in the clinical implementation of hydroxyproline as a biomarker.

The Coronin family is one of the WD-repeat domain containing families that are diverse in both of their structures and functions. The first coronin was identified in the cytoskeleton composition of Dictyostelium discoideum, which was discovered to regulate the actin functions. So far, 723 coronins have been identified throughout the eukaryotic kingdom by bioinformatics analysis in 358 species. In mammals, 7 coronins have been identified to date, which are named through Coronin 1 to Coronin 7; all of these isoforms contain two structurally conservational region: a 7-bladed β-propeller scaffold in N-terminal and a C-terminal variable coiled coil domain. Although some studies were showing that mammalian coronins have regulated the actin dynamics, recently many other functions such as calcium signaling regulation, cAMP signaling regulation, have been also reported beyond the actin modulation. Furthermore, many diseases have been found to be extensively associated with the abnormal expression of coronins, such as auto-immunity, bacterial and virus infection, neuronal behavior disorder and cancer. In this review, we would like to systematically discuss the recent progresses of mammalian coronins and associated diseases, as well as possible underlying molecular mechanisms.

This is a second part of the three-part article from a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. We continue to describe α-lactalbumin, a small globular Ca2+-binding protein, which besides being one of the two components of lactose synthase that catalyzes the final step of the lactose biosynthesis in the lactating mammary gland, possesses a multitude of other functions. In fact, recent studies indicated that some partially folded forms of this protein possess noticeable bactericidal activity and other forms might be related to induction of the apoptosis of tumor cells. In its anti-tumorigenic function, oligomeric α-lactalbumin serves as a founding member of a new family of anticancer drugs termed liprotides (for lipids and partially denatured proteins), where an oligomeric molten globular protein acts as an “oil container” or cargo for the delivery of oleic acid to the cell membranes.