Current Medicinal Chemistry - Volume 18, Issue 14, 2011

Drug discovery is constantly stimulated by new technologies and new paradigms. Nanotechnology has already had unprecedented impacts on every area of modern technologies, from energy to materials to medicine [1-3], and more impacts and discoveries are still to come. The term “nanomedicine” appeared in the literature only a decade ago, and now it has already become a rapidly advancing research field with focus on developing novel therapy and imaging approaches for various diseases, particularly cancer [4-9]. In this special issue of Current Medicinal Chemistry, leading experts in the interdisciplinary areas of nanomedicine and nanobiotechnology critically review the impacts of nanotechnology on drug discovery and medicine, particularly in areas previously affected by the limitations of traditional drug design and delivery methods. An ideal drug should enter cells and selectively inhibit the disease target while possessing suitable solubility, blood pool retention time, metabolic stability, and pharmacokinetic/ pharmacodynamic properties, and with no evident toxicity. Traditional small-molecule drugs have to incorporate all these functions into a single molecule with a molecular weight around 500. This is a tremendous challenge! However, nanoparticles with dimensions less than hundreds of nanometers are approximately 0.01-1.0% of the size of human cells. They can easily enter cells or pass through the leaky vasculature in tumors. On the other hand, they are bigger than small molecules, so they can be built into a nanoplatform that easily integrates targeting molecules, drugs, imaging moiety, and biocompatible side chains on a single nanoparticle, taking advantage of their large surface areas. In this special issue, articles by Sun, Huang, Kanwar, and their coworkers describe several typical nanoplatforms with the aims of overcoming difficulties in conventional drug design and formulation, “sugar code” on cell surfaces for cell targeting, and oral delivery of peptides and proteins. Articles by Boppart, Yan, and their coworkers describe research into nanomedicinal constructs with imaging or with integrated imaging, therapy, and targeting functions. Absorption, distribution, metabolism, and excretion, as well as toxicity, are important concerns for nanomedicine candidates, as for small molecule drugs. Nanotoxicology has evolved into a research discipline of its own. Wick and coworkers describe research in this aspect on a promising nanoplatform called carbon nanotubes. With rapid development in nanotechnology and nanomedicine, this collection can only provide a glimpse of this dynamic field. We expect that nanomedicine research will soon provide new clinical approaches to diagnosing disease, delivering therapy, and monitoring therapeutic effects quickly and non-invasively.

Fullerenes as a unique class of carbon allotropes have been studied extensively for their distinctive material properties and potential technological applications, including those in biology and medicine. Since a major focus in the latter has been on drug development and formulation, in this paper we highlight some representative studies related to such a focus, including the use of fullerenes for drug-like functions and for their improving the formulation of established drugs. Also discussed are some other potential medically relevant applications of fullerenes, such as their serving as potent agents in photodynamic therapy and magnetic imaging.

Over the past decade, diagnostics and therapeutics have changed gradually towards the use of more specific and targeted approaches. The most profound impact has been in the nanotechnology sectors, where an explosion in directing biomolecules to specific biomarkers has illustrated great potentials not only in detection but also in targeted therapy. Increased knowledge of the diseases at the molecular level catalyzed a shift towards identifying new biological indicators. In particular, carbohydrate-mediated molecular recognitions using nano-vehicles are likely to increasingly affect medicine opening a new area of biomedical applications. This article provides an overview of the recent progress made in recruiting the “sugar code” functionalized on various nano-platforms to decipher cellular information for both in vitro and in vivo applications. Today's glyco-technologies are enabling better detection with great therapeutic potentials. Tomorrow they are likely to bring a full understanding of the “cell-glyconanomaterial bio-conversation” where major biomedical problems will be overcome translating insights from the “glyco-nanoworld” into clinical practice.

This review aims to highlight many of the difficulties encountered in trying to achieve the task of delivering proteins and peptides through oral administration. The necessity of controlled protein and peptide release, protection and stability in the gastrointestinal tract, and ability to target specific areas are only a handful of the many problems associated with trying to engineer a useful solution. Current research gives strong indication that both cyclodextrins and nanoparticles could be highly useful in the search for a suitable method for such successful oral delivery of proteins and peptides. This review focuses on the use of cyclodextrins in pharmaceuticals, aiming to discuss the use of cyclodextrins in conjunction with nanoparticles for oral delivery of proteins. Both classical applications and more advanced “nanomedical” approaches are discussed. In order to achieve a complete overview this review will include background information about cyclodextrins, nanomedicine and their role in oral delivery systems. The use of absorption enhancers like cyclodextrins, bile salts and surfactants was used to facilitate bio-availability into the system. The state-of-the-art technology and challenges in this area are discussed, with typical examples.

Nanotechnology has provided many promising nanoplatforms for targeted cancer imaging and therapy. Among these platforms, gold nanoparticles (GNPs) play a unique role in medicine because of their excellent physical and chemical properties. To expand the applications of GNPs in medicine, amounts of targeting moieties, imaging labels, and therapeutic agents have been integrated into these particles to form multifunctionalized GNPs. In this review, we highlight recent advances of the fabrication of cancer-targeting multifunctionalized GNPs and their applications in imaging and therapy.

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 main approaches towards imaging at a molecular level are the development of high resolution imaging modalities with high penetration depths and increased sensitivity, and the development of molecular probes with high specificity. The development of novel molecular contrast agents and their success in molecular optical imaging modalities have lead to the emergence of molecular optical imaging as a more versatile and capable technique for providing morphological, spatial, and functional information at the molecular level with high sensitivity and precision, compared to other imaging modalities. In this review, we discuss a new class of dynamic contrast agents called magnetomotive molecular nanoprobes for molecular-specific imaging. Magnetomotive agents are superparamagnetic nanoparticles, typically iron-oxide, that are physically displaced by the application of a small modulating external magnetic field. Dynamic phase-sensitive position measurements are performed using any high resolution imaging modality, including optical coherence tomography (OCT), ultrasonography, or magnetic resonance imaging (MRI). The dynamics of the magnetomotive agents can be used to extract the biomechanical tissue properties in which the nanoparticles are bound, and the agents can be used to deliver therapy via magnetomotive displacements to modulate or disrupt cell function, or hyperthermia to kill cells. These agents can be targeted via conjugation to antibodies, and in vivo targeted imaging has been shown in a carcinogeninduced rat mammary tumor model. The iron-oxide nanoparticles also exhibit negative T2 contrast in MRI, and modulations can produce ultrasound imaging contrast for multimodal imaging applications.

Although nanotechnology is a relatively new scientific field, quite many different products are already introduced in the market containing nanosized particles. A special class of nanosized materials namely the carbon nanotubes (CNT) possesses outstanding new properties and extraordinary potential for creating new products. Carbon nanotubes are already used in various consumer products, industrial applications and science. It is not as this time clear how CNT are able to affect human health since most types of CNTs differ significantly in terms of structural characteristics (morphology, size, shape and length), surface properties (surface chemistry and surface charge) and chemical composition. This review provides an overview about contradicting reports that are found in the literature. We summarize the studies that report about nontoxic as well as toxic effects of CNT in-vitro and in-vivo. We describe how carbon nanotubes can readily be degraded under certain conditions. Another phenomenon is that despite the observed toxic effects which may occur to cells, organs and animals after uptake of CNT, intensive research investigations were undertaken in order to use these outstanding materials in medical applications. The second part of this review starts with a short description of the main principles in metrology. Observed conflicts were discussed in CNT toxicity assays into terms of measurement science or metrology issues. It was demonstrated that any specification of a measurand is only valid within the given framework. This means that many of the published results are within their measurement framework correct, but there are no means to compare them outside this framework.

Bacteria are able to adapt to undesirable changes in nutrient availability, environmental conditions and presence of antimicrobial products, as well as to immunological defenses. One particularly important example of bacterial adaptation is the ability to grow as part of a sessile community, commonly referred to as biofilm. It is a natural tendency of microorganisms to attach to biotic or abiotic surfaces, to multiply and to embed themselves in a slimy matrix, resulting in biofilms. Biofilms are the leading example of physiological adaptation and are one of the most important sources of bacterial resistance to antimicrobials. It is now recognized that most bacterial-associated infections, including endocarditis, dental caries, middle ear infections, osteomyelitis, medical device-related infections and chronic lung infections in cystic fibrosis patients are problematic because of biofilms. Bacteria in biofilms demonstrate intrinsic resistance to antimicrobial stress more effectively than the planktonic counterparts. Antimicrobial concentrations necessary to inhibit bacterial biofilms can be up to 10-1000 times higher than those needed to inhibit the same bacteria grown planktonically. Thus, in the presence of therapeutically available antibiotic concentrations biofilms remain viable after treatment. Therefore, the identification of new antimicrobials that inhibit or destroy biofilms is needed. The aim of this review is to cover the recent advances on the studies of antimicrobial strategies effective against infectious bacterial biofilms, including the current developments in the structure-activity relationship of those effective antimicrobials.

In the treatment of chronic myeloid leukemia (CML) with Bcr-Abl kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents, such as imatinib, nilotinib and dasatinib, by discrupting important contact interactions between the inhibitors and the enzyme. To overcome this particular resistance, several different strategies have been explored and many molecules have been investigated as capable of potently inhibiting Bcr-Abl T315I. Herein, this review reports on some predominant examples of third generation inhibitors of Bcr-Abl active against the T315I mutation, and special attentions are paid to the “hybrid-design” strategy for creating type-II class ATP-competitive inhibitors.

The development of novel drugs against obesity is one of the top priorities of worldwide drug research. In recent years, it has been facilitated by the application of virtual screening methods. In this review, we give a short introduction into obesity-related protein targets and computer-aided drug design techniques. Furthermore, we highlight the most successful virtual screening studies, outline their results, and provide suggestions for future anti-obesity drug development.

Lymphatic filariasis, onchocerciasis and loiasis caused by human filarial nematodes are diseases of tropical and subtropical countries causing considerable morbidity. The available control strategies have significant limitations such that current drugs are ineffective against macrofilariae (adult worms), require repeated and prolonged treatment over years and are threatened by emergence of drug resistance. Due to this concern, these diseases are the focus of renewed scientific interest and much has been done in filariasis research in the past decade. This review summarizes the current status of filariasis, different control strategies, recent advances in antifilarial chemotherapy including currently used drugs, their pros and cons, their mechanism of action, and recently discovered targets and prototypes.

Twenty years of effective clinical application have consolidated non-nucleoside reverse transcriptase inhibitors (NNRTI) as essential components of the Highly Active Antiretroviral Therapy (HAART) employed in the treatment of Human Immunodeficiency Virus (HIV). However, as the disease has come under control, there has been growing emphasis on the long-term adverse effects induced by this chronic pharmacological therapy. Although traditionally considered to be safe and well-tolerated drugs, there is mounting evidence that associates NNRTI with the onset of cutaneous reactions, neuropsychiatric symptoms, hepatotoxicity, metabolic disturbances and gastrointestinal toxicity. Though the clinical manifestations of these detrimental events are increasingly recognised, the cellular and molecular mechanisms underlying them have received little attention. This review revaluates the toxicities associated with the use of NNRTI by analysing data from both clinical trials and recent in vitro studies. Particular emphasis is placed on the specific characteristics of each of the compounds that comprise this class of anti-HIV drugs, including some that are currently in clinical development. A deeper understanding of the causes of NNRTI-induced side effects would greatly help to improve existing anti-HIV-1 therapies and to develop safer and better tolerated drugs in the future, thus increasing the long term efficacy of NNRTI-containing regimens.

In this review we consider diseases associated with pathological mineralization/ossification, namely, ankylosing spondylitis (AS), osteoarthritis (OA), generalized artery calcification of infancy (GACI), vascular calcification as well as chondrocalcinosis (CC) and pseudo gout. Deciphering the key enzymes implicated in the calcification process is an objective of prime importance and the ultimate goal is to synthesize inhibitors of these enzymes in order to provide efficient alternate therapeutic strategies that will slow down the pathologic mineralization and complement the arsenal of anti-inflammatory drugs. One of the difficulties in the definition of diseases associated with pathologic mineralization/ossification lies in the controversial relationship between the type of calcification and the nature of the disease. Here, we propose to clarify this relationship by making a distinction between diseases associated with hydroxyapatite (HA) and calcium pyrophosphate dihydrate (CPPD) deposits. AS, OA, GACI and vascular calcification are usually characterized by mineralization/ossification associated with HA deposits, while CC and pseudo gout are mostly characterized by CPPD deposits. Although both HA and CPPD deposits may occur concomitantly, as in chronic pyrophosphate arthritis or in OA with CPPD, they are formed as a result of two antagonistic processes indicating that treatment of distinct diseases can be only achieved by diseasespecific drug therapies. The hydrolysis of PPi, an inhibitor of HA formation, is mostly controlled by tissue non-specific alkaline phosphatase TNAP, while PPi production in the extracellular medium is controlled by ANK, a PPi transporter, and/or NPP1 which generates PPi from nucleotide triphosphates. Low PPi concentration may lead to a preferential deposition of HA while high PPi concentration will favor the formation of CPPD deposits. Thus, HA and CCPD deposition cannot occur concomitantly because they are determined by the Pi/PPi ratio which, in turn, depends on the relative activities of antagonistic enzymes, TNAP hydrolyzing PPi or ANK and NPP1 producing PPi. TNAP inhibitors could prevent HA formation in AS, in late OA, in GACI, as well as in vascular calcifications, while ANK or NPP1 inhibitors could slow down CCPD deposition in CC and pseudo gout.