Current Drug Metabolism - Volume 13, Issue 8, 2012

Cancer is a major public health problem in the world. There is a great need to apply novel technologies and drugs to revolutionize multiple aspects of cancer diagnosis and therapy. Advances in nanotechnology and nanomaterials have the potential to achieve the objective of early diagnosis and early therapy of cancer in the future. During the past few years, fullerene and its derivatives have been considered as some of the most promising nanomaterials because of their unique properties that enable a variety of medicinal applications. They can deliver drugs or small therapeutic molecules to the cancer cells. In this review, we will discuss how fullerene derivatives have been introduced into the field of cancer diagnosis and therapy. It will be highlighted that fullerene derivatives are used as anti-tumor drugs. Furthermore, preparation, characterization, pharmacokinetics and bio-distribution of fullerene and its derivatives reported in recent years will be summarized.

The rapid advancement of nanotechnology has brought us some new types of fluorescent probes, which are indispensable for bioimaging in life sciences. Because of their innate biocompatibility, good resistance against photobleaching, long fluorescence lifetime and wide fluorescence spectral region, fluorescent carbon quantum dots (C-Dots) and nanosized diamonds (nanodiamonds, NDs) are gradually evolving into promising reagents for bioimaging. In this review, we summarize the recent achievements in fluorescent C-Dots and NDs with emphases on their preparation, properties, imaging application, pharmacokinetics and toxicity. Perspectives on further investigations and opportunities to develop C-Dots and NDs into the safer and more sensitive imaging probes for both living cells and animal models are discussed.

Owing to their interesting physical and chemical properties, carbon nanotubes (CNTs) have attracted wide attentions in nanomedicine for applications in biological sensing, drug delivery, as well as biomedical imaging. The in vivo behaviors and toxicology of CNTs in biological systems, which are important fundamental questions, although have been intensively studied in recent years, remain to be clarified as distinctive results have been reported by various teams, confusing the scientific community as well as the public. In this article, we review the research on the in vivo behaviors of CNTs, and summarize the toxicity studies of CNTs in animals by different groups. Similar to other nanomaterials, the in vivo pharmacokinetics and biodistribution of CNTs are closely associated with their surface coatings. The excretion of CNTs from animals may happen via renal and fecal pathways, depending on the CNT surface chemistry, shape, and sizes. Regarding the toxicology of CNTs, which has been a debating topic for years, the administration routes, doses, and again the surface functionalization are critical to the in vivo toxicity of nanotubes. Much more efforts are still required to develop functional CNT bioconjugates with improved biocompatible coatings and controllable optimal sizes to achieve fast excretion and minimal toxicity, for various applications in biomedicine.

Several of the newly developed drug molecules show potent biological activity, but exhibit poor pharmacokinetic properties that may hinder their effective delivery to the intended site of action. In order to improve their pharmacological effect, these molecules can be associated with drug carriers in order to overcome these inherent difficulties. An ideal drug delivery agent requires therefore biocompatibility, improved solubility of a loaded drug or peptide, releasing of the payload at the absorption site and, at the same time, leaving undisturbed cell structure and function, and maintaining the physiological milieu. By taking advantage of the valuable properties of nanoscale delivery systems, such as increased surface area, improved solubility of hydrophobic drugs, possibility to encapsulate and protect drugs from degradation and reduced immunogenic potential and toxicological effect, new therapeutic options can be brought forth and improve the clinical arsenal for numerous diseases. The use of nanodelivery systems can even promote the re-investigation of pharmacokinetically less favourable, but biologically more active compounds. Although very promising, these systems may also encompass inherent toxicological issues, mainly due to their size and shape, physical interaction with cellular membranes and organelles, immunological reactions, long- or short-term tissue accumulation, and degradation products. Pharmaceutical nanodelivery systems, such as liposomes, polymeric nanoparticles, dendrimers and mesoporous silica and silicon based nanoparticles have shown great potential in preclinical applications and several of these nanosystems are even undergoing clinical trials. They have been found to combine drug delivery properties with an acceptable toxicological profile, which has made them prime candidates for several drug delivery approaches. This review aims to provide and correlate the toxicological studies with the drug delivery properties of the abovementioned nanodelivery systems in particular concerning uptake and accumulation as well as the critical aspects in each system regarding their optimal performance, while pointing out to the most relevant references.

Chemotherapy is among the most common means for clinicians in the fight against various types of tumors. However, severe toxicity with undesirable toxic effects against normal tissues and cells significantly hinders the applications of these chemotherapeutic agents and leads to multiple complications for patients. Recent developments of nanotechnology-enabled drug delivery platforms allow simultaneous delivery of multiple chemotherapeutic agents to target different metabolic pathways of tumor cells, thus providing new opportunities for higher therapeutic efficacy and lower cytotoxicity. Furthermore, multifunctional nanocarriers can also deliver diagnostic agents, including MRI contrast agents and fluorescent probes, to achieve cancer diagnosis and therapy at the same time. This present review discusses the various aspects of current co-delivery strategies and emphasizes the need for novel designs of biocompatible and non or low toxic nanocarriers. Further studies on potential adverse effects of various nanocarriers are warranted.

Dendrimers represent a class of monodispersed synthetic macromolecules with a well defined three-dimensional structure of nanometer dimension in which a series of layered branches regularly extend from a central core molecule. Due to their precise nanoscale sizes, well-defined branched structures, and various surface modifications, dendrimers have been extensively investigated in a wide range of applications in the biomedical field, particularly in the therapeutics and diagnosis of cancer. This article gives an overview of the recent advances of dendrimers and dendrimer-based hybrid nanoparticles for cancer therapeutics and diagnosis applications.

Oral administration remains the most preferred route for the treatment of many diseases due to its convenience and adaptability. However, the presystemic metabolism may be an important barrier that prevents lipophilic drugs from achieving their pharmacological effects following oral delivery. Nano-based drug delivery system provides an effective strategy to reduce the presystemic metabolism and increase the systemic exposure of lipophilic drugs. In this review, we described the physiological factors affecting the presystemic metabolism of lipophilic drugs, intestinal transport of nanosystems, strategy of nanosystems to avoid the presystemic metabolism, and the current application of various oral nanosystems including lipid and polymeric nanocarriers. The nano-based drug delivery system has a lot of potential for reducing the presystemic metabolism and enhancing the bioavailability of orally administrated lipophilic drugs.

Photodynamic therapy (PDT) is a new technology using photodynamic effect for disease diagnosis and treatment. It is a twostep technique involving the uptake of a photosensitizer by cancer tissue followed by light irradiation that excites the photosensitizer to produce highly reactive oxygen species, the latter execute apoptosis of cancerous cells. As a second-generation of photosensitizers, phthalocyanine demonstrates higher absorption in the 650-800nm range and short tissue accumulation compared to their first generation. However, many potent phthalocyanine photosensitizers are hydrophobic and poorly water-soluble, which limit their therapeutic applications. As a result, advanced delivery systems and different strategies are called for to improve the effectiveness of PDT. Facts have proved that using nanoparticles as carries of photosensitizers is a very promising route. Nanoparticles have the potentials to increase photosensitizers' aqueous solubility, bioavailability and stability, and deliver photosensitizers to the target tissues. This article reviewed the commonly-used nanoparticles, including colloid gold, quantum dots, paramagnetic nanoparticles, silica-based materials, polymer-based nanoparticles, as potential delivery systems for phthalocyanine photosensitizers, and summarized the improved biological functions of phthalocyanine photosensitizers in PDT.

Endothelial cells have very important functions, one of which is their contribution to regulating molecule and nutrient exchanges between the blood and peripheral tissues. Dysfunction of endothelial cells plays an essential role in the progression of cardiovascular diseases (CVD) such as atherosclerosis and coronary heart disease. With the recent progress of nanotechnology, increasing numbers of studies have focused on the effects of nanoparticles on CVD. In this article, we review the biological characters of endothelial cells, evaluate the impacts of nanoparticles on the behavior and functions of endothelial cells, analyze advantages and disadvantages of various nanoparticles, and discuss potential applications of nanoparticles to CVD treatment.

Nucleic acid aptamers are molecules that are being used in a large number of biomedical applications. Aptamers have the properties to bind to a wide range of molecules with high specificity and affinity for their target. These properties together with their small size and their ease of synthesis make them very attractive and promising for targeting diseases and therapeutic applications. Aptamers can serve as cancer diagnostic tools by detecting specific biomarkers, circulating cancer cells or imaging diseased tissue. On the other hand, aptamers can be used as therapeutic agents due to their potential antagonist activity, or as targeting agents. Therefore, they can be designed to deliver antitumor molecules such as chemotherapeutic drugs, siRNA or photodynamic therapy sensitizers to diseased tissues. Attempts are also made to synthesize aptamers-targeted nanoplatforms capable to ferry cargo and load onto them both imaging and therapeutic functions creating so called nanotheragnostics agents. In the future, its seems likely that aptamers will play an important role in diagnosis and treatment of several pathologies including cancer.

This review focuses on identification of important active-site residues of the cytochrome P450 2C (CYP2C) subfamily in terms of substrate specificity. A meta-analysis was performed on the reported literature regarding (1) values of the Michaelis-Menten constant (Km), maximal velocity (Vmax), and intrinsic clearance (Vmax/Km) for 74 metabolic reactions of 45 substrates mediated by human CYP2C8, CYP2C9, CYP2C18, and CYP2C19 and (2) inhibition constants (Ki) for 3 inhibitors. Although the kinetic behaviors of these CYP2C subfamily members depend on the metabolic reaction, the ratios of Vmax/Km values for CYP2C19/CYP2C9 and CYP2C8/CYP2C19, but not for CYP2C8/CYP2C9, were more closely correlated with Km values than with Vmax values, suggesting that, for many metabolic reactions, differences in affinity may be more important than differences in capacity for the substrate/reaction specificity of the CYP2C subfamily, especially for CYP2C19. In addition, it has been proposed that the residues involved in substrate recognition sites (SRS) 1, SRS 3, and/or SRS 4 are important for the metabolizing capacity and/or the substrate binding of CYP2C9 and CYP2C19. In contrast to the reasonable amount of kinetic data available, there are few reports comparing the effects of inhibitors [inhibitory constant (Ki) or 50% inhibitory concentration (IC50)] on metabolic reactions mediated by the CYP2C subfamily. Collectively, these findings provide insights into the contributions of CYP2C subfamily members to drug metabolism and adverse drug interactions.

The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum of lesions, e.g., steatosis and phospholipidosis. Steatosis is increased lipid accumulation, mainly as triglycerides, in the liver, while phospholipidosis is a lysosomal storage disorder characterised by intracellular accumulation of phospholipids. These alterations can be induced by several factors, including exposure to certain drugs. Drug-induced steatosis is often reversible, and prolonged exposure to certain drugs can cause macrovacuolar steatosis, a benign hepatic lesion, that can evolve into steatohepatitis and cirrhosis in some patients. Some drugs may acutely induce microvesicular steatosis which, despite having a good short-term prognosis, can lead to chronic lipid peroxidation and to the development of steatohepatitis lesions with time. Over 50 marketed drugs have been reported to induce phospholipidosis in different tissues, including the liver. Although drug-induced phospholipidosis is often reversible and there is no definitive evidence for its toxicological implications, it is considered an adverse side finding by regulatory agencies. As developing new drugs is a complex, lengthy and expensive process that aims to identify pharmacologically active, low-toxicity drug candidates among closely related compounds, it could be advantageous to determine which drugs are able to induce lipid metabolic disorders in early developmental stages. To this end, in vitro predictive screening assays, particularly cell-based approaches in which many drug candidates are evaluated, have been developed to identify and rule out compounds with a strong liver steatosis and/or phospholipidosis-inducing potential.

HIV protease inhibitors (PIs) are the cornerstone of Highly Active Antiretroviral Therapy (HAART). Their antiretroviral potent is attributable to their pharmacokinetic properties. Yet, as the pharmacologic target of HIV PIs is localized within HIV-infected cells, cellular pharmacokinetic properties must also be determined to predict not only efficacy, but also toxicity. In this review, we review recent studies about cellular pharmacokinetics of current marketed HIV PIs, as well as the physicochemical properties of HIV PIs and their drug transporters and enzymes. Additionally, a summary of potential strategies for optimizing cellular pharmacokinetics of HIV PIs and initial ideas to study cellular pharmacokinetics is also discussed. Cellular pharmacokinetics of HIV PIs is an important budding field of research that will significantly influence efficacy and toxicity profiles of these essential drugs, and we hope our review will aid in fundamental knowledge for future research.

An increase in folate intake before and during pregnancy can prevent many neural tube defects. This prompted over 50 countries worldwide to mandate fortification of breakfast cereals or staple foods with folic acid (FA), which is the synthetic oxidised form of the vitamin used in supplements and fortified foods. After ingestion, FA is reduced by dihydrofolate reductase (DHFR) and then converted to the biologically active forms. The presence of detectable amounts of unmetabolised FA in blood of individuals who have consumed supplements or fortified foods has attracted attention in recent years. A direct correlation exists between FA intake and unmetabolised FA in serum and suggests that a saturable level of DHFR exists. Factors affecting FA reduction, such as age, intestinal pH, alcohol, FA dose and duration of supplement usage, and possibly polymorphisms of folate-metabolising enzymes, can affect the presence of FA in blood. However, minor amounts of FA might also be produced during sample preparation. In pregnant women taking supplements, FA does not seem to accumulate in the newborns. Concentrations of unmetabolized FA are correlated to and predicted by those of total folate or 5-MTHF. Evidence of a negative health effect of free FA in blood is not consistent and suggests rather artificial factors. FA has no known cofactor function that would increase the likelihood of a causal role for free FA in disease development.

Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of several drugs that are currently in clinical use. The gene encoding CYP2C19 is polymorphic with the existence of different alleles resulting in altered enzyme activity. In addition, CYP2C19 activity is also dependent on its basal expression levels determined by the transcriptional regulation. Genetic variations located in the CYP2C19 promoter region may alter the interaction of promoter with transcription factors causing variable transcription. Genetic variants may also influence the induction, inhibition of CYP2C19 and may as well affect drug-drug interactions involving CYP2C19 substrates. The role of various transcription factors and genetic variants in the promoter region of CYP2C19 regulating its expression are discussed in this review. Furthermore, induction and inhibition of CYP2C19 by various drugs in clinically meaningful drug interactions are also discussed.