Targeting Fas in osteoresorptive disorders

Importance of the field: Fas receptor is a mediator of the external apoptotic pathway in many cells and tissues. It is proposed that Fas receptor mediates osteoresorptive effects of estrogen deficiency and local/systemic inflammation.

Areas covered in this review: This review covers the past two decades of research on the expression and function of the Fas–Fas ligand system on bone cells, involvement in the pathogenesis of osteoresorption and potential therapeutic modulation.

What the reader will gain: We review the structure, biological function and intracellular signaling pathways of the Fas–Fas ligand system emphasizing the role of the non-apoptotic signaling pathways in bone cells, particularly osteoblast differentiation. We also present data on the in vitro expression and function of the Fas–Fas ligand system on osteoblast/osteoclast lineage cells, animal and human studies confirming its involvement in osteoresorptive disorders and potential therapeutic approaches to modulate its function.

Take home message: Tissue specific therapeutic approaches need to be established to modify the Fas–Fas ligand system in osteoresorptive disorders as systemic targeting has many side effects. The most promising approach would be to target Fas signaling molecules coupled with osteoblast/osteoclast differentiation pathways, but a precise definition of these targets is still needed.     

Interest of glycolipids in drug delivery: from physicochemical properties to drug targeting

Importance of the field: The need for new products derived from natural sources for the replacement of the commonly used non-ionic surfactants containing ethylene oxide units with degradable carbohydrate headgroups has become an important area of research. Glycolipids offer a wide range of applications in the pharmaceutical and cosmetic fields and can compete with the most commonly used surfactants. Involved in molecular recognition mechanisms at the surface of cells, glycolipids are also used for drug targeting.

Areas covered in this review: The structure and pharmaceutical applications of the main glycolipid categories are summarized. The review focuses on marketed glycolipids, biosurfactants and compounds developed at laboratory scale for applications such as self-assembly or drug targeting.

What the reader will gain: This article aims to provide an overview of the different sugar-based surfactant classes and their potential uses.

Take home message: Beside their use as surfactants or absorption enhancers in basic formulations, glycolipids can build gels, niosomes, hexosomes and cubosomes, whose structure is directly related to lyotropic properties. These systems allow solubilization and entrapment of drugs. In innovative delivery systems, glycolipids are also used for drug targeting because their sugar moieties can be specifically recognized by carbohydrate-binding proteins exposed at the surface of cells.     

Checkpoint kinase inhibitors: a review of the patent literature

Background: The checkpoint kinases, Chk1 and Chk2 are Ser/Thr protein kinases, which function as key regulatory kinases in cellular DNA damage response pathways limiting cell-cycle progression in the presence of DNA damage. The development of checkpoint kinase inhibitors for the treatment of cancer has been a major objective in drug discovery over the past decade, as evidenced by three checkpoint kinase inhibitors entering clinic trials since late 2005. Objectives: This review describes and discusses the most recent inhibitors of checkpoint kinases Chk1 and Chk2, as reported in the patent literature, including an evaluation of chemical structure and biological activity. Methods: Using a variety of approaches, we searched and analyzed all patent applications claiming chemical matter in which Chk1 or Chk2 were stated as targets of inhibition from January 2006 through August 2008. Conclusions: A large number of chemically diverse Chk1 and Chk2 kinase inhibitors have appeared in the recent patent literature. Common structural motifs of the checkpoint kinase inhibitors were identified. There are currently three checkpoint kinase inhibitors in clinical development, a continuing effort by the pharmaceutical industry to identify novel scaffolds for checkpoint kinase inhibition.     

Aptamer-dendrimer bioconjugate: a nanotool for therapeutics,diagnosis, and imaging

Introduction: Aptamers hold great promise as molecular tool in biomedical applications due to the therapeutic utility exhibited by their target specificity and sensitivity. Although current development of aptamer is hindered by its probable in vivo degradation, inefficient immobilization on probe surface, and generation of low detection signal, bioconjugation with nanomaterials can feasibly solve these problems. Nanostructures such as dendrimers, with multivalency and nonimmunogenicity, bioconjugated with aptamers have opened newer vistas for better pharmaceutical applications of aptamers.

Areas covered: This review covers brief overview of aptamers and dendrimers, with specific focus on recent progresses of aptamer-dendrimer (Apt-D) bioconjugate in areas of targeted drug delivery, diagnosis, and molecular imaging along with the discussion on the currently available conjugates, using their in vitro and in vivo results.

Expert opinion: The novel Apt-D bioconjugates have led to advances in targeting cancer cell, have amplified biosensing, and offered in vivo cell imaging. Because of the unique properties and applications, Apt-D bioconjugate propose an exciting future. However, further research in synthesis of new target-specific aptamers and their conjugation with dendrimers is required to establish full potential of Apt-D bioconjugate.     

肝素前体heparosan的制备及药学应用研究进展

目的 综述肝素前体heparosan的制备技术及其在药学领域应用的最新研究进展,为其进一步研究和开发提供参考。方法 查阅国内外关于heparosan的制备方法及药学应用的文献,对其分析、概括和总结。结果 现有heparosan的制备方法主要包括微生物发酵提取法、代谢工程改造菌生产法、体外重组酶合成法;heparosan不仅可作为起始原料用于非动物源肝素的生物合成和非抗凝肝素衍生物的制备,还可作为药物载体。结论 发酵工程、代谢工程及酶工程等技术的成功应用推动heparosan的制备规模显著提高,但尚难以定制合成分子量可控的heparosan及衍生物;目前heparosan在药学领域的应用发展迅速,新的制备与结构改造策略将进一步拓宽其在药物发现与研究中的应用。     

Emerging trend in nano-engineered polyelectrolyte-based surrogate carriers for delivery of bioactives

Importance of the field: In recent decades a new colloidal drug delivery system based on layer-by-layer (LbL) technology has emerged, which offers promising means of delivering bioactive agents, specifically biological macromolecules including peptides and DNA. Nano-engineered capsules specifically fabricated from biocompatible and biodegradable polyelectrolytes (PEs) can provide a better option for encapsulation of cells thereby protecting cells from immunological molecules in the body, and their selective permeability can ensure the survival of encapsulated cells.

Areas covered in this review: This review encompasses a strategic approach to fabricate nano-engineered microcapsules through meticulous selection of polyelectrolytes and core materials based on LbL technology. The content of the article provides evidence for its wide array of applications in medical therapeutics, as indicated by the quantity of research and patents in this area. Recent developments and approaches for tuning drug release, biocompatibility and cellular interaction are discussed thoroughly.

What the reader will gain: This review aims to provide an overview on the development of LbL capsules with specific orientation towards drug and macromolecular delivery and its integration with other drug delivery systems, such as liposomes.

Take home message: Selection of PEs for the fabrication of LbL microcapsules has a profound effect on stability, drug release, biocompatibility and encapsulation efficacy. The release can be easily modulated by varying different physicochemical as well as physiological conditions. Scale-up approaches for the fabrication of LbL microcapsules by means of automation must be considered to improve the possibility of application of LbL microcapsules on a large scale.     

Therapeutic use of colchicine and its derivatives: a patent review

Introduction: Colchicine, the major alkaloid extracted from the meadow saffron (Colchicum autumnale) is one of the most prominent natural products belonging to the class of organic compounds known as tropones. Colchicine’s medicinal properties have been long-known, but it has been attracting renewed attention due to its action as an antimitotic agent.

Areas covered: This review presents an update and analysis of the patents claiming therapeutic activity of colchicine and its derivatives published in the last five years (2010–2015). Other patents claiming the application of colchicine in the areas of biotechnology, veterinary, and agriculture are therefore excluded from this review.

Expert opinion: Rapid increase in the number of publications and patent filings in recent years for the significant therapeutic potential of colchicine, for several conditions beyond gout, clearly indicates the growing interest of research on this molecule. Although the molecular structure of colchicine fulfils the four Lipinski’s requisites for high oral bioavailability, the toxic side effects resulting from its fast metabolism need to be assessed. Further efforts are therefore required to explore the appropriate dosage and possible administration techniques of colchicine for practical use.     

Renal toxic ingredients and their toxicology from traditional Chinese medicine

Introduction: There have been increasing concerns regarding adverse reactions and toxicity incidents caused by traditional Chinese medicines (TCMs), among which the nephrotoxicity is particularly worrying.

Areas covered: This review summarizes the ingredients with renal toxicity from some TCMs through searching the relevant literature published over the past two decades. Renal toxicity components from TCMs include aristolochic acids (AAS), alkaloids, anthraquinones and others. TCM renal toxicity is most commonly caused by AAS and some alkaloids. AAS mainly come from Aristolochia contorta Bunge, Aristolochia manshuriensis Kom, Clematis Chinensis Osbeck, Aristolochia cathcartii Hook. Some renal toxic alkaloids are derived from Tripterygium regelii Sprague et Takeda, Stephania tetrandra S. Moore, Strychnos nux-vomica Linn. and Aconitum carmichaeli Debx. A few kinds of anthraquinones, flavonoids, and glycosides from TCMs also cause renal toxicity. All of these renal toxicity components and their associated renal toxicity, structures and toxic mechanism are introduced in detail in this review.

Expert opinion: Given the complexity of the toxic components, a lot of work needs to be done to analyze the specific modes of action of toxic components in vivo and in vitro, in particular, to elucidate the molecular mechanism of toxicity, in order to reduce the occurrence of renal toxicity of TCM.     

Selective Paracellular Permeability in Two Models of Intestinal Absorption: Cultured Monolayers of Human Intestinal Epithelial Cells and Rat Intestinal Segments

New data on the permeabilities of hydrophilic markers in two commonly used in vitro models, i.e., excised intestinal segments from the rat and monolayers of Caco-2 cells, are presented. The results are compared to human in vivo data. Two groups of hydrophilic marker molecules were tested: (1) monodisperse polyethylene glycols of molecular weights ranging from 194 to 502 g/mol and (2) a heterogeneous group of molecules consisting of urea, creatinine, erythritol, and mannitol (60–182 g/mol). The permeabilities of the marker molecules showed a nonlinear dependence on the molecular weight and decreased in the order rat ileum > rat colon > Caco-2 cells. Surprisingly, the polyethylene glycols permeated more easily than the other marker molecules, indicating that characteristics other than molecular weight, e.g., the flexibility of the structure, may also be important for permeation through the membrane. Comparisons with the published permeability profiles of polyethylene glycols in human intestinal segments in vivo (i.e., calculated permeability coefficients as a function of molecular weight) indicate that the human intestine is more permeable than the in vitro models. However, the permeability profiles of the corresponding segments in the human intestine and the in vitro models were comparable. Thus, good correlations were established between permeabilities of the human ileum and rat ileum and between those of human colon, rat colon, and the Caco-2 cells. We conclude that the paracellular absorption in humans can be studied mechanistically in these in vitro models.     

Nontargeted detection of designer androgens: Underestimated role of in vitro bioassays

Androgens, both steroidal and nonsteroidal in nature, are among the most commonly misused substances in competitive sports. Their recognized anabolic and performance enhancing effects through short- and long-term physiological adaptations make them popular. Androgens exist as natural steroids, or are chemically synthesized as anabolic androgenic steroids (AAS) or selective androgen receptor modulators (SARMs). In order to effectively detect misuse of androgens, targeted strategies are used. These targeted strategies rely heavily on mass spectrometry, and detection requires prior knowledge of the targeted structure and its metabolites. Although exquisitely sensitive, such approaches may fail to detect novel structures that are developed and marketed. A nontargeted approach to androgen detection involves the use of cell-based in vitro bioassays. Both yeast and mammalian cell androgen bioassays demonstrate a clear ability to detect AAS and SARMS, and if paired with high resolution mass spectrometry can putatively identify novel structures. In vitro cell bioassays are successfully used to characterize designer molecules and to detect exogenous androgens in biological samples. It is important to continue to develop new and effective detection approaches to prevent misuse of designer androgens, and in vitro bioassays represent a potential solution to nontargeted detection strategies.     

Engineering RNA for Targeted siRNA Delivery and Medical Application

RNA engineering for nanotechnology and medical applications is an exciting emerging research field. RNA has intrinsically defined features on the nanometre scale and is a particularly interesting candidate for such applications due to its amazing diversity, flexibility and versatility in structure and function. Specifically, the current use of siRNA to silence target genes involved in disease has generated much excitement in the scientific community. The intrinsic ability to sequence-specifically downregulate gene expression in a temporally- and spatially controlled fashion has led to heightened interest and rapid development of siRNA-based therapeutics. Although methods for gene silencing have been achieved with high efficacy and specificity in vitro, the effective delivery of nucleic acids to specific cells in vivo has been a hurdle for RNA therapeutics. This article covers different RNA-based approaches for diagnosis, prevention and treatment of human disease, with a focus on the latest developments of non-viral carriers of siRNA for delivery in vivo. The applications and challenges of siRNA therapy, as well as potential solutions to these problems, the approaches for using phi29 pRNA-based vectors as polyvalent vehicles for specific delivery of siRNA, ribozymes, drugs or other therapeutic agents to specific cells for therapy will also be addressed.     

Phenylpiperazine derivatives: a patent review (2006 – present)

Introduction: The N-phenylpiperazine subunit represents one of the most versatile scaffolds used in the medicinal chemistry field. Recently, some N-phenylpiperazine derivatives have reached late stage clinical trials for the treatment of CNS disorders, thus, this is clearly a molecular template that already has proven its “druglikeness,” However, this scaffold is still strictly seen as a “CNS structure” by great part of the scientific community. The aim of this review is to draw a contemporary profile of the patents regarding N-phenylpiperazine derivatives and, them, suggest new research fields to be explored.

Areas covered: The site of the World Intellectual Property Organization (WIPO) was used as the main source in order to perform the research of the patents containing N-phenylpiperazine compounds with therapeutic uses. This review highlights some examples to show that this heterocyclic moiety can successfully yield new classes of hits and prototypes for many other therapeutic fields through appropriate substitution of the molecular skeleton.

Expert opinion: The patent research concerning N-phenylpiperazine derivatives indicated for therapeutic uses from 2006 to present date resulted in thirty three documents. It is a low number if one considers the several compounds bearing the N-phenylpiperazine nucleus that reached the market and/or clinical trials. Therefore, this subunit seems to be much underrated at the moment. The adequate use of the N-phenylpiperazine moiety, through modulation of its basicity and substitution pattern of the aromatic ring, can yield pharmacokinetic and pharmacodynamic improvements that are certainly useful in several therapeutic areas, thus, being able to diversify the application and utility of this scaffold. We expect and strongly suggest the growth of this diversification.     

Drug transport across the blood — brain barrier II. Experimental techniques to study drug transport

This is part II of a review on the transport of drugs across the blood-brain barrier. In this part, the emphasis is on the various experimental techniques that can be used to characterize the blood — brain barrier transport of drugs. Generally speaking, three approaches can be distinguished:in vitro techniques using isolated brain capillaries, cerebrovascular endothelial cells in primary culture or endothelium-derived cell lines;in vivo techniques (both single-passage and multi-passage techniques) andin situ perfusion techniques. Each of these techniques has specific advantages and disadvantages associated with it. Therefore, in many instances, a combination of different approaches is needed to study the fundamental aspects of drug transport across the blood-brain barrier.     

2-Indolinone a versatile scaffold for treatment of cancer: a patent review (2008–2014)

Introduction: 2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block.

Areas covered: The present review gives an account of the recent patent literature (2008–2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed.

Expert opinion: 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2-indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.     

Botanicals used in complementary and alternative medicine treatment of cancer: clinical science and future perspectives

Background: Botanicals and herbal combinations are among the most common complementary and alternative medicine (CAM) approaches used by cancer patients both for cancer treatment and management of cancer symptoms. Despite their widespread use, however, the safety and efficacy of many botanicals has not been established in controlled clinical trials. Objectives: This article reviews the published evidence for the safety and clinical benefit of botanicals used in the treatment of cancer and cancer symptom management and describes the continuing clinical trials of botanicals with applications in oncology. Methods: Literature searches were conducted in PubMed, EMBASE, Cochrane Clinical Trials databases, Pharmaprojects and CRISP (Computer Retrieval of Information on Scientific Projects) clinical trials databases. Conclusion: A number of botanicals have shown promise for cancer symptom management but need further study. A limited number of multi-agent nutritional supplement approaches are being explored in clinical trials. Botanical immunomodulators and botanical products shown to affect pathways of angiogenesis, apoptosis and cell signaling in vitro have stimulated research interest and may broaden the range of available cancer treatments.     

Magnetic targeting for site-specific drug delivery: applications and clinical potential

Background: Magnetic vehicles are very attractive for delivery of therapeutic agents as they can be targeted to specific locations in the body through the application of a magnetic field gradient. The magnetic localization of a therapeutic agent results in the concentration of the therapy at the target site consequently reducing or eliminating the systemic drug side effects. Objective: The aim of this review is to provide an update on the progress made in the development of the magnetic targeting technique addressing characteristics of the magnetic carriers and limitations of the current targeting magnet systems. Methods: This review discusses fundamental requirements for the optimal formulation of the magnetic carrier, current applications and potentially new approaches for the magnetically mediated, site-specific localization of therapeutic agents, including drugs, genes and cells. Results/conclusion: More efficient targeting magnetic systems in combination with prolonged circulation lifespan and carriers' surface recognition properties will improve the targeting efficiency of magnetic nanocarriers and enhance therapeutic agent availability at the molecular site of agent action. The main future magnetic targeting applications were categorized emphasizing the most promising directions and possible strategies for improving the magnetic targeting technique.     

Cellular Reprogramming: A New Technology Frontier in Pharmaceutical Research

Induced pluripotent stem cells via cellular reprogramming are now finding multiple applications in the pharmaceutical research and drug development pipeline. In the pre-clinical stages, they serve as model systems for basic research on specific diseases and then as key experimental tools for testing and developing therapeutics. Here we examine the current state of cellular reprogramming technology, with a special emphasis on approaches that recapitulate previously intractable human diseases in vitro. We discuss the technical and operational challenges that must be tackled as reprogrammed cells become incorporated into routine pharmaceutical research and drug discovery.     

Zinc oxide nanoparticles impacts: cytotoxicity,genotoxicity, developmental toxicity,and neurotoxicity

Zinc oxide (ZnO) is the most commonly used nanoparticles among different nanoparticles. Its applications ranged from personal care products, sensors, antibacterial creams, and biomedical applications. The broad range of applications raises concern in regards to their potential toxicity. Therefore, it is required to understand their toxicity mechanism and pattern on various levels. The primary aim of this review is to summarize the cytotoxicity, genotoxicity, neurotoxicity, and developmental toxicity of ZnO nanoparticles in various kinds of cells in vitro and in vivo. Literatures available on ZnO nanoparticles toxicity suggest that dissolution, organism dependent cellular uptake, generation of reactive oxygen species (ROS), and induced inflammatory responses seem to be common factors which govern the toxicity of ZnO nanoparticles.     

What's new in Nanotoxicology? Brief review of the 2007 literature

The use and commercial potential of engineered nanomaterials is increasing, but questions of occupational and public health safety remain. Here, we review research published in 2007 concerning toxicology of nanomaterials. Articles were selected from the Medline Pubmed database, published or pre-published during 2007, using keywords (nanomaterials or nanoparticles or nanostructures) and (toxicity or health). From the 238 articles, we chose to concentrate mainly on research into carbonaceous (carbon nanotubes [CNTs] and fullerenes) and metallic materials (pure metal, oxides), because of their relevance. The induction of oxidative stress was repeatedly reported, and new information on the movement of nanomaterials through membranes was publicized. Concerning CNTs, information was revealed on DNA damage in vitro and pulmonary and systemic in vivo effects. Several of the reports failed to follow recent expert recommendations concerning good practice for nanotoxicologic research, complicating the integration of the new data into the larger picture of safety of nanomaterials.