Current Medicinal Chemistry - Volume 21, Issue 22, 2014

The use of nanobiotechnology in the formulation of drug carriers has been gaining popularity in recent years. Peptide self-assembly technology is a particularly attractive option due to its simplicity and programmability. Selfassembling peptide amphiphiles are surfactant-like molecules that are capable of spontaneous organization into a variety of nanostructures. The structural and functional features of these nanostructures can be designed through alterations to the peptide sequence. With a keen understanding of the supramolecular principles governing the non-covalent interactions involved, drug loading strategies can be customised. Hydrophobic drugs can be hidden within the core via aromatic interactions while gene-based therapeutics can be complexed with a cationic region of lysine residues. This review article focuses on the application of self-assembling peptide amphiphiles to drug delivery in the area of anti-cancer therapeutics, protein- and peptide-based therapeutics and nucleic acid-based therapeutics. Specific examples are used to discuss the various systems available and emphasis is given to the encapsulation and release mechanism.

Hydrogel system, as one of the most important biomaterials, is widely studied because of its tremendous potential in regenerative medicine conferred by its wide range of malleable biochemical and physical characteristics, which include its biocompatibility with the elemental biomolecules in vital tissues, its high water retention capability and adjustable soft-tissue-like physicochemical properties. These properties are modifiable to facilitate the targeted tissue protected from external damaging disturbance and having the encapsulated cells’ physiology-functional phenotypes induced or maintained in situ. Recently, hydrogels are increasingly used in the R&D of regenerative medicine to build complex tissue. Most of the insightful work focuses on how to select and fabricate the hydrogel models with desired physicochemical properties, flexibility of auto response to various bio-stimuli, and capability of efficiently forming the complex tissuemimicking construct at different scales. The present review introduced the major types of hydrogeis, the desirable physicochemical properties, the current fabrication methodologies and special organ-based cases of applications of hydrogels, which are used in complex tissue engineering. In addition, this review also discussed the major hurdles faced by the R&D of hydrogel systems for complex tissue medicine.

Heart disease is one of the major global health issues. Despite rapid advances in cardiac tissue engineering, limited successful strategies have been achieved to cure cardiovascular diseases. This situation is mainly due to poor understanding of the mechanism of diverse heart diseases and unavailability of effective in vitro heart tissue models for cardiovascular drug screening. With the development of microengineering technologies, three-dimensional (3D) cardiac microtissue (CMT) models, mimicking 3D architectural microenvironment of native heart tissues, have been developed. The engineered 3D CMT models hold greater potential to be used for assessing effective drugs candidates than traditional twodimensional cardiomyocyte culture models. This review discusses the development of 3D CMT models and highlights their potential applications for high-throughput screening of cardiovascular drug candidates.

Metastasis is responsible for most deaths of cancer burdens. Given that metastatic cancer cells are generally very low in quantity but high in multiplicity, and able to migrate to diverse organs, the diagnosis and intervention of metastatic cancers face varieties of challenges. For example, the biomarker for early diagnosis, and detection of circulating tumor cells by way of epithelial cell adhesion molecule, are complicated by the epithelial-mesenchymal-transition (EMT). Enhanced permeation and retention have been widely explored but with limitations, especially for microscale metastatic tumors. Furthermore, drug-resistance and side-effects of chemotherapy remain problematic for diverse cancers. Interfaces of cells play essential roles in many physiological activities including signal transduction and immunological recognition, which can be exploited for medical application of interfacial materials; indeed, given unique chemical and physical interfacial properties, numerous micro/nano particles and interfacial materials exhibit great potentials for diagnosis and intervention of metastatic cancers. Here we highlight current research, opportunities and challenges for application potentials of biological interfacial engineering in diagnosis and intervention of metastatic cancers.

Metabolizing and eliminating toxic chemicals in the liver are key processes in the body’s defense system. Drug-metabolizing enzymes (DMEs) play central roles in such processes. The activity and expression of several key DMEs are changed in various liver diseases and thus lead to significantly altered drug disposition. This phenomenon severely affects the pharmacotherapy of clinical medications in terms of the safety and efficacy of drug responses. This review highlights liver physiological functions, altered DMEs, and altered drug disposition in liver diseases. Moreover, the implications of changes in DMEs on the fate of clinically relevant drugs are also discussed. Pregnane X receptor and constitutive androstane receptor are two liver-enriched nuclear receptors originally defined as xenobiotic sensors that affect regulation of DMEs. Altered regulation of DMEs in liver diseases contributes to the development of powerful in vitro and in vivo tools to predict drug responses and options for improved drug delivery and development. Although a number of treatment drugs are available for liver diseases, they are limited by their low drug concentration in the target site, presence of side effects, and instability in the human body. The nanoparticle drug delivery system has recently attracted research attention because of its potential to offer solutions to current obstacles that involve the use of therapeutic drugs for liver diseases. Conclusively, this review aims to improve understanding on the regulation of DMEs in liver diseases and on corresponding implications in drug disposition, including novel therapeutic medications.

Microarray-based kinomics, which measure the enzymatic activity or the presence of intracellular protein kinases, are now regarded as alternative tools to conventional mass spectrometry-based kinomics for examining intracellular kinomics. Here, we reviewed the principal advantages, recent progress, and remaining problems of representative microarray- based kinomics, including substrate peptide and protein microarrays, anti-protein kinase antibody microarrays, and reverse protein microarrays. Microarray-based kinomics are not as good at quantitative evaluation of kinomics as the conventional mass spectrometry-based kinomics. However, their simplicity and high throughput make the microarraybased kinomics unique tools, being especially suited for a practical analysis; monitoring drug effects on cellular kinomics as a tool for drug development, and for the diagnosis and prognosis of diseases based on kinomics.

Despite the significant advances in cardiac surgery, heart valve replacement still faces a dilemma. While mechanical valves offer lifelong durability they also commit patients to anticoagulation treatment for the rest of their life. On the other hand, bioprosthetic valves have superior hemodynamic performance but durability of the bioprosthesis limits their use to the elderly, with early onset calcification being the primary cause of biomaterial breakdown. Considering that bioprosthetic valves are not reliant upon anticoagulation, there has been much focus on measures to overcome their issues with durability. Firstly, the calcification process has been studied and factors such as young patient age, use of glutaraldehyde fixative, the presence of phospholipids along with cell debris in the valve tissue and mechanical stress have been identified to influence tissue mineralization. Therefore different calcification reduction strategies are being sought: new fixatives have been developed and tested and post-treatments have been added to tissue processing. This review presents the pathophysiology of tissue valve calcification and focuses on the multiple approaches developed to prevent bioprosthetic heart valve calcification, as well as on their general outcomes and translation to clinical applications.

Others and we have shown in several studies that the natural tetrahydropyrimidine ectoine protects mammalian cells and tissues against various stress factors including ischemia/reperfusion injury, UV-irradiation, and inflammation. Since little is known about the molecular mechanism of this protective effect, which was ascribed exclusively to an extracellular action of this small water-soluble molecule, we asked whether and how a hydrophobic anchor modulates the inflammation protective properties of ectoine. We therefore investigated the influence of ectoine and of its semi-synthetic derivative lauryl-ectoine on inflammation in RAW 264.7 macrophages and primary cultured rat intestinal smooth muscle (RISM) cells. Both, ectoine and lauryl-ectoine considerably decreased lipopolysaccharide (LPS)-induced interleukin (IL)- 1, IL-6, tumor necrosis factor (TNF)- α, and cyclooxygenase (COX)-2 gene expression in macrophages as well as TNF-α- induced IL-1, IL-6 and COX-2 expression in RISM cells. This reduction of inflammatory agents was accompanied on the one hand by a significant decrease of nuclear translocation of nuclear factor (NF)-κB and on the other hand by a reduction of cellular ceramide content. Interestingly, lauryl- ectoine was much more active exerting its effect at about 10-fold lower concentrations than its natural counterpart. Note that ectoine was almost completely recovered in the medium whereas lauryl-ectoine was found to be cell-associated. Together our data indicate that a lipid anchor considerably improves a possible preventive and/or therapeutic implementation of ectoine in inflammatory processes.