Targeted therapeutics and nanodevices for vascular drug delivery: quo vadis?

This issue of the journal is dedicated to targeted delivery of therapeutics in the vasculature, an approach that holds promise to optimize treatment of diverse pathological conditions ranging from ischemia and tumor growth to metabolic and genetic diseases. From the standpoint of drug delivery, circulation system represents the natural route to the targets, whereas its components (blood and vascular cells) represent targets, carriers or barriers for drug delivery. Diverse nanodevices and targeted therapeutic agents that are designed and tested in animal and early clinical studies to achieve optimal and precise spatiotemporal control of the pharmacokinetics, destination, metabolism and effect of pharmacological agents will be discussed in this introductory essay and subsequent critical reviews in this series.     

Natural extracellular nanovesicles and photodynamic molecules: is there a future for drug delivery?

Photodynamic molecules represent an alternative approach for cancer therapy for their property (i) to be photo-reactive; (ii) to be not-toxic for target cells in absence of light; (iii) to accumulate specifically into tumour tissues; (iv) to be activable by a light beam only at the tumour site and (v) to exert cytotoxic activity against tumour cells. However, to date their clinical use is limited by the side effects elicited by systemic administration. Extracellular vesicles are endogenous nanosized-carriers that have been recently introduced as a natural delivery system for therapeutic molecules. We have recently shown the ability of human exosomes to deliver photodynamic molecules. Therefore, this review focussed on extracellular vesicles as a novel strategy for the delivery of photodynamic molecules at cancer sites. This completely new approach may enhance the delivery and decrease the toxicity of photodynamic molecules, therefore, represent the future for photodynamic therapy for cancer treatment.     

Water-soluble polymer–drug conjugates for combination chemotherapy against visceral leishmaniasis

There is a need for new safe, effective and short-course treatments for leishmaniasis; one strategy is to use combination chemotherapy. Polymer–drug conjugates have shown promise for the delivery of anti-leishmanial agents such as amphotericin B. In this paper, we report on the preparation and biological evaluation of polymer–drug conjugates of N-(2-hydroxypropyl)methacrylamide (HPMA), amphotericin B and alendronic acid. The combinatorial polymer–drug conjugates were effective anti-leishmanial agents in vitro and in vivo, but offered no advantage over the single poly(HPMA)–amphotericin B conjugates.     

Lipophilic drug transfer between liposomal and biological membranes: what does it mean for parenteral and oral drug delivery?

This review presents the current knowledge on the interaction of lipophilic, poorly water soluble drugs with liposomal and biological membranes. The center of attention will be on drugs having the potential to dissolve in a lipid membrane without perturbing them too much. The degree of interaction is described as solubility of a drug in phospholipid membranes and the kinetics of transfer of a lipophilic drug between membranes. Finally, the consequences of these two factors on the design of lipid-based carriers for oral, as well as parenteral use, for lipophilic drugs and lead selection of oral lipophilic drugs is described. Since liposomes serve as model-membranes for natural membranes, the assessment of lipid solubility and transfer kinetics of lipophilic drug using liposome formulations may additionally have predictive value for bioavailability and biodistribution and the pharmacokinetics of lipophilic drugs after parenteral as well as oral administration.     

Tubulin delivery: polymerization chaperones for microtubule assembly?

A new paper by Slep and Vale in a recent issue of Molecular Cell provides structural clues as to how three different +TIP proteins interact with tubulin and suggests that +TIPs deliver oligomers of tubulin dimers to growing microtubule ends.     

TWEAK: a novel biomarker for lupus nephritis?

Renal involvement is common in systemic lupus erythematosus. Early diagnosis of lupus nephritis (LN), allowing the instigation of appropriate therapy, remains an important clinical challenge. Current biomarkers in clinical practice are less than ideal, lacking both sensitivity and specificity. In the previous issue of Arthritis Research & Therapy, Schwartz and colleagues demonstrated the potential value of urinary TNF-like weak inducer of apoptosis (uTWEAK) as a biomarker for LN. They showed that uTWEAK is elevated in subjects with LN at diagnosis compared with those with systemic lupus erythematosus but no renal disease, and correlates with the degree of clinical disease activity. These data are thought-provoking and provide the platform for future longer-term studies.     

Bacterial components as naturally inspired nano-carriers for drug/gene delivery and immunization: Set the bugs to work?

Drug delivery is a rapidly growing area of research motivated by the nanotechnology revolution, the ideal of personalized medicine, and the desire to reduce the side effects of toxic anti-cancer drugs. Amongst a bewildering array of different nanostructures and nanocarriers, those examples that are fundamentally bio-inspired and derived from natural sources are particularly preferred. Delivery of vaccines is also an active area of research in this field. Bacterial cells and their components that have been used for drug delivery, include the crystalline cell-surface layer known as “S-layer”, bacterial ghosts, bacterial outer membrane vesicles, and bacterial products or derivatives (e.g. spores, polymers, and magnetic nanoparticles). Considering the origin of these components from potentially pathogenic microorganisms, it is not surprising that they have been applied for vaccines and immunization. The present review critically summarizes their applications focusing on their advantages for delivery of drugs, genes, and vaccines.     

Emulsan-based nanoparticles for in vivo drug delivery to tumors

Nanoparticles have been widely used as drug carriers, and finding new materials for them is important for efficient drug delivery. Herein, we developed a new nanoparticle using emulsan and flax seed oil. Emulsan is one of the representative biosurfactants obtained from Acinetobacter calcoaceticus RAG-1. The resulting nanoparticles have an emulsan shell and a hydrophobic oil core, into which pheophorbide a (Pba) was loaded as a model drug. The nanoparticles were about 165.7?nm and were stably dispersed in an aqueous condition for more than one week. They demonstrated fast uptake in SCC7 mouse squamous cell carcinoma cells and killed the tumor cells after laser irradiation due to the photodynamic effect of Pba. After injection into SCC7 tumor-bearing mice via the tail vein, the particles showed longer blood circulation and 3.04-fold higher tumor accumulation in tissue than free Pba. These results demonstrate that emulsan-based nanoparticles have promising potential in drug delivery.     

Vertebrate somitogenesis: a novel paradigm for animal segmentation?

In vertebrates, the primary segmented tissue of the body axis is the paraxial mesoderm, which lies bilaterally to the axial organs, neural tube and notochord. The segmental pattern of the paraxial mesoderm is established during embryogenesis through the production of the somites which are transient embryonic segments giving rise to the vertebrae, the skeletal muscles and the dorsal dermis. Somitogenesis can be subdivided into three major phases (see Fig. 1). First a growth phase during which new paraxial mesoderm cells are produced by a growth zone (epiblast and blastopore margin or primitive streak and later on tail bud) and become organized as two rods of mesenchymal tissue,forming the presomitic mesoderm. Second a patterning phase occuring in the PSM, during which the segmental pattern is established at the molecular level. Third, the somitic boundaries are formed during the morphological segmentation phase. In all vertebrates, all cells of the paraxial mesoderm, during their maturation in the PSM, go successively through these three phases, which are tightly regulated at the spatio-temporal level. The first phase of paraxial mesoderm production falls out of the scope of this review, as it essentially pertains to the gastrulation process. Here, I essentially discuss the segmental patterning phase in vertebrates. Recent data suggest that establishment of the segmental pattern relies on a clock and wavefront mechanism which has been conserved in vertebrates. Furthermore, conservation of this system could extend to invertebrates, suggesting that the clock and wavefront is an ancestral mechanism.     

Chitinase: a novel target for blocking parasite transmission?

In many species of blood-sucking arthropod, the internal tissues are covered by chitinous material that may hinder parasite invasion. To circumvent this potential barrier, therefore, parasites have developed mechanisms that involve the enzyme chitinase. In this review, Mohammed Shohobuddin and David C. Kaslow examine the relationship between chitinase and parasite transmission.     

Increasingly accurate dynamic molecular models of G-protein coupled receptor oligomers: Panacea or Pandora's box for novel drug discovery?

For years, conventional drug design at G-protein coupled receptors (GPCRs) has mainly focused on the inhibition of a single receptor at a usually well-defined ligand-binding site. The recent discovery of more and more physiologically relevant GPCR dimers/oligomers suggests that selectively targeting these complexes or designing small molecules that inhibit receptor–receptor interactions might provide new opportunities for novel drug discovery. To uncover the fundamental mechanisms and dynamics governing GPCR dimerization/oligomerization, it is crucial to understand the dynamic process of receptor–receptor association, and to identify regions that are suitable for selective drug binding. This minireview highlights current progress in the development of increasingly accurate dynamic molecular models of GPCR oligomers based on structural, biochemical, and biophysical information that has recently appeared in the literature. In view of this new information, there has never been a more exciting time for computational research into GPCRs than at present. Information-driven modern molecular models of GPCR complexes are expected to efficiently guide the rational design of GPCR oligomer-specific drugs, possibly allowing researchers to reach for the high-hanging fruits in GPCR drug discovery, i.e. more potent and selective drugs for efficient therapeutic interventions.     

PI3-kinase inhibition: a target for drug development?

The phosphoinositide 3-kinases (PI3-kinases) are a ubiquitously expressed enzyme family that, through the generation of phospholipid second messengers, play a key role in the regulation of many cellular processes. These include motility, proliferation and survival, and carbohydrate metabolism. Members of the PI3-kinase family and related kinases, their mechanism of activation and the cellular events that they influence are described in this review. As knowledge of their involvement in disease processes increases, the PI3-kinases appear to be an increasingly attractive target for drug development, particularly in the fields of cancer and other proliferative diseases, and in the treatment of inflammatory and immunological conditions. Evidence of the functional specialization of PI3-kinase isoforms suggests that selective inhibition with acceptable toxicity might be possible.