Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer

The discovery of underlying mechanisms of drug resistance, and the development of novel agents to target these pathways, is a priority for patients with advanced colorectal cancer (CRC). We previously undertook a systems biology approach to design a functional genomic screen and identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of drug resistance. The aim of this study was to examine the role of FGFR4 in drug resistance using RNAi and the small-molecule inhibitor BGJ398 (Novartis). We found that FGFR4 is highly expressed at the RNA and protein levels in colon cancer tumour tissue compared with normal colonic mucosa and other tumours. Silencing of FGFR4 reduced cell viability in a panel of colon cancer cell lines and increased caspase-dependent apoptosis. A synergistic interaction was also observed between FGFR4 silencing and 5-fluorouracil (5-FU) and oxaliplatin chemotherapy in colon cancer cell lines. Mechanistically, FGFR4 silencing decreased activity of the pro-survival STAT3 transcription factor and expression of the anti-apoptotic protein c-FLIP. Furthermore, silencing of STAT3 resulted in downregulation of c-FLIP protein expression, suggesting that FGFR4 may regulate c-FLIP expression via STAT3. A similar phenotype and downstream pathway changes were observed following FGFR4 silencing in cell lines resistant to 5-FU, oxaliplatin and SN38 and upon exposure of parental cells to the FGFR small-molecule inhibitor BGJ398. Our results indicate that FGFR4 is a targetable regulator of chemo-resistance in CRC, and hence inhibiting FGFR4 in combination with 5-FU and oxaliplatin is a potential therapeutic strategy for this disease.

Efficient Drug Delivery and Induction of Apoptosis in Colorectal Tumors Using a Death Receptor 5-Targeted Nanomedicine

Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles. We describe the development of an optimized polymer-based nanotherapeutic incorporating both a functionalized polyethylene glycol (PEG) layer and targeting antibodies to limit premature phagocytic clearance whilst enabling targeting of DR5-expressing tumor cells. Using the HCT116 colorectal cancer model, we show that following binding to DR5, the nanoparticles activate caspase 8, enhancing the anti-tumor activity of the camptothecin payload both in vitro and in vivo. Importantly, the combination of nanoparticle-induced DR5 clustering with camptothecin delivery overcomes resistance to DR5-induced apoptosis caused by loss of BAX or overexpression of anti-apoptotic FLIP. This novel approach may improve the clinical activity of DR5-targeted therapeutics while increasing tumor-specific delivery of systemically toxic chemotherapeutics.Molecular Therapy (2014); doi:10.1038/mt.2014.137.

In Situ Gelling Ophthalmic Drug Delivery System: An Overview and Its Applications.

Ophthalmic drug delivery system is very interesting and challenging due to the normal physiologically factor of eyes which reduces the bioavailability of ocular products. The development of a new ophthalmic dosage forms with the existing drugs to improve efficacy and bioavailability including better patients' compliance and convenience has become trend in the most pharmaceutical industries. The present review encompasses various conventional and novel ocular drug delivery systems, methods of preparation, characterization, recent researches carried out. Furthermore, the information on various commercially available in situ gel preparations and the existing patents of in situ drug delivery systems i.e. in situ gel formation of pectin, in situ gel for therapeutic use, medical uses of in situ formed gels and in situ gelling systems as sustained delivery for front of eye also covered in this review.

Parasite neuropeptide biology:Seeding rational drug target selection?

The rationale for identifying drug targets within helminth neuromuscular signalling systems is based on the premise that adequate nerve and muscle function is essential for many of the key behavioural determinants of helminth parasitism, including sensory perception/host location, invasion, locomotion/orientation, attachment, feeding and reproduction. This premise is validated by the tendency of current anthelmintics to act on classical neurotransmitter-gated ion channels present on helminth nerve and/or muscle, yielding therapeutic endpoints associated with paralysis and/or death. Supplementary to classical neurotransmitters, helminth nervous systems are peptide-rich and encompass associated biosynthetic and signal transduction components - putative drug targets that remain to be exploited by anthelmintic chemotherapy. At this time, no neuropeptide system-targeting lead compounds have been reported, and given that our basic knowledge of neuropeptide biology in parasitic helminths remains inadequate, the short-term prospects for such drugs remain poor. Here, we review current knowledge of neuropeptide signalling in Nematoda and Platyhelminthes, and highlight a suite of 19 protein families that yield deleterious phenotypes in helminth reverse genetics screens. We suggest that orthologues of some of these peptidergic signalling components represent appealing therapeutic targets in parasitic helminths.

Thermodynamically stable amorphous drug dispersions in amorphous hydrophilic polymers engineered by hot melt extrusion.

In this study thermodynamically stable dispersions of amorphous quinine, a model BCS class 2 therapeutic agent, within an amorphous polymeric platform (HPC), termed a solid-in-solid dispersion, were produced using hot melt extrusion. Characterisation of the pre-extrudates and extrudates was performed using hyper-differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Raman spectroscopy. Water uptake by the raw materials was determined using dynamic vapour sorption (DVS) analysis. Furthermore, the presence or absence of crystalline drug following storage at 25 °C/60% relative humidity and 40 °C/75% relative humidity in a sealed glass jar, and at 40 °C/75% relative humidity in an open glass jar for 3 months was determined using PXRD. Amorphous quinine was generated in situ during extrusion from both quinine base (5%, 10%, 20% w/w drug loading) and from quinine hydrochloride (5%, 10% w/w drug loading) and remained thermodynamically stable as a solid-in-solid dispersion within the HPC extrudates. When processed with HPC, quinine hydrochloride (20% w/w) was converted to amorphous quinine hydrochloride. Whilst stable for up to 3 months when stored under sealed conditions, this amorphous form was unstable, resulting in recrystallisation of the hydrochloride salt following storage for 1 month at 40 °C/75% relative humidity in an open glass jar. The behaviour of the amorphous quinine hydrochloride (20% w/w) HPC extrudate was related, at least in part, to the lower stability and the hygroscopic properties of this amorphous form.

Stoichiometric Molecularly Imprinted Polymers for the Recognition of Anti-Cancer Pro-drug Tegafur

Molecularly Imprinted Polymers (MIPs) targeting tegafur, an anti-cancer 5-fluorouracil pro-drug, have been prepared by stoichiometric imprinting using 2,6-bis(acrylamido)pyridine (BAAPy) as the functional monomer. Solution association between tegafur and BAAPy was studied by 1H NMR titration, which confirmed the formation of 1:1 complexes with an affinity constant of 574±15 M-1 ¬in CDCl3. Evaluation of the synthesised materials by HPLC and equilibrium rebinding experiments revealed high selectivity of the imprinted polymer for the pro-drug versus 5-fluorouracil and other competing analytes, with maximum imprinting factors of 25.3 and a binding capacity of 45.1 μmol g-1. The synthesised imprinted polymer was employed in solid-phase extraction of the pro-drug using an optimised protocol that included a simple wash with the porogen used in the preparation of the material. Tegafur recoveries of up to 96% were achieved from aqueous samples and 92% from urine samples spiked with the template and three competing analytes. The results demonstrate the potential of the prepared polymers in the pre-concentration of tegafur from biological samples, which could be an invaluable tool in the monitoring of patient compliance and drug uptake and excretion.

Integrative analysis of chemo-transcriptomic profiles for drug-feature specific gene expression signatures

One of the major challenges in systems biology is to understand the complex responses of a biological system to external perturbations or internal signalling depending on its biological conditions. Genome-wide transcriptomic profiling of cellular systems under various chemical perturbations allows the manifestation of certain features of the chemicals through their transcriptomic expression profiles. The insights obtained may help to establish the connections between human diseases, associated genes and therapeutic drugs. The main objective of this study was to systematically analyse cellular gene expression data under various drug treatments to elucidate drug-feature specific transcriptomic signatures. We first extracted drug-related information (drug features) from the collected textual description of DrugBank entries using text-mining techniques. A novel statistical method employing orthogonal least square learning was proposed to obtain drug-feature-specific signatures by integrating gene expression with DrugBank data. To obtain robust signatures from noisy input datasets, a stringent ensemble approach was applied with the combination of three techniques: resampling, leave-one-out cross validation, and aggregation. The validation experiments showed that the proposed method has the capacity of extracting biologically meaningful drug-feature-specific gene expression signatures. It was also shown that most of signature genes are connected with common hub genes by regulatory network analysis. The common hub genes were further shown to be related to general drug metabolism by Gene Ontology analysis. Each set of genes has relatively few interactions with other sets, indicating the modular nature of each signature and its drug-feature-specificity. Based on Gene Ontology analysis, we also found that each set of drug feature (DF)-specific genes were indeed enriched in biological processes related to the drug feature. The results of these experiments demonstrated the pot- ntial of the method for predicting certain features of new drugs using their transcriptomic profiles, providing a useful methodological framework and a valuable resource for drug development and characterization.

Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development

Transdermal drug delivery offers a number of advantages for the patient, due not only its non-invasive and convenient nature, but also factors such as avoidance of first pass metabolism and prevention of gastrointestinal degradation. It has been demonstrated that microneedle arrays can increase the number of compounds amenable to transdermal delivery by penetrating the skin's protective barrier, the stratum corneum, and creating a pathway for drug permeation to the dermal tissue below. Microneedles have been extensively investigated in recent decades for drug and vaccine delivery as well as minimally invasive patient monitoring/diagnosis. This review focuses on a range of critically important aspects of microneedle technology, namely their material composition, manufacturing techniques, methods of evaluation and commercial translation to the clinic for patient benefit and economic return. Microneedle research and development is finally now at the stage where commercialisation is a realistic possibility. However, progress is still required in the areas of scaled-up manufacture and regulatory approval.

Novel methods of drug administration for the treatment and care of older patients

The number of older people globally is increasing, contributing to a growing burden of morbidity and mortality. With this shift in population demographic, comes a new challenge in terms of appropriate healthcare for the over 65 years age group. As medication is the principal therapeutic intervention, it is essential that it be fully optimised, to meet the needs of this heterogeneous population. The most common routes of drug administration are oral and injectable, which may display some limitations for older people, in cases of dysphagia or frailty for example. This review considers alternative methods of drug delivery to the norm, specifically discussing the nasal, pulmonary and transdermal routes, as well as novel orally disintegrating tablets. The changing physiology as ageing occurs must be considered in the development of novel drug delivery devices. This review considers the various aspects of ageing that will influence future drug formulation design and development.

Future of the transdermal drug delivery market – have we barely touched the surface?

Introduction: Transdermal drug delivery is themovement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive trans- dermal products donot disrupt the stratumcorneumto facilitate deliverywhereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally. Areas Covered: This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each high- lighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed. Expert Opinion: Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation.

Stimuli-Responsive Microneedle Arrays For On-Demand Drug Delivery

Pulsatile, or “on-demand”, delivery systems have the capability to deliver a therapeutic molecule at the right time/site of action and in the right amount (1). Pulsatile delivery systems present multiple benefits over conventional dosage forms and provide higher patient compliance. The combination of stimuli-responsive materials with the drug delivery capabilities of hydrogel-forming MN arrays (2) opens an interesting area of research. In the present work we describe, a stimuli-responsive hydrogel-forming microneedle (MN) array that enable delivery of a clinically-relevant model drug (ibuprofen) upon application of UV radiation (Figure 1A). MN arrays were prepared using a micromolding technique using a polymer prepared from 2-hydroxyethyl methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA) (Figure 1B). The arrays were loaded with up to 5% (w/w) ibuprofen included in a light-responsible conjugate (3,5-dimethoxybenzoin conjugate) (2). The presence of the conjugate inside the MN arrays was confirmed by Raman spectroscopy measurements. MN arrays were tested in vitro showing that they were able to deliver up to three doses of 50 mg of ibuprofen after application of an optical trigger (wavelength of 365 nm) over a long period of time (up to 160 hours) (Figure 1C and 1D). The work presented here is a probe of concept and a modified version of the system should be used as UV radiation is shown to be the major etiologic agent in the development of skin cancers. Consequently, for future applications of this technology an alternative design should be developed. Based on the previous research dealing with hydrogel forming MN arrays a suitable strategy will be to use hydrogel-forming MN arrays containing a backing layer made with the material described in this work as the drug reservoir (2). Finally, a porous layer of a material that blocks UV radiation should be included between the MN array and the drug reservoir. Therefore radiation can be applied to the system without reaching the skin surface. Therefore after modification, the system described here interesting properties as “on-demand” release system for prolonged periods of time. This technology has potential for use in “on-demand” delivery of a wide range of drugs in a variety of applications relevant to enhanced patient care.

Controlled release of a model antibacterial drug from a novel self-lubricating silicone biomaterial

Abstract There is considerable interest in developing medical devices that provide controlled delivery of biologically active agents, for example, to reduce the incidence of device-related infection. Silicone elastomers are one of the commonest biomaterials used in medical device production. However, they have a relatively high coefficient of friction and the resulting lack of lubricity can cause pain and tissue damage on device insertion and removal. Novel silicone cross-linking agents have recently been reported that produce inherently ‘self-lubricating’ silicone elastomers with very low coefficients of friction. In this study, the model antibacterial drug metronidazole has been incorporated into these self-lubricating silicone elastomers to produce a novel bioactive biomaterial. The in vitro release characteristics of the bioactive component were evaluated as a function of cross-linker composition and drug loading. Although conventional matrix-type release kinetics were observed for metronidazole from the silicone systems, it was also observed that increasing the concentration of the cross-linking agent responsible for the lubricious character (tetra(oleyloxy)silane) relative to that of the standard non-lubricious cross-linking agent (tetrapropoxysilane) produced an increase in the metronidazole flux rate by up to 65% for a specified drug loading. The results highlight the potential for developing lubricious silicone medical devices with enhanced drug release characteristics.