Lauryl-gemcitabine loaded nanomedicine hydrogel for the local treatment of glioblastoma

Glioblastoma (GBM) is one of the greatest challenges in oncology. The standard of care therapy of this highly malignant brain tumor includes surgical resection followed, one month after, by radiotherapy and chemotherapy with Temozolomide. However, GBM still remains incurable mainly because of its anatomical location, high intra - and inter-tumor heterogeneity and intrinsic characteristics that inevitably lead to the formation of recurrences [1]. Considering that 80-90% of GBM recurrences are localized in proximity of resection cavity borders we hypothesized to deliver an injectable nanomedicine hydrogel directly in the tumor resection cavity after surgery in order to obtain a sustained release of the drug. This could avoid the formation of recurrences before starting the conventional treatment. The hydrogel that we have developed and selected is formed of lipid nanocapsules (LNC) loaded with the prodrug Lauroyl -gemcitabine (GemC12), which shows excellent radio-sensitizing properties, could potentiate cancer immunotherapy and has a MGMT -independent mechanism of action [2,3]. This nanomedicine hydrogel is injectable, adapted for brain implantation and able to release the drug over one month in vitro [2]. In vivo, the anti-tumor efficacy studies in a subcutaneous and ortothopic GBM rodent models have shown, respectively, to decrease the tumor growth and increase the survival of the mice after intratumoral injection of the hydrogel compared to the controls. Also, to better mimic the clinical conditions, we have developed and validated a resection model of the GBM orthotopic tumor and on -going anti -tumor efficacy studies after administration of the treatment in the resection cavity are showing promising results. Moreover, short -, mid- and long- term tolerability studies (1 week, 2 months and 6 months) indicated that this system is well tolerated in the brain. In conclusion, we have demonstrated the fe asibility, safety and efficiency of the GemC12 -LNC hydrogel for the local treatment of GBM. This system, which has a very simple formulation and combines the properties and advantages of nanomedicines and hydrogels, could be considered as a promising platform for the delivery of GemC12 for the local treatment of GBM

Effect of functionalization of polymeric nanoparticles incorporated with whole attenuated rabies virus antigen on sustained release and efficacy

AbstractNanovaccines introduced a new dimension to prevent or cure diseases in an efficient and sustained manner. Various polymers have been used for the drug delivery to increase the therapeutic value with minimal side effects. Thus the present study incorporates both nanotechnology and polymers for the drug delivery. Poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol) was incorporated with the rabies whole attenuated viral antigen using double emulsion (W/O/W) method and characterized by Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). Chitosan-PEG nanoparticles incorporated with the rabies whole attenuated virus antigen (CS-PEG NP-RV Ag.) were prepared using Ionic Gelation method. The CS-PEG NP-RV Ag. was surface modified with biocompatible polymers such as Acacia, Bovine Serum Albumin (BSA), Casein, Ovalbumin and Starch by Ionic Gelation method. The morphology was confirmed by SEM and Transmission Electron Microscopy (TEM). The surface modification was confirmed by Fourier Transform Infrared Spectroscopy (FTIR), Zeta potential. The size distribution of CS-PEG-RV Ag. and surface modified CS-PEG-RV Ag. by respective biocompatible polymers was assessed by Zetasizer. Release profile of both stabilized nanoparticles was carried out by modified centrifugal ultrafiltration method which showed the sustained release pattern of the Rabies Ag. Immune stimulation under in-vitro condition was studied using rosette assay and phagocytosis assay. In-vitro toxicity using human blood and genotoxicity using human blood DNA was also studied to assess the toxicity of the nanoformulations. The results of these studies infer that PLGA-b-PEG nanoparticles, CS-PEG and surface modified CS-PEG nanoparticles may be an efficient nanocarrier for the RV Ag. to elicit immune response sustainably with negligible toxic effect to the human system

Probing the interaction of nanoparticles with mucin for drug delivery applications using dynamic light scattering

Drug delivery via the eye, nose, gastrointestinal tract and lung is of great interest as they represent patient-compliant and facile methods to administer drugs. However, for a drug to reach the systemic circulation it must penetrate the “mucus barrier”. An understanding of the characteristics of the mucus barrier is therefore important in the design of mucus penetrating drug delivery vehicles e.g. nanoparticles. Here, a range of nanoparticles – silica, aluminium coated silica, poly (lactic-co-glycolic acid) (PLGA) and PEGylated PLGA – each with known but different physicochemical characteristics were examined in the presence of mucin to identify those characteristics that engender nanoparticle/mucin interactions and thus, to define “design rules” for mucus penetrating (nano)particles (MPP), at least in terms of the surface characteristics of charge and hydrophilicity. Dynamic light scattering (DLS) and rheology have been used to assess the interaction between such nanoparticles and mucin. It was found that negatively charged and hydrophilic nanoparticles do not exhibit an interaction with mucin whereas positively charged and hydrophobic nanoparticles show a strong interaction. Surface grafted poly (ethylene glycol) (PEG) chains significantly reduced this interaction. This study clearly demonstrates that the established colloid science techniques of DLS and rheology are very powerful screening tools to probe nanoparticle/mucin interactions

Language-specific information structure in German and Spanish route directions

This paper investigates which linguistic resources speakers use to produce understandable and coherent route directions. These resources include how the information ows from one sentence to the next, how the information is mapped onto the topological route and how this information is encoded linguistically in order to be organized into a text. The aim of this paper is to show that syntactical differences between Spanish and German (the marking of subordination and the boundary crossing constraint) have consequences for the way the information is structured in route directions. The analyses are based on a corpus of 124 empirically collected route directions. The results include language-speci c differences regarding information ow and information packaging

An apoferritin-based drug delivery system for the tyrosine kinase inhibitor gefitinib

Anticancer drug Gefitinib encapsulated within human heavy chain apoferritin by diffusion allows pH-controlled sustained release of cargo. The combination of increased cellular uptake, and potent and enhanced antitumor activity against the HER2 overexpressing SKBR3 cell line compared to Gefitinib alone, makes it a promising carrier for delivery of drugs to tumor sites. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Design and testing of hydrophobic core/hydrophilic shell nano/micro particles for drug-eluting stent coating

In this study, we designed a novel drug-eluting coating for vascular implants consisting of a core coating of the anti-proliferative drug docetaxel (DTX) and a shell coating of the platelet glycoprotein IIb/IIIa receptor monoclonal antibody SZ-21. The core/shell structure was sprayed onto the surface of 316L stainless steel stents using a coaxial electrospray process with the aim of creating a coating that exhibited a differential release of the two drugs. The prepared stents displayed a uniform coating consisting of nano/micro particles. In vitro drug release experiments were performed, and we demonstrated that a biphasic mathematical model was capable of capturing the data, indicating that the release of the two drugs conformed to a diffusion-controlled release system. We demonstrated that our coating was capable of inhibiting the adhesion and activation of platelets, as well as the proliferation and migration of smooth muscle cells (SMCs), indicating its good biocompatibility and anti-proliferation qualities. In an in vivo porcine coronary artery model, the SZ-21/DTX drug-loaded hydrophobic core/hydrophilic shell particle coating stents were observed to promote re-endothelialization and inhibit neointimal hyperplasia. This core/shell particle-coated stent may serve as part of a new strategy for the differential release of different functional drugs to sequentially target thrombosis and in-stent restenosis during the vascular repair process and ensure rapid re-endothelialization in the field of cardiovascular disease

The application of non-linear curve fitting routines to the analysis of mid-infrared images obtained from single polymeric microparticles

For the first time, we report a series of time resolved images of a single PLGA microparticle undergoing hydrolysis at 70 °C that have been obtained using attenuated total reflectance-Fourier transform infrared spectroscopic (ATR-FTIR) imaging. A novel partially supervised non-linear curve fitting (NLCF) tool was developed to identify and fit peaks to the infrared spectrum obtained from each pixel within the 64 × 64 array. The output from the NLCF was evaluated by comparison with a traditional peak height (PH) data analysis approach and multivariate curve resolution alternating least squares (MCR-ALS) analysis for the same images, in order to understand the limitations and advantages of the NLCF methodology. The NLCF method was shown to facilitate consistent spatial resolution enhancement as defined using the step-edge approach on dry microparticle images when compared to images derived from both PH measurements and MCR-ALS. The NLCF method was shown to improve both the S/N and sharpness of images obtained during an evolving experiment, providing a better insight into the magnitude of hydration layers and particle dimension changes during hydrolysis. The NLCF approach facilitated the calculation of hydrolysis rate constants for both the glycolic (kG) and lactic (kL) acid segments of the PLGA copolymer. This represents a real advantage over MCR-ALS which could not distinguish between the two segments due to colinearity within the data. The NLCF approach made it possible to calculate the hydrolysis rate constants from a single pixel, unlike the peak height data analysis approach which suffered from poor S/N at each pixel. These findings show the potential value of applying NLCF to the study of real-time chemical processes at the micron scale, assisting in the understanding of the mechanisms of chemical processes that occur within microparticles and enhancing the value of the mid-IR ATR analysis

Lipid-coated polymeric nanoparticles for cancer drug delivery

Polymeric nanoparticles and liposomes have been the platform of choice for nanoparticle-based cancer drug delivery applications over the past decade, but extensive research has revealed their limitations as drug delivery carriers. A hybrid class of nanoparticles, aimed at combining the advantages of both polymeric nanoparticles and liposomes, has received attention in recent years. These core/shell type nanoparticles, frequently referred to as lipid–polymer hybrid nanoparticles (LPNs), possess several characteristics that make them highly suitable for drug delivery. This review introduces the formulation methods used to synthesize LPNs and discusses the strategies used to treat cancer, such as by targeting the tumor microenvironment or vasculature. Finally, it discusses the challenges that must be overcome to realize the full potential of LPNs in the clinic

Weganweisungen im Deutschen und Spanischen: Eine Vergleichsanalyse unter Anwendung von Visualisierungen

Diese Arbeit bietet den bis jetzt ausführlichsten Gesamtüberblick über die Produktion von Weganweisungen. Dafür wurden experimentell erhobene schriftliche Weganweisungen, die sich auf Routen innerhalb von Gebäuden bezogen, sprachvergleichend untersucht. Die Sprachdaten setzen sich aus Texten monolingualer Muttersprachler des Deutschen und Spanischen zusammen. Die Untersuchung ergab, dass Sprecher des Deutschen und des Spanischen Weganweisungen unterschiedlich formulieren. Unterschiede in den Grammatiken der beiden Sprachen führen zu Effekten auf Ebene der sprachlichen Form, da die Sprecher andere Informationen für die Beschreibung auswählen und diese Informationen auch anders formulieren. Sprachspezifische Unterschiede konnten in folgenden Bereichen festgestellt werden: In der Aufteilung der Gesamtaufgabe in Teilaufgaben, in der Textstruktur und in der Informationsdichte. Ebenso werden Rauminformationen in jeder Sprache anders ausgedrückt, wodurch deutlich wird, auf welche Raumkonzepte sich die Sprecher in den Weganweisungen beziehen. Die Bereiche, in denen Unterschiede zwischen den Sprachen bestehen, sind auf der Textebene voneinander abhängig, sodass sich unterschiedliche Muster für Weganweisungen in der jeweiligen Sprache ergeben. Die sprachspezifischen Unterschiede sind subtil und können nur durch Einsatz der speziell dafür entwickelten Spektrums-Methode identifiziert werden. Die Datensätze und die Ergebnisse werden mit Hilfe von innovativen Visualisierungen des Datensatzes dargestellt