Changes in the EEG spectral power during dual-task walking with aging and Parkinson’s disease: initial findings using Event-Related Spectral Perturbation analysis

Journal of Neurology - The ability to maintain adequate motor-cognitive performance under increasing task demands depends on the regulation and coordination of neural resources. Studies have shown...     

Novel long-term anticonvulsant treatment with gabapentin without causing memory impairment in mice

We previously reported that administration of a single dose of gabapentin (GBP) immediately after training improves memory of mice in an inhibitory avoidance task (IA), whereas GBP administered repeatedly for 7 days impairs memory. This is in accordance with the observation that long-term clinical treatment with GBP may be associated with adverse cognitive side effects. In the present work we used a GBP-loaded poly(ε-caprolactone) implant, allowing controlled release of the drug and maintenance of constant plasma levels over 1 week. When GBP-loaded implants were inserted subcutaneously into mice, immediately after training in the IA task, memory consolidation was enhanced. Moreover, GBP released from implants had an anticonvulsant action against pentylenetetrazole-induced seizures. These results suggest that maintenance of stable GBP plasma levels could protect against seizures without causing memory impairment. Hence, the adverse cognitive effects might be avoided by stabilizing plasma levels of the drug.     

Triclosan-loaded poloxamine micelles for enhanced topical antibacterial activity against biofilm

Our research group is interested in the study of different technological approaches to treat hospital biofilm as a means to constrain nosocomial-acquired infections. The present work investigated the effect of the incorporation of the antibacterial agent triclosan (TS) into polymeric micelles of poloxamine T1107 (MW=15 kDa, 70 wt% PEO). The aggregation phenomenon was primarily investigated by means of Critical Micellar Concentration in a broad range of pH. Then, the effect of the polymer concentration on the micellar size was evaluated by Dynamic Light Scattering. Solubility levels increased up to 4 orders of magnitude. The drug inclusion affected the micellization, resulting in size increase and micellar fusion. This phenomenon was only apparent in TS-saturated systems. TS-loaded aggregates proved to be active in vitro against a broad spectrum of bacteria but more importantly, also against two representative clinical pathogens: methicilin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF). While the former was sensitive to even very low TS levels attainable in poloxamine-free aqueous media, the later was inhibited only when exposed to higher drug levels affordable exclusively using an inclusion system. These findings indicated the release of the drug from the reservoir. Finally, the activity of a TS-containing 5% poloxamine combination of pH 7.4 was assessed on biofilms of Staphylococcus epidermidis. Results showed a significant decrease (p<0.001) in the number of Colony-Formation Units when the biofilm was exposed to the TS/poloxamine as compared to the limited activity of the polymer-free TS control.     

Crosslinkable PEO-PPO-PEO-based reverse thermo-responsive gels as potentially injectable materials

This paper describes the functionalization and crosslinking of PluronicRTM derivatives in aqueous solution at 37 degrees C. Pluronic dimethacrylate was obtained by reacting native PEO-PPO-PEO triblocks with methacryloyl chloride and then crosslinking them by free radical polymerization at 37 degrees C, using a redox system. The resulting gel and its rheological behavior were characterized by different techniques. The swelling study of the crosslinked polymer was indicative of its reverse thermo-responsive behavior, as illustrated by the almost 800% water uptake of the polymer at 37 degrees C, as opposed to the 1600% attained by the polymer at 25 degrees C. As expected, while the Pluronic dimethacrylate gel displayed an Ec value of 142.5 +/- 29.7 kPa at 37 degrees C, the crosslinked system attained a Young's modulus three times higher: 415.2 +/- 45.7 kPa. Finally, the environmental SEM analysis revealed the porous microstructure of the crosslinked gels.     

Drug Delivery Systems and Liver Targeting for the Improved Pharmacotherapy of the Hepatitis B Virus (HBV) Infection

In spite of the progress made in vaccine and antiviral therapy development, hepatitis B virus (HBV) infection is still the most common cause of liver cirrhosis and hepatocellular carcinoma, with more than 400 million people chronically infected worldwide. Antiviral therapy with nucleos(t)ide analogues and/or immunomodulating peptides is the only option to control and prevent the progression of the disease in chronic hepatitis B (CHB)-infected patients. So far, the current antiviral monotherapy remains unsatisfactory because of the low efficacy and the development of drug resistance mutants. Moreover, viral rebound is frequently observed following therapy cessation, since covalent closed circular DNA (cccDNA) is not removed from hepatocytes by antiviral therapy. First, this review describes the current pharmacotherapy for the management of CHB and the new drug candidates being investigated. Then, the challenges in the development of drug delivery systems for the targeting of antiviral drugs to the liver parenchyma are discussed. Finally, perspectives in the design of a more efficient pharmacotherapy to eradicate the virus from the host are addressed.     

PEO-PPO block copolymers for passive micellar targeting and overcoming multidrug resistance in cancer therapy

Drug carriers tailored to fit the physicochemical properties of anticancer agents and the therapeutic peculiarities of tumor management are envisioned for improving the effectiveness/toxicity ratio of the current treatments. Polymeric micelles are attracting much attention owing to their unique beneficial features: i) core-shell structure capable to host hydrophobic drugs, raising the apparent solubility in aqueous medium; ii) size adequate for a preferential accumulation (passive targeting) within the tumor, exhibiting enhanced permeability and retention (EPR effect), and iii) unimers that modulate the activity of efflux pumps involved in multidrug resistance (MDR). This review focuses on amphiphilic poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers, namely the linear poloxamers (Pluronic? or Lutrol?) and the X-shaped poloxamines (Tetronic?), as components of polymeric micelles able to play these three roles. Specific facets of poloxamers have been highlighted some years ago, but recently their wide range of possibilities is beginning to be fully elucidated and understood. Poloxamines are new excipients in the cancer arena and the comparison of their performance with that of poloxamers may enable to identify aspects of their architecture relevant for the optimization of micellar carriers. Clinical trials in progress indicate that drug-loaded polymeric micelles are beneficial regarding efficiency, safety, and compliance of the treatment and quality of life of the patients. The fact that some copolymers are already approved for internal use and several chemotherapy agents will be off patent soon may help to bring the clinical use of poloxamer- or poloxamine-based micelles into a reality in the coming years.     

PEO-PPO-PEO-based poly(ether ester urethane)s as degradable reverse thermo-responsive multiblock copolymers

Aiming at developing biodegradable thermo-responsive polymers that display enhanced rheological properties, a family of PEO-PPO-PEO based poly(ether ester urethane)s, was developed. The materials were produced following a two-step synthetic pathway. The PEO-PPO-PEO triblocks were first end-capped with LA or CL oligo(ester)s whereby pentablocks were produced. Then, the different precursors were chain extended using hexamethylene diisocyanate to create the respective polymers. The length and type of the ester block influenced the behavior of the molecules in water, especially their viscosity versus temperature response. The gelation temperature increased from 23 degrees C for a 20wt% F127 solution to 26 and 31 degrees C for pentablocks with 4.4 and 7.5 lactoyl units, respectively. Materials containing longer LA units failed to show any reverse thermo-responsiveness. The presence of the oligo(ester) blocks also reduced the viscosity of the gel at 37 degrees C. While F127 displayed a viscosity of around 28,000Pas, pentablocks containing 4.4 and 7.5 LA units showed values of 15,400 and 12,600Pas. Also, the viscosity at 37 degrees C as well as the gelation temperature decreased as the molecular weight of the oligo(ester)s increased. Finally, the degradation process of the gels was studied by monitoring their viscosity at body temperature and determining the molecular weight of the polymers, over time. Polymers were tailored so to combine high initial viscosity values with diverse degradation rates, as a function of the length and type of the oligo(ester) present along the polymeric backbone.     

Surface study of collagen/poloxamine hydrogels by a 'deep freezing' ToF-SIMS approach

In order to determine the presence of collagen molecules at the surface of a collagen-modified poloxamine hydrogel (a semi-interpenetrating network), the surface composition was studied using Time-of-Flight Secondary Ion Mass Spectra (ToF-SIMS). Collagen was added to the poloxamine hydrogel (poloxamine is a commercially available four-arm poly(ethylene oxide)/poly(propylene oxide) block copolymer, PEO/PPO) to promote the attachment of endothelial or liver cells. X-ray photoelectron spectroscopy (XPS) of dry samples showed a sharp increase in the N content from 0.6% in a pure poloxamine hydrogel to 8.8% in the collagen-containing material. Afterwards, the surface was studied by a 'deep freezing' ToF-SIMS approach under progressive heating from -120 to -60 degrees C. The positive spectrum of collagen/poloxamine at -65 degrees C displayed distinct signals corresponding to different amino acid fragments such as CH4N+ (30 m/z, Gly), C3HN2+ (43 m/z, Arg), C2H6N+ (44 m/z, Ala) and C4H5N2+(81m/z, His) and others corresponding to the PEO and PPO blocks of poloxamine. In addition, the negative spectrum showed peaks at 26 m/z (CN-), 32 m/z (S-) and 42 m/z (CNO-) characteristic of fragments of the collagen molecule. Imaging experiments indicated the homogeneous distribution of the collagen on the surface. These results supported the use of ToF-SIMS for the surface characterization of hydrated hydrogels and confirmed the collagen presence as the means whereby cells attach to the modified poloxamine matrix.     

Semi-synthetic collagen/poloxamine matrices for tissue engineering

Collagen-containing poloxamine hydrogels were produced with the aim of overcoming the low stiffness displayed by collagen gels that are not otherwise chemically crosslinked. Matrices were obtained by functionalization of a four-arm PEO-PPO block copolymer (poloxamine, Tetronic) with methcrylate groups and subsequent free radical polymerization of water solutions of the modified polymer in the presence of collagen. The resulting matrices had a sharp increase in stiffness, when compared to pure collagen gels. For example, whereas collagen had a storage modulus (G') around 70 Pa and a loss modulus (G') of 10 Pa, a crosslinked collagen/poloxamine system containing 8.3% crosslinked poloxamine had G' and G' values of 7400 and 1000 Pa, respectively. HepG2 cells were seeded within the gels before the crosslinking and the viability levels estimated by AlamarBlue assay were between 65% and 91% for systems containing 0.04-0.09 wt% photoinitiator. HepG2 and endothelial cells also adhered to and spread on the surface of the collagen-containing specimens, suggesting their potential utility in tissue engineering.