Synthesis and characterization of biocompatible, thermoresponsive ABC and ABA triblock copolymer gelators

The synthesis of doubly thermoresponsive PPO-PMPC-PNIPAM triblock copolymer gelators by atom transfer radical polymerization using a PPO-based macroinitiator is described. Provided that the PPO block is sufficiently long, dynamic light scattering and differential scanning calorimetry studies confirm the presence of two separate thermal transitions corresponding to micellization and gelation, as expected. However, these ABC-type triblock copolymers proved to be rather inefficient gelators: free-standing gels at 37 degrees C required a triblock copolymer concentration of around 20 wt%. This gelator performance should be compared with copolymer concentrations of 6-7 wt% required for the PNIPAM-PMPC-PNIPAM triblock copolymers reported previously. Clearly, the separation of micellar self-assembly from gel network formation does not lead to enhanced gelator efficiencies, at least for this particular system. Nevertheless, there are some features of interest in the present study. In particular, close inspection of the viscosity vs temperature plot obtained for a PPO43-PMPC160-PNIPAM(81) triblock copolymer revealed a local minimum in viscosity. This is consistent with intramicelle collapse of the outer PNIPAM blocks prior to the development of the intermicelle hydrophobic interactions that are a prerequisite for macroscopic gelation.

Biocompatible, biomimetic ampholyte materials

New ampholyte biomaterial compounds containing ampholyte moieties are synthesized and integrated into polymeric assemblies to provide hydrophilic polymers exhibiting improved biocompatibility, haemocompatibility, hydrophilicity non-thrombogenicity, anti-bacterial ability, and mechanical strength, as well as suitability as a drug delivery platform.

Neuronal-glial populations form functional networks in a biocompatible 3D scaffold

Monolayers of neurons and glia have been employed for decades as tools for the study of cellular physiology and as the basis for a variety of standard toxicological assays. A variety of three dimensional (3D) culture techniques have been developed with the aim to produce cultures that recapitulate desirable features of intact. In this study, we investigated the effect of preparing primary mouse mixed neuron and glial cultures in the inert 3D scaffold, Alvetex. Using planar multielectrode arrays, we compared the spontaneous bioelectrical activity exhibited by neuroglial networks grown in the scaffold with that seen in the same cells prepared as conventional monolayer cultures. Two dimensional (monolayer; 2D) cultures exhibited a significantly higher spike firing rate than that seen in 3D cultures although no difference was seen in total signal power (<50 Hz) while pharmacological responsiveness of each culture type to antagonism of GABAAR, NMDAR and AMPAR was highly comparable. Interestingly, correlation of burst events, spike firing and total signal power (<50 Hz) revealed that local field potential events were associated with action potential driven bursts as was the case for 2D cultures. Moreover, glial morphology was more physiologically normal in 3D cultures. These results show that 3D culture in inert scaffolds represents a more physiologically normal preparation which has advantages for physiological, pharmacological, toxicological and drug development studies, particularly given the extensive use of such preparations in high throughput and high content systems.

3D printing of biocompatible supramolecular polymers and their composites

A series of polymers capable of self-assembling into infinite networks via supramolecular interactions have been designed, synthesized, and characterized for use in 3D printing applications. The biocompatible polymers and their composites with silica nanoparticles were successfully utilized to deposit both simple cubic structures, as well as a more complex twisted pyramidal feature. The polymers were found to be not toxic to a chondrogenic cell line, according to ISO 10993-5 and 10993-12 standard tests and the cells attached to the supramolecular polymers as demonstrated by confocal microscopy. Silica nanoparticles were then dispersed within the polymer matrix, yielding a composite material which was optimized for inkjet printing. The hybrid material showed promise in preliminary tests to facilitate the 3D deposition of a more complex structure.

Biocompatible in-tube solid phase microextraction coupled with liquid chromatography-fluorescence detection for determination of interferon alpha in plasma samples

The present work demonstrates the successful application of automated biocompatible in-tube solid-phase microextraction coupled with liquid chromatography (in-tube SPME/LC) for determination of interferon alpha(2a) (IFN alpha(2a)) in plasma samples for therapeutic drug monitoring. A restricted access material (RAM, protein-coated silica) was employed for preparation of a lab-made biocompatible in-tube SPME capillary that enables the direct injection of biological fluids as well as the simultaneous exclusion of macromolecules by chemical diffusion barrier and drug pre-concentration. The in-tube SPME variables, such as sample volume, draw/eject volume, number of draw-eject cycles, and desorption mode were optimized, to improve the sensitivity of the proposed method. The IFN alpha(2a) analyses in plasma sample were carried out within 25 min (sample preparation and LC analyses). The response of the proposed method was linear over a dynamic range, from 0.06 to 3.0 MIU mL(-1), with correlation coefficient equal to 0.998. The interday precision of the method presented coefficient of variation lower than 8%. The proposed automated method has adequate analytical sensitivity and selectivity for determination of IFN alpha(2a) in plasma samples for therapeutic drug monitoring. (C) 2010 Elsevier B.V. All rights reserved.

Structure and viscoelastic behavior of pharmaceutical biocompatible anionic microemulsions containing the antitumoral drug compound doxorubicin

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structural Properties Induced by the Composition of Biocompatible Phospholipid-Based Microemulsion and Amphotericin B Association

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effect of cosurfactant on the supramolecular structure and physicochemical properties of non-ionic biocompatible microemulsions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Doxorubicin biocompatible O/W microemulsion stabilized by mixed surfactant containing soya phosphatidylcholine

Microemulsions (ME) containing soya phosphatidylcholine (SPC/polyoxyethylenglycerol trihydroxystearate 40 (EU)/sodium oleate (SO) as surfactant cholesterol (CHO) as oil phase and aqueous buffer were studied. Pseudo-ternary phase diagrams of the investigated systems were obtained at constant SPC/EU/SO weight ratio 3.5:3.5:3.0 by titration, in order to characterize the proportions between the components to form clear systems. The dynamic light scattering results showed that the size of the oil droplets decreases significantly with the ratio of surfactant/oil phase added to system. Depending on the composition ME system could exhibit a thixotropic behavior. The apparent viscosity increased 25- and 13-folds with cholesterol concentration for drug-free and drug-load ME, respectively. It was also verified that the octanol/aqueous buffer partition coefficient (K-O/B) of doxorubicin (DOX) was pH dependent increasing abruptly above pH 6.0. It was possible to incorporate 2.24 mg/ml of DOX into ME. The incorporation of DOX in the ME systems increased the droplets size for all surfactant concentrations used in the system. The results suggest that DOX interacts with the microstructure of the ME at the studied pH increasing significantly the drug solubility. It was possible to conclude that the investigated ME can be a very promising vehicle as drug-carrier for administration of doxorubicin. (c) 2006 Elsevier B.V. All rights reserved.

Relationship between structural features and in vitro release of doxorubicin from biocompatible anionic microemulsion

In this work structural features of anionic microemulsions, containing the pharmaceutical biocompatible components soya phosphatidylcholine (SPC), eumulgin HRE 40 (EU) and sodium oleate (SO) as surfactant, cholesterol (CHO) as oil phase and aqueous buffer were studied. Microemulsions were formulated with and without the antitumor drug doxorubicin (DOX). The various microstructures characterized in the pseudo-temary phase diagram were analyzed by polarized light microscopy, small-angle X-ray scattering (SAXS) and X-ray diffraction (XRD) as well as by their ability to incorporate and release DOX. The experimental results demonstrated a correlation between the composition, the structural features and drug delivery. It was found that at higher cholesterol contents, the crystallization of CHO polymorph phases changed the mobility of DOX molecules. Droplets were formed with short-range spatial correlation from a microemulsion (ME) with a low surfactant:oil ratio. More ordered structures with lamellar arrangements formed by the increasing of the CHO proportions in the formulation may be due to CHO crystallization. The in vitro release of DOX showed that the presence of a high content of crystalline CHO prolongs the release of DOX from ME. The retention of DOX in the internal oil phase of the ME may modulate the drug release for a prolonged time. These results clearly demonstrate the potential of ME as a drug-delivery system. (c) 2007 Elsevier B.V. All rights reserved.

Structural changes of biocompatible neutral microemulsions stabilized by mixed surfactant containing soya phosphatidylcholine and their relationship with doxorubicin release

Depending on the composition, the mixture of surfactant, oil and water, may form supramolecular aggregates with different structures which can significantly influence the drug release. In this work several microemulsion (ME) systems containing soya phosphatidylcholine (SPC) and eumulgin HRE40 (TM) (EU) as surfactant, cholesterol (O) as oil phase, and ultra-pure water as an aqueous phase were studied. MEs with and without the antitumoral drug doxorubicin (DOX) were prepared. The microstructures of the systems were characterized by photon correlation spectroscopy, rheological behavior, polarized light microscopy, small-angle X-ray scattering (SAXS) and X-ray diffraction (XRD). The results reveal that the diameter of the oil droplets was dependent on the surfactant (S) amount added to formulations. The apparent viscosity was dependent on the O/S ratio. High O/S ratio leads to the crystallization of cholesterol polymorphs phases which restricts the mobility of the DOX molecules into the ME structure. Droplets with short-range spatial correlation were formed from the ME with the low O/S ratio. The increase of the cholesterol fraction in the O/S mixture leads to the formation of ordered structures with lamellar arrangements. These different structural organizations directly influenced the drug release profiles. The in vitro release assay showed that the increase of the O/S ratio in the formulations inhibited the constant rate of DOX release. Since the DOX release ratio was directly dependent on the ratio of O/S following an exponential decay profile, this feature can be used to control the DOX release from the ME formulations. (C) 2008 Elsevier B.V. All rights reserved.

Reduction of bacterial adhesion to biocompatible polymer surfaces via plasma processing

Plasma processing of the surfaces of biomaterials is interesting because it enables modification of the characteristics of a surface without affecting bulk properties. In addition, the results are strongly influenced by the conditions of the treatment. Therefore, by adjusting the plasma parameters it is possible to tailor the surface properties to best fulfill the requirements of a given application. In this work, polyurethane substrates have been subjected to sulfur hexafluoride glow discharge plasmas. The influences of different SF 6 plasma exposure times and pressures on the adhesion of Staphylococcus aureus and Pseudomonas aeruginosa to the polymer have been investigated. The wettability and surface free energy have been evaluated via contact angle measurements. At low pressure (6.7 Pa) the contact angle decreases with increasing exposure time in the 180 s to 540 s interval, but at higher pressure (13.3 Pa) it increases as a function of the same variable. Bacterial adhesion has been quantified from in vitro experiments by determining the growth of colonies on Petri dishes treated with agar nutrient. It has been observed that the surface properties play an important role in microbe adhesion. For instance, the density of adhered P. aeruginosa decreased as the surface contact angle increased. S. aureus preferred to adhere to hydrophobic surfaces. © 2011 by Begell House, Inc.

Biocompatible microemulsion modifies the pharmacokinetic profile and cardiotoxicity of doxorubicin

Doxorubicin (DOX) is an anthracycline antibiotic with a broad antitumor spectrum. However, the clinical use of DOX is limited because of its cardiotoxicity, a dose-dependent effect. Colloidal drug delivery systems, such as microemulsions (MEs), allow the incorporation of drugs, modifying the pharmacokinetic (PK) profile and toxic effects. In this study, we evaluated the PK profile and cardiotoxicity of a new DOX ME (DOX-ME). The PK profile of DOX-ME was determined and compared with that of the conventional DOX after single-dose administration (6mg/kg, intravenous) in male Wistar rats (n = 12 per group). The cardiotoxicity of DOX formulations was evaluated by serum creatine kinase MB (CKMB) activity in both animal groups before and after drug administration. The plasma DOX measurements were performed by high-performance liquid chromatography with fluorescence detection, and the CKMB levels were assayed using the CKMB Labtest® kit. The ME system showed a significant increase in plasma DOX concentrations and lower distribution volume when compared with conventional DOX. Serum CKMB activity increased after conventional DOX administration but was unchanged in the DOX-ME group. These results demonstrate modifications in drug access to susceptible sites using DOX-ME. DOX-ME displayed features that make it a promising system for future therapeutic application. © 2012 Wiley Periodicals, Inc.

Development and characterization of biocompatible isotropic and anisotropic oil-in-water colloidal dispersions as a new delivery system for methyl dihydrojasmonate antitumor drug

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Biocompatible Microemulsion Modifies the Tissue Distribution of Doxorubicin

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)