Biomedical subjects

Jean-Christophe Leroux

Publications and source records attributed to Jean-Christophe Leroux.

34 records · Page 2Linked to original sources

PubMed2004

In situ-forming pharmaceutical organogels based on the self-assembly of L-alanine derivatives.

PURPOSE: To characterize novel pharmaceutical organogels based on the self-assembly of L-alanine derivatives in hydrophobic vehicles. METHODS: The gelation properties of N-lauroyl-L-alanine (LA) and N-lauroyl-L-alanine methyl ester (LAM) were investigated in the presence of various solvents. Gel-sol and sol-gel transitions were evaluated by the inverse flow method, and gelation kinetics were determined by turbidimetry. The in vitro release kinetics of labeled dextran physically dispersed in the oil-based organogel was assessed in phosphate-buffered saline. In situ formation of the implants was evaluated in rats by subcutaneously injecting a solution containing LAM, an oil, and a water-diffusible inhibitor of self-assembly (ethanol). RESULTS: The LAM-containing formulations showed a hysteretic gelling behavior with transition temperatures between 10 and 55 degrees C. Gelation kinetics exhibited a lag time of 10 and 30 min at 25 and 37 degrees C, respectively. In vitro, fluorescein isothiocyanate-dextran was released from the gel in a sustained manner with less than 6% released after 20 days. The addition of ethanol to the LAM/oil mixture inhibited gelation and allowed subcutaneous injection of the solution at room temperature. After injection, ethanol diffusion led to the formation of a solid implant. CONCLUSIONS: Low-molecular weight self-assembling organogelators may allow the preparation of novel in situ-forming hydrophobic implants.

Alanine↗

PubMed2004

A novel one-step drug-loading procedure for water-soluble amphiphilic nanocarriers.

PURPOSE: The lack of water-solubility hampers the use of many potent pharmaceuticals. Polymeric micelles are self-assembled nanocarriers with versatile properties that can be engineered to solubilize, target, and release hydrophobic drugs in a controlled-release fashion. Unfortunately, their large-scale use is limited by the incorporation methods available, especially when sterile dosage forms are sought. METHODS: In this manuscript, we describe a straightforward, economical, and innovative drug-loading procedure that consists in dissolving both the drug and an amphiphilic diblock copolymer in a water/tert-butanol mixture that is subsequently freeze-dried. RESULTS: We demonstrate that monodisperse 20-60 nm-sized drug-loaded polymeric micelles are produced directly and spontaneously upon rehydration of the freeze-dried cake. To establish the proof-of-principle, two hydrophobic taxane derivatives were solubilized in the micelles, and their partition coefficient was determined. CONCLUSIONS: This approach is efficient yet astonishingly simple and may be of great interest for scientists working in nanotechnology and pharmaceutical sciences.

Bridged-Ring Compounds↗

PubMed2004

Novel long-circulating lipid nanocapsules.

PURPOSE: To develop and evaluate novel long-circulating lipid nanocapsules (LN) designed for tumor delivery of lipophilic drugs. METHODS: Nanocapsules were produced by a solvent-free phase inversion process and were coated with polyethylene glycoldistearoylphosphatidylethanolamine conjugate (DSPE-PEG) during preparation or by a post-insertion step. In vivo studies were conducted in rats to assess LN pharmacokinetics and biodistribution. RESULTS: Post-insertion of DSPE-PEG appeared to be a convenient and effective method of obtaining LN of controlled sizes with high PEG density at their surface. After intravenous injection to rats, PEGylated lipid nanocapsules obtained by the post-insertion method exhibited long-circulating properties. Up to 50% of the injected dose was still present in the blood 8 h after administration for LN containing 6 mol% PEG 5000 or 10 mol% PEG 2000. This represented an area under the blood concentration-time curve of almost 70% that of liposomes used in the Doxil formulation. CONCLUSION: With a simple solvent free-process, it was possible to produce long-circulating LN of controlled sizes. Such LN could prove useful for the passive delivery of lipophilic anticancer drugs to solid tumors.

Algorithms↗

PubMed2003

Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers.

The intracellular delivery of active biomacromolecules from endosomes into the cytoplasm generally requires a membrane-disrupting agent. Since endosomes have a slightly acidic pH, anionic carboxylated polymers could be potentially useful for this purpose since they can destabilize membrane bilayers by pH-triggered conformational change. In this study, five different pH-sensitive methacrylic acid (MAA) copolymers were characterized with respect to their physicochemical and membrane lytic properties as a function of pH. pH-dependent conformational changes were studied in aqueous solution by turbidimetry and spectrofluorimetry. The hydrophobic domains that formed upon a decrease in pH were found to be dependent on copolymer's composition. Hemolysis and cytotoxicity assays demonstrated that the presence of the hydrophobic ethyl acrylate monomer and/or sufficient protonation of the carboxylic acid groups were important parameters for efficient membrane destabilization. Excessive copolymer hydrophobicity was not associated with membrane destabilization, but resulted in high macrophage cytotoxicity. Overall, this study gave more insights into the structure-activity relationship of MAA copolymers with membrane bilayers. Gaining knowledge of modulation of the physicochemical properties of copolymers and the optimization of copolymer-lipid interactions may lead to the elaboration of much more efficient drug delivery systems.

Animals↗

PubMed2003

Characterization of binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethylcellulose used in the preparation of controlled release tablets.

Cross-linked amylose starch (CLA), hydroxypropylmethylcellulose (HPMC), and HPMC/CLA matrices were prepared by direct compression. HPMC was used to slow down the enzymatic degradation of CLA matrices. CLA was either granulated alone and mixed with HPMC or cogranulated with the latter. Compaction characteristics of the powder, hydration and mechanical properties of the resulting matrices, as well as the release profiles of three model drugs were investigated. The results showed that wet granulation of CLA in the presence of 10% HPMC improved significantly the flow properties of the powder without compromising its compactibility. Both CLA and HPMC deformed mainly by plastic flow (yield pressures are 75 and 124 MPa, respectively), but CLA exhibited a stronger elastic component (elastic recoveries are 18.4 and 11.5%, respectively). The values of yield pressure increased linearly with the concentration of HPMC. The addition of HPMC to CLA slightly decreased the resistance to consolidation but the crushing force of the final compacts was found to be proportional to the HPMC concentration. Mechanical studies on swollen matrices revealed that CLA formed a stronger gel than HPMC or CLA/HPMC mixture, and swelling and erosion of the tablets increased with HPMC content and incubation time. The in vitro release kinetics of three model drugs (pseudeoephedrine sulfate, sodium diclofenac, and prednisone) showed a clear effect of drug solubility and presence of alpha-amylase in the dissolution medium on the release rate. The addition of HPMC to CLA protected the tablets against alpha-amylase hydrolysis and reduced the release rate of prednisone and sodium diclofenac. The release of pseudoephedrine sulfate was fast and independent of HPMC and occurred mainly by diffusion.

Amylose↗

PubMed2002

Polymer based pH-sensitive carriers as a means to improve the cytoplasmic delivery of drugs.

pH-sensitive niosomal and liposomal formulations bearing alkylated N-isopropylacrylamide (NIPAM) copolymers were characterized with regard to vesicle-polymer interaction, pH-responsiveness and stability in human serum. The interactions between the pH-sensitive NIPAM copolymer and the vesicles were studied by spectrofluorimetry, using covalently-attached pyrene as a probe. In contrast to liposomes, where complexation of copolymer to the lipid bilayer is essentially mediated by hydrophobic interactions, the binding between niosomes and PNIPAM was mainly driven by hydrogen bonding. Both formulations were found to rapidly release their contents under mildly acidic conditions. However, the niosomes lost their pH-sensitivity after incubation in serum, whereas liposomes maintained their ability to respond to pH only when complexed with a copolymer containing a high proportion of hydrophobic anchor. The ability of pH-sensitive liposome/polymer complexes to enhance the cytotoxicity of cytosine arabinofuranoside (ara-C) was evaluated in vitro using macrophage-like J774 cells. Ara-C encapsulated in pH-sensitive liposomes exhibited a higher cytotoxicity than the control formulation. This study showed that both niosomes and liposomes can be rendered pH-sensitive by anchoring a randomly-alkylated NIPAM copolymer to their surface. The interactions that take place between the polymer and the vesicles strongly depend on the vesicle nature. pH-sensitive PNIPAM-based liposomes can improve the in vitro efficiency of ara-C.

Acrylamides↗

PubMed2002

Steric stabilization of liposomes by pH-responsive N-isopropylacrylamide copolymer.

The aim of this study was to characterize a pH-sensitive liposome formulation bearing a terminally alkylated N-isopropylacrylamide (NIPAM) copolymer with regard to its pH responsiveness, surface properties, and pharmacokinetics. The interacting forces between two lipid bilayers bearing the anchored NIPAM copolymer were measured with a surface force apparatus. The pH-triggered content release was evaluated in buffer before and after incubation in human serum. The pharmacokinetics was determined in rats following the intravenous injection of 67Ga-loaded liposomes with or without the polymer coating. The force measurements between lipid bilayers showed that NIPAM copolymers provide a steric barrier that was dependent on pH. The pH-sensitive liposomes maintained their pH sensitivity after incubation in serum. In vivo, the polymer-coated liposomes exhibited a prolonged circulation time in rats, with an area under the blood concentration-time curve that is 1.6-fold higher than the control formulation. This study showed that liposomes can be rendered pH sensitive by anchoring a terminally alkylated NIPAM copolymer at their surface. At neutral pH, the polymer provides a steric barrier that increases the liposome circulation time in vivo.

Acrylamides↗

PubMed2002

Biocompatibility of thermosensitive chitosan-based hydrogels: an in vivo experimental approach to injectable biomaterials.

Chitosan, an amino-polysaccharide obtained from the alkaline deacetylation of chitin, presents an interest as a drug vehicle. Indeed, chitosan solutions containing glycerol-2-phosphate (beta-GP) undergo sol-gel transition at a temperature close to 37 degrees C, which make them suitable for the parenteral administration of drugs. However, before using these chitosan derivatives for biomedical applications, it is important to evaluate their biocompatibility, and particularly to test their inflammatory effects. When injected in the hindpaw of the rat, we have shown that: (i) four chitosan/beta-GP solutions tested triggered a non-specific response, with solutions prepared with chitosans of higher deacetylation degrees yielding a lesser inflammatory reaction and (ii) systemic pretreatment of animals with icatibant, apafant and diphenhydramine did not significantly diminish this response; dexamethasone practically abolished it for all solutions and ketanserine only slightly decreased it in one preparation at two different times. In conclusion, it appears that a higher degree of deacetylation of the chitin chain is desirable for superior biocompatibility.

Anesthetics, Local↗

PubMed2002

Influence of physical parameters and lubricants on the compaction properties of granulated and non-granulated cross-linked high amylose starch.

Cross-linked high amylose starch (CLA) is a pharmaceutical excipient used in direct compression for the preparation of controlled release tablets and implants. In this work the compression properties of CLA in bulk and granulated forms (without binder) were evaluated for the first time. Tablets were prepared on an instrumented single punch machine. The flow properties and the compression characteristics (compressibility, densification behavior, work of compression) of the materials as well as the mechanical strength of the finished compacts (compactibility) were systematically examined. Wet granulation was found to improve the flowability and the compressibility of CLA but concomitantly reduced its compactibility. It was demonstrated that CLA was a plastically deforming material with a plasticity index and a yield pressure value comparable to those of pregelatinized starch. The compactibility of granulated CLA was independent of particle size in the range of 75 to 500 microm, but slightly decreased when the percentage of the fine particles (<75 microm) in the bulk powder was increased. Water and colloidal silicone dioxide facilitated the consolidation of CLA, while magnesium stearate had an opposite effect on the tablet crushing force.

Adsorption↗

PubMed2002

Irradiating or autoclaving chitosan/polyol solutions: effect on thermogelling chitosan-beta-glycerophosphate systems.

The effects of steam sterilization and gamma-irradiation on chitosan and thermogelling chitosan-beta-glycerophosphate (GP) solutions containing polyol additives were investigated. The selected polyols were triethylene glycol, glycerol, sorbitol, glucose and poly(ethylene glycol) (PEG). They were incorporated to chitosan solutions prior to sterilization in a proportion ranging from 1 to 5% (w/v). The solutions were characterized with respect to their viscosity, thermogelling properties, compressive stress relaxation behavior and chitosan degradation. All polyols reduced the autoclaving-induced viscosity loss and had a positive impact on the solution thermogelling properties and compressive performance of the gels. Steam sterilization in the presence of glucose resulted in a substantial increase in the solution viscosity and gel strength. This was associated with a strong discoloration suggesting chemical alteration of the system. PEG was the most effective agent in preventing hydrolytic degradation of chitosan chains. Gamma-irradiation strongly decreased the chitosan solution viscosity regardless of the presence of additives, even when sterilization was carried out at -80 degrees C. Moreover, the thermogelling properties were dramatically altered, and thus, gamma-irradiation would not be an appropriate method to sterilize chitosan solutions. In conclusion, polyols are potentially useful additive to maximise the viscoelastic and mechanical properties of chitosan-GP after steam sterilization.

Chitin↗

PubMed1999

Autonomous gel/enzyme oscillator fueled by glucose: Preliminary evidence for oscillations.

A novel prototype gel oscillator that functions by dissipating the chemical energy of glucose by an enzyme-mediated reaction is proposed. The product of the reaction modulates the degree of swelling and hence the permeability of a poly(N-isopropylacrylamide-co-methacrylic acid) gel membrane which in turn regulates the flow of substrate to the enzyme. No external energy is required aside from the chemical energy of glucose present externally at constant concentration. A negative chemomechanical feedback loop is established which, coupled with hysteresis in the membrane permeability characteristics, produces pulsing oscillations. In this study, we introduce a simple model which provides guidelines for experimental design, and report preliminary experimental evidence for oscillation. Application of this prototype system to the episodic delivery of drugs and hormones is envisaged. (c) 1999 American Institute of Physics.

Journal Article↗

PubMedDate not supplied

Preparation and tumor cell uptake of poly(N-isopropylacrylamide) folate conjugates.

Folate conjugates (PNIPAM-NH-FA) of a copolymer of N-isopropylacrylamide (NIPAM) and amino-N'-ethylenedioxy-bis(ethylacrylamide) were prepared by an efficient synthesis leading to random grafting, via a short dioxyethylene spacer, of approximately 7 folic acid residues per macromolecule. The chemical composition of the copolymer was characterized by (1)H NMR and UV/vis spectroscopy. A fluorophore-labeled folate PNIPAM conjugate was tested by in vitro assays performed with cultured KB-31 cells overexpressing the folate receptor. The cellular uptake of the copolymer was found to be temperature dependent and was competitively decreased by free folic acid, indicating that the polymer uptake is mediated specifically by the folate receptor. Hydrophobically modified folate conjugates of NIPAM, amino-N'-ethylenedioxy-bis(ethylacrylamide) copolymers, bearing a small number of n-octadecyl groups were prepared following a modified synthetic procedure for use in future studies of FA-targeted liposomes.

Acrylic Resins↗

PubMedDate not supplied

pH-sensitive unimolecular polymeric micelles: synthesis of a novel drug carrier.

Novel amphiphilic star-shaped polymers showing pH-sensitivity were synthesized by atom transfer radical polymerization. These new polymers present a core-shell structure similar to polymeric micelles, but are inherently stable to dilution and are referred to as unimolecular polymeric micelles. A four-armed multifunctional initiator was used for the sequential polymerization of hydrophobic ethyl methacrylate and tert-butyl methacrylate and hydrophilic poly(ethylene glycol)methacrylate. Polymers of molecular weight ranging from 9000 to 20,000 were obtained. Results of dynamic light scattering showed micelle size ranging from 11 to 40 nm. Unimolecular micelles were also analyzed by static light scattering in aqueous environment. Star-shaped polymers which presented the highest molar ratio of hydrophobic monomers tended to form high molecular weight aggregates in water. Hydrolysis of the tert-butyl methacrylate units permitted the introduction of ionizable methacrylic acid functions. Size distributions were bimodal at both acidic and basic pH. Since, the polymers were designed as potential delivery systems for the oral administration of hydrophobic drugs, they were titrated to evaluate the degree of ionization as a function of pH. In the stomach, the carboxylic functions are expected to be fully protonated. However, in the intestine, the micelles will be more than 40% ionized. Fluorescence studies were conducted in order to evaluate the polarity of the micellar core. Results showed an increase in polarity with pH due to the ionization of the acid functions present along the polymer chains. The pH rise was associated with an increase in the in vitro release rate of progesterone, which was used as hydrophobic drug model.

Drug Carriers↗

PubMedDate not supplied

Thiol-functionalized polymeric micelles: from molecular recognition to improved mucoadhesion.

Surface-modified colloids which can selectively interact with biological species or surfaces show promise as drug delivery systems. However, the preparation of such targeted devices remains challenging, especially when considering polyion complex micelles for which side reactions with the ionic core components (typically carboxylic acid or amino groups) can occur. To solve this issue, an innovative synthetic strategy is proposed and used to prepare an asymmetric poly(ethylene glycol)-block-poly(2-(N,N-dimethylamino)ethyl methacrylate) copolymer presenting a thiol group at the end of the poly(ethylene glycol) chain. Thiol groups are highly appealing given that they react almost exclusively and quantitatively with maleimides under physiological conditions, thereby facilitating the chemical functionalization of the copolymer. The simplicity of the derivatization procedure is illustrated by preparing model biotin-capped copolymers. The biotinylated copolymers are shown to self-assemble with an oligonucleotide in aqueous media to form polyion complex micelles with biotin groups at their outer surface. These micelles are capable of molecular recognition toward streptavidin. Alternatively, thiol-decorated (nonderivatized) micelles are prepared and show improved mucoadhesion through the formation of disulfide bonds with mucin. Finally, intermicellar disulfide bonds are generated under oxidative conditions to promote the formation of stimuli-responsive micellar networks.

Animals↗

PubMedDate not supplied

On the characterization of pH-sensitive liposome/polymer complexes.

A randomly alkylated copolymer of N-isopropylacrylamide, methacrylic acid and N-vinyl-2-pyrrolidone was characterized with regard to its pH- and temperature-triggered conformational change. It was then complexed to liposomes to produce pH-responsive vesicles. Light scattering and differential scanning calorimetry experiments performed at neutral pH revealed that the polymer underwent coil-to-globule phase transition over a wide range of temperatures. At 37 degrees C and pH 7.4, although the polymer was water-soluble, Fourier transform infrared spectroscopy analysis showed that it was partly dehydrated. At acidic pH, the decrease in the lower critical solution temperature was accompanied by an increase in cooperativity degree of the phase transition. Complexation of copolymer to liposomes did not substantially influence its phase transition. The liposome/copolymer complexes were stable at neutral pH but rapidly released their contents under acidic conditions. The copolymer slightly increased liposome circulation time following intravenous administration to rats. The addition of poly(ethylene glycol) to the formulation had a detrimental effect on pH-sensitivity but enhanced substantially the circulation time.

Animals↗

PubMedDate not supplied

Report on the use of poly(organophosphazenes) for the design of stimuli-responsive vesicles.

A novel family of amphiphilic temperature- and pH-sensitive poly(organophosphazenes) with varying ratios of ethylene oxide, alkyl chains and free acid units was synthesized by living cationic polymerization. Depending on their composition, these poly(organophosphazenes) exhibited lower critical solution temperatures ranging from 32 to 44 degrees C, which were pH-dependent for copolymers bearing carboxylic acid groups. The alkylated copolymers were then anchored into phospholipid bilayers to obtain stimuli-responsive liposomes that released their content upon a change in temperature or pH. Such polymer/vesicle complexes could find practical applications for site-specific and intracellular drug delivery.

Biocompatible Materials↗