Biomedical subjects

Jean-Christophe Leroux

Publications and source records attributed to Jean-Christophe Leroux.

At least 19 recordsLinked to original sources

PubMed2007

Long circulating lipid nanocapsules for drug detoxification.

Uncoated and poly(ethylene glycol) (PEG)-decorated lipid nanocapsules (NC) prepared from medium chain triglycerides were investigated both in vitro and in vivo as parenteral detoxifying colloids for their ability to sequester haloperidol, docetaxel and paclitaxel. In vitro studies showed that the uptake depended on the nature of the drug and the composition of NC core and shell. In the case of haloperidol, maximal affinity was achieved upon incorporation of a complexing fatty acid. In plasma lipoprotein distribution studies, the association of both haloperidol and docetaxel into triglyceride-rich lipoprotein fraction was significantly increased in the presence of NC. The ability of the NC to lower the free drug concentrations in incubation medium was confirmed by cytotoxicity studies, where the antiproliferative activity of docetaxel was significantly decreased in the presence of NC. Using docetaxel as drug model, the NC were finally evaluated for their uptake potential in mice by one of the following administration sequences between the drug solution (Taxotere, DTX) and NC: NC-DTX, PEG(NC)-DTX and DTX-PEG(NC). Irrespective of the administration sequence, the NC increased the blood levels of docetaxel due to the in situ sequestration of drug by the circulating carrier. These findings suggest that lipid NC could be used as a non-specific mode to deal with the sequestration of molecules with high affinity for oils.

Animals↗

PubMed2006

Self-assembled nanocages for hydrophilic guest molecules.

Reverse polymeric micelles are obtained following the association of polymeric amphiphiles in apolar media. To this date, reports of pharmaceutical applications for such micelles have been scarce, mainly because these systems have been studied in solvents that are not suitable for medical use. Here, alkylated star-shaped poly(glycerol methacrylate) polymers have been proposed in the design of oil-soluble reverse polymeric micelles. Micellar behavior was studied in various apolar solvents, including ethyl oleate, a pharmaceutically acceptable vehicle. The polymers were shown to assemble into spherical nanostructures (<40 nm) as determined by cryogenic transmission electron microscopy and atomic force microscopy studies. Interestingly, the reverse micelles were able to encapsulate various peptides/proteins (vasopressin, myoglobin, and albumin) in substantial amounts and facilitate their solubilization in oil. The nature of both the polymer used in micelle formation and the guest molecules was found to influence the ability of the micelle to interact with hydrophilic compounds.

Magnetic Resonance Spectroscopy↗

PubMed2006

pH-responsive polymeric micelles of poly(ethylene glycol)-b-poly(alkyl(meth)acrylate-co-methacrylic acid): influence of the copolymer composition on self-assembling properties and release of candesartan cilexetil.

The objective of the present study was to investigate the influence of chemical structure and molecular weight of pH-sensitive block copolymers on their self-assembling properties, the loading and the release of candesartan cilexetil (CDN). Block copolymers of poly(ethylene glycol) and t-butyl methacrylate, iso-butyl acrylate, n-butyl acrylate or propyl methacrylate were synthesized by atom transfer radical polymerization. pH-sensitivity was obtained by hydrolysis of t-butyl groups. The poorly water-soluble drug CDN was incorporated in the micelles and the in vitro drug release was evaluated as a function of pH. The critical aggregation concentration of hydrolyzed copolymers (pK(a)=6.2-6.6) was higher compared to the unhydrolyzed ones. Dynamic light scattering studies and atomic force microscopy images revealed uniform size micelles with aggregation numbers ranging from 60 to 160. The entrapment efficiency of CDN was generally found to be above 90%, with drug loading levels reaching approximately 20% (w/w). Differential scanning calorimetry studies showed the amorphous nature of entrapped CDN. The release of CDN from pH-sensitive micelles was triggered upon an increase in pH from 1.2 to 7.2. These findings suggest that the PEG-b-poly(alkyl(meth)acrylate-co-methacrylic acid)s can self-assemble to form micelles which exhibit high loading capacities for CDN and release the drug in a pH-dependent fashion.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Characterization and in vitro evaluation of spherulites as sequestering vesicles with potential application in drug detoxification.

The aim of the present investigation was to prepare and characterize lecithin spherulites as parenteral drug sequestering agents with potential application in the treatment of drug overdose and chemical poisoning. The spherulites (approximately 200 nm) obtained by controlled hydration and shearing of lipid-alcohol mixtures, revealed unexpected differences in the physical properties of the bilayer when compared to liposomes. Differential scanning calorimetry, 31-phosphorus nuclear magnetic resonance, and pH-sensitive pyranine steady-state fluorescence studies indicated that although spherulites retained the typical bilayer conformation, the arrangement of the phospholipid molecules was perturbed relative to native liposome bilayer. The loosened packing of the phospholipids in bilayers was strongly supported by the relative ease with which spherulites lost the established pH-gradient. This permeability problem was overcome via incorporation of cholesterol in the bilayer. Subsequently, albumin/buffer components were encapsulated in these spherulites and the drug sequestration potential for detoxification application was examined. Citrate pH-gradient spherulites accumulated 75% of external haloperidol while those loaded with approximately 20% (w/w) albumin were able to take up 45% of haloperidol and 91-95% of taxanes (docetaxel and paclitaxel). In cytotoxicity studies, the competitive internalization of docetaxel by albumin-loaded spherulites resulted in an increase of the IC50 value for the free drug. Thus, the spherulite technology could be a versatile approach for actively sequestering toxins in the blood and for reducing the adverse effects by altering the pharmacokinetics and biodistribution of overdosed drugs.

Alcohols↗

PubMed2006

Long circulating poly(ethylene glycol)-decorated lipid nanocapsules deliver docetaxel to solid tumors.

PURPOSE: The purpose of this study was to evaluate the ability of poly(ethylene glycol)-coated lipid nanocapsules (LN) to deliver the highly potent hydrophobic anticancer drug docetaxel to solid tumors. METHODS: Docetaxel-loaded nanocapsules (80-120 nm) were produced by a solvent-free phase inversion process and were coated with polyethylene glycol distearoylphosphatidylethanolamine conjugate by a postinsertion step. In vivo studies were conducted in mice bearing subcutaneously implanted C26 colon adenocarcinoma to assess the pharmacokinetics and biodistribution of both the drug and LN. RESULTS: Incorporation of docetaxel into the LN dramatically increased the drug's biological half-life while providing substantial accumulation at the tumoral site. The pharmacokinetics and biodistribution pattern were found to depend on the specific surface area and shell composition of the nanocapsules. CONCLUSION: This study demonstrates that docetaxel physically entrapped into a lipid colloidal drug carrier can be efficiently targeted to neoplastic tissues.

Animals↗

PubMed2005

On the role of methacrylic acid copolymers in the intracellular delivery of antisense oligonucleotides.

The delivery of active biomacromolecules to the cytoplasm is a major challenge as it is generally hindered by the endosomal/lysosomal barrier. Synthetic titratable polyanions can overcome this barrier by destabilizing membrane bilayers at pH values typically found in endosomes. This study investigates how anionic polyelectrolytes can enhance the cytoplasmic delivery of an antisense oligonucleotide (ODN). Novel methacrylic acid (MAA) copolymers were examined for their pH-sensitive properties and ability to destabilize cell membranes in a pH-dependent manner. Ternary complex formulations prepared with the ODN, a cationic lipid and a MAA copolymer were systematically characterized with respect to their size, zeta potential, antisense activity, cytotoxicity and cellular uptake using the A549 human lung carcinoma cell line. The MAA copolymer substantially increased the activity of the antisense ODN in inhibiting the expression of protein kinase C-alpha. Uptake, cytotoxicity and antisense activity were strongly dependent on copolymer concentration. Metabolic inhibitors demonstrated that endocytosis was the major internalization pathway of the complexes, and that endosomal acidification was essential for ODN activity. Confocal microscopy analysis of cells incubated with fluorescently-labeled complexes revealed selective delivery of the ODN, but not of the copolymer, to the cytoplasm/nucleus. This study provides new insight into the mechanisms of intracellular delivery of macromolecular drugs, using synthetic anionic polyelectrolytes.

Active Transport, Cell Nucleus↗

PubMed2005

Block copolymer micelles: preparation, characterization and application in drug delivery.

Block copolymer micelles are generally formed by the self-assembly of either amphiphilic or oppositely charged copolymers in aqueous medium. The hydrophilic and hydrophobic blocks form the corona and the core of the micelles, respectively. The presence of a nonionic water-soluble shell as well as the scale (10-100 nm) of polymeric micelles are expected to restrict their uptake by the mononuclear phagocyte system and allow for passive targeting of cancerous or inflamed tissues through the enhanced permeation and retention effect. Research in the field has been increasingly focused on achieving enhanced stability of the micellar assembly, prolonged circulation times and controlled release of the drug for optimal targeting. With that in mind, our group has developed a range of block copolymers for various applications, including amphiphilic micelles for passive targeting of chemotherapeutic agents and environment-sensitive micelles for the oral delivery of poorly bioavailable compounds. Here, we propose to review the innovations in block copolymer synthesis, polymeric micelle preparation and characterization, as well as the relevance of these developments to the field of biomedical research.

Animals↗

PubMed2005

First report on the efficacy of l-alanine-based in situ-forming implants for the long-term parenteral delivery of drugs.

The recent advent of biotechnologies has led to the development of labile macromolecular therapeutic agents that require complex formulations for their efficient administration. This work reports a novel concept for the systemic, sustained delivery of such agents. The proposed approach is based on the spontaneous self-assembly of low-molecular weight amphiphilic amino acid derivatives in a hydrophobic pharmaceutical vehicle. The injectable, in situ-forming organogels were obtained by mixing N-stearoyl l-alanine (m)ethyl esters with a vegetable oil and a biocompatible hydrophilic solvent. The gels' in vivo-delivering properties were evaluated in rats with leuprolide, a luteinizing hormone-releasing hormone agonist used in prostate cancer, endometriosis and precocious puberty treatment. Following subcutaneous injection, the gels degraded and gradually released leuprolide for 14 to 25 days. Drug release was accompanied by sustained castration lasting up to 50 days, as assessed by testosterone levels. This study demonstrates that in situ-forming implants based on l-alanine derivatives represent a novel injectable platform for the controlled delivery of hydrophilic compounds, which is simpler than currently available implant and microsphere technologies.

Alanine↗

PubMed2005

Preparation and in vivo evaluation of PEGylated spherulite formulations.

Spherulites are multilamellar vesicles obtained by shearing a lamellar phase of lipids and surfactants. They consist of concentric bilayers of amphiphiles alternating with layers of aqueous medium in which hydrophilic drugs can be sequestered with high yield. To be useful for drug targeting applications, spherulites should be small and long circulating. The objectives of this work were threefold. First, the spherulite size was optimized to obtain a mean diameter of less than 300 nm. Second, the vesicle composition was adjusted to minimize in vitro leakage of internal content. Third, the spherulites were coated with 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy poly(ethylene glycol)] (DSPE-PEG) to impart them with a long half-life. Then, the PEGylated spherulites (Phospholipon 90G/Solutol HS15/cholesterol/DSPE-PEG 2000 or 5000) were loaded with 1-beta-d-arabinofuranosylcytosine (ara-C) and injected intravenously to rats. They were compared to uncoated spherulites and to an ara-C solution. The surface-modified vesicles exhibited long circulation times with areas under the blood concentration vs. time curve exceeding by 3.1- to 6.9-fold that of uncoated spherulites. Similarly, blood levels of ara-C encapsulated in PEGylated vesicles were higher than those of the controls, but they did not parallel the carrier pharmacokinetics. Two hours post-injection, most of the drug was cleared from the systemic circulation, reflecting rapid leakage of ara-C from the vesicles.

Animals↗

PubMed2005

Enhancement of oral bioavailability of poorly water-soluble drugs by poly(ethylene glycol)-block-poly(alkyl acrylate-co-methacrylic acid) self-assemblies.

The purpose of the present study was to determine whether pH-sensitive polymeric micelles could improve the oral bioavailability of a poorly water-soluble drug. Poly(ethylene glycol)-block-poly(alkyl acrylate-co-methacrylic acid)s were synthesized by atom transfer radical polymerization and the composition of the ionizable polymer block was varied to maximize drug loading and pH-dependent release. Poorly water-soluble model drugs viz. fenofibrate (FNB) and progesterone (PRG) were incorporated in the self-assemblies by the oil-in-water emulsion or film casting methods. The pH-dependent release of several formulations was studied in vitro and the oral bioavailabilities of FNB-loaded micelles, Lipidil Micro and FNB coarse suspension were assessed in Sprague-Dawley rats at a dose of 7.5 mg/kg. Entrapment efficiency (defined as the ratio of experimental drug loading in self-assemblies to the initial amount of drug added) ranged between 55-75% and was dependent on polymer composition and drug-loading method. Hydrophobic chain composition of the polymer had tremendous impact on in vitro release kinetics, with only poly(ethylene glycol)-block-poly(n-butyl acrylate(17)-co-methacrylic acid(17)) micelles showing the desired pH-dependent drug-release profile. The oral bioavailability of FNB from these self-assemblies revealed 156% and 15% increases vs. FNB coarse suspension and Lipidil Micro, respectively. The results suggest that these pH-sensitive self-assemblies have potential for improving the oral bioavailability of poorly water-soluble drugs.

Acrylates↗

PubMed2005

Characterization and biocompatibility of organogels based on L-alanine for parenteral drug delivery implants.

The development of simple and efficient drug delivery systems for the sustained release of peptides/proteins and low molecular weight hydrophilic molecules is an ongoing challenge. The purpose of this work was to prepare and characterize novel biodegradable in situ-forming implants obtained via the self-assembly of L-alanine derivatives in pharmaceutical oils. Six different amphiphilic organogelators based on L-alanine were synthesized. These derivatives could successfully gel various vegetable and synthetic oils approved for parenteral administration. Gelation was thermoreversible, and phase transition temperatures depended on gelator structure, concentration and solvent. Hydrogen bonds and van der Waals interactions were shown to be the main forces implicated in network formation. Selected formulations were then injected subcutaneously in rats for preliminary assessment of biocompatibility. Histopathological analysis of the surrounding tissues revealed mild, chronic inflammation and an overall good biocompatibility profile of the implants over the 8 wk evaluation period. This study demonstrates that in situ-forming organogels represent a potentially promising platform for sustained drug delivery.

Alanine↗

PubMed2005

Stereocomplex block copolymer micelles: core-shell nanostructures with enhanced stability.

Monodisperse stereocomplex block copolymer micelles were obtained through the self-assembly of equimolar mixtures of poly(ethylene glycol)-block-poly(l-lactide) and poly(ethylene glycol)-block-poly(d-lactide) in water. These micelles possessed partially crystallized cores and mean hydrodynamic diameters ranging from 31 to 56 nm, depending on the lactide content. They exhibited kinetic stability and redispersion properties superior to micelles prepared with isotactic or racemic polymers alone. This study demonstrates the advantages of stereocomplex formation in the design of stabilized water-soluble nanoparticles.

Colloids↗

PubMed2004

Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization.

The objective of the present study was to synthesize novel pH-sensitive block copolymers forming supramolecular assemblies and to explore their potential as poorly water-soluble drug carriers for oral delivery. Diblock copolymers of polyethylene glycol and t-butyl methacrylate (tBMA), ethyl acrylate (EA) or n-butyl acrylate (nBA) were synthesized by atom transfer radical polymerization (ATRP). The pH-sensitive polymers obtained by hydrolysis of t-butyl groups were characterized for aggregation behaviour. Poorly water-soluble model drugs, i.e., indomethacin (IND), fenofibrate (FNB) and progesterone (PRG), were incorporated in supramolecular assemblies by dialysis or oil-in-water (O/W) emulsion methods. Process parameters for emulsion method were studied to maximize drug loading. Progesterone release was evaluated in vitro as a function of pH. Polymers with controlled molecular weights and low polydispersities were obtained by ATRP. All polymers exhibited pH-dependent aggregation behaviour and their critical aggregation concentration (CAC) decreased with increase in the hydrophobic block length. Drug loadings of <6% and 6-14% w/w were achieved by the dialysis and emulsion methods, respectively. Polymer composition, drug concentration and solubilization of polymer in water or dichloromethane (DCM) affected the loading. Progesterone release from supramolecular assemblies increased when the pH of the release medium was raised from 1.2 to 7.2. The results suggest that these supramolecular assemblies with high drug loadings and pH-dependent release kinetics can potentially enhance the oral bioavailability of poorly water-soluble drugs.

Acrylic Resins↗

PubMed2004

Membrane-destabilizing polyanions: interaction with lipid bilayers and endosomal escape of biomacromolecules.

Water-soluble synthetic polyanions are employed nowadays in a multitude of industrial and biomedical applications and are studied extensively as simplified models of natural polyelectrolytes. The most interesting feature of carboxylated polymers is undoubtedly their ability to undergo coil-to-globule conformational change upon a decrease in pH of the surrounding environment. Over the years, scientists have gained better insights into the conformational behavior of these polymers in solution and in the presence of membrane bilayers. In addition, when used as protein models, anionic polyelectrolytes can provide valuable information on physiological processes such as domain formation in biological membranes. Recently, polyanions have been evaluated as part of drug delivery systems, either as complexes/conjugates with biomolecules, or in the preparation of pH-sensitive liposomal formulations. This article reviews the fundamental and practical aspects of pH-responsive synthetic polyanions in drug delivery. The pH-dependent conformational behavior of these polymers in aqueous solution is described in detail using poly(methacrylic acid) as the model polymer. Since binding to cellular membranes is a fundamental issue in understanding the mechanism of action of polyanions in cytoplasmic drug delivery, studies characterizing their interactions with phospholipid bilayers at neutral as well as at acidic pH are reviewed. Finally, pH-responsive delivery systems based on these polymers are described. As the conformational properties of pH-sensitive polyanions can be easily modulated by carefully adjusting their composition, such formulations may represent an attractive strategy to improve the escape of active biomolecules from acidic endosomal compartments.

Animals↗

PubMed2004

Serum-stable and long-circulating, PEGylated, pH-sensitive liposomes.

pH sensitive liposomes were prepared using a terminally-alkylated copolymer of N-isopropylacrylamide (NIPAM) and methacrylic acid (MAA) and poly(ethylene glycol) phospholipid derivative. The pH-triggered content release was evaluated before and after incubation in serum. Pharmacokinetic and biodistribution profiles of the formulations were established in rats. This study showed that a pH-sensitive, serum-stable and long-circulating liposomal formulation can be produced.

Acrylamides↗

PubMed2004

In situ-forming hydrogels--review of temperature-sensitive systems.

In the past few years, an increasing number of in situ-forming systems have been reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. There are several possible mechanisms that lead to in situ gel formation: solvent exchange, UV-irradiation, ionic cross-linkage, pH change, and temperature modulation. The thermosensitive approach can be advantageous for particular applications as it does not require organic solvents, co-polymerization agents, or an externally applied trigger for gelation. In the last 2 decades, several thermosensitive formulations have been proposed. This manuscript focuses on aqueous polymeric solutions that form implants in situ in response to temperature change, generally from ambient to body temperature. It mainly reviews the characterization and use of polysaccharides, N-isopropylacrylamide copolymers, poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (poloxamer) and its copolymers, poly(ethylene oxide)/(D,L-lactic acid-co-glycolic acid) copolymers, and thermosensitive liposome-based systems.

Animals↗

PubMed2004

A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel.

A novel injectable thermosensitive in situ gelling hydrogel has been developed. The system, which falls under the BST-Gel platform technology developed at Biosyntech Inc. (Laval, QC, Canada), consists of a chitosan solution (C) neutralized with beta-glycerophosphate (GP) that is liquid at room temperature but gels when heated to body temperature. We propose to use this thermosensitive hydrogel for the sustained release of paclitaxel at tumor resection sites in order to prevent local tumor recurrence. The in vitro release profiles demonstrated controlled delivery over 1 month. The initial drug loading substantially affected the release. Local delivery of paclitaxel from the formulation injected intratumorally was investigated using EMT-6 tumors implanted subcutaneously on Balb/c mice. These experiments showed that one intratumoral injection of the thermosensitive hydrogel containing paclitaxel was as efficacious as four intravenous injections of Taxol in inhibiting the growth of EMT-6 cancer cells in mice, but in a less toxic manner. Further histological analysis revealed that while the proportion of necrotic areas was similar for the C/GP/paclitaxel and the Taxol-treated tumors, a disparity between tumor-associated inflammatory cell populations may suggest differing anti-tumor mechanisms.

Animals↗

PubMed2004

Study of the micellization behavior of different order amino block copolymers with heparin.

PURPOSE: The purpose of this study was to prepare and characterize copolymers presenting different pendant amino groups and to study their ability to form polyelectrolyte complexes with heparin. The responsiveness of the complexes to variations in pH and ionic strength was correlated to the nature of the copolymers. METHODS: Copolymers composed of different aminoethyl methacrylate monomers were synthesized by atom transfer radical polymerization (ATRP) from a poly(ethylene glycol) macroinitiator. Copolymers were characterized by gel permeation chromatography and nuclear magnetic resonance spectroscopy. Micellization properties were assessed by atomic force microscopy, multiangle static light scattering, and dynamic light scattering on complexes formed from the addition of heparin to a solution of polymer. RESULTS: Primary, tertiary, and quaternary amine-based diblock copolymers with molecular weights ranging from 4900 to 7400 and low polydispersity indexes were prepared. The synthesis of a copolymer bearing primary amines was achieved for the first time by ATRP. Micellization was found to be pH- and polymer-dependent. All polymers interacted with heparin at acidic pH to yield monodisperse assemblies of less than 30 nm. Complexes dissociated in response to increases in ionic strength. CONCLUSIONS: Electrostatic interactions between the amino copolymers and heparin triggered the formation of small, monodisperse, and stable complexes that present great potential as oral drug delivery systems.

Amines↗