Françoise Winnik - Academia.edu (original) (raw)

Papers by Françoise Winnik

Gels: Structures, Properties, and Functions, 2009

Collapse of a poly(N-isopropylacrylamide) (PNIPAM) chain upon heating in aqueous solutions is the... more Collapse of a poly(N-isopropylacrylamide) (PNIPAM) chain upon heating in aqueous solutions is theoretically studied on the basis of cooperative dehydration (simultaneous dissociation of bound water molecules in a group of correlated sequence), and compared with the experimental observation of temperature-induced coil-globule transition by light scattering methods. The transition becomes sharper with the cooperativity parameter σ of hydration. Phase diagrams with very flat LCST phase separation line for aqueous poly(N-isopropylacrylamide) (PNIPAM) solutions are theoretically derived on the basis of sequential hydrogen bond formation between polymer chains and water molecules (cooperative hydration), and compared with experimental spinodal curves. The two-phase region systematically changes its shape with the cooperativity parameter σ, and the spinodals turned out to be almost independent of the polymer molecular weight for strongly cooperative hydration (small σ) as observed in PNIPAM solutions. Reentrant coil-globule-coil transition in mixed solvent of water and methanol is also studied from the viewpoint of competitive hydrogen bonds between polymer-water and polymer-methanol. The downward shift of the cloud-point curves (LCST cononsolvency) with the mol fraction of methanol due to the competition is calculated and compared with the experimental data.

Polymer, 2003

Dilute aqueous solutions of thermo-responsive poly(N-vinyl caprolactam)-graft-polyethylene oxide ... more Dilute aqueous solutions of thermo-responsive poly(N-vinyl caprolactam)-graft-polyethylene oxide (PVCL-g-PEO) copolymers were studied by light scattering and high sensitivity differential scanning microcalorimetry. These copolymers are double hydrophilic at low temperatures, but become amphiphilic upon heating the solutions above the cloud point temperature of the PVCL segments ðT CP Þ: The selfassembly properties of the copolymers are investigated by dynamic light scattering as a function of the temperature, degree of grafting and concentration. It was found that a certain critical polymer concentration is needed for the polymers to form stable aggregates. These structures are expected to consist of a hydrophobic PVCL core, stabilized by a hydrophilic PEO shell. The size of these aggregates increases with the degree of grafting. Microcalorimetry results revealed that the grafting of PVCL with hydrophilic PEO does not influence the phase transition enthalpy of PVCL. q

Macromolecules, 1992

A spin label was attached to poly(N4sopropylacrylamide) (PNIPAM) to allow EPR spectroscopy to be ... more A spin label was attached to poly(N4sopropylacrylamide) (PNIPAM) to allow EPR spectroscopy to be used as a probe of the interactions between the solvent and this polymer in water, methanol, and watermethanol mixtures. Labeled polymers were prepared by reaction of a copolymer of N-isopropylacrylamide and N-(acry1oxy)succinimide with 4-amino-2,2,6,6-tetramethylpiperidine 1-oxide. The label contents of the polymers (M, 2.9 X lo6) were 1 X 10" and 1.6 X lo4 mol g*. EPR spectra of solutions of the labeled polymers (3 g L-9 were recorded (a) at constant temperature as a function of solvent composition and (b) for several water-methanol mixtures as a function of temperature (-10 to +35 O C ) . The spectra were analyzed in terms of the isotropic hyperfine coupling constant and the correlation time for the reorientation motion. The temperature and composition dependence of the parameters was determined by fitting the line shapes of the experimental spectra to simulated spectra. The results support a model involving preferential adsorption of methanol to the polymer chains in mixed methanol-water solutions, as the main contributor to the cononsolvency phenomenon.

Langmuir, 2008

Biomimetic coatings offer exciting options to modulate the biocompatibility of biomaterials. The ... more Biomimetic coatings offer exciting options to modulate the biocompatibility of biomaterials. The challenge is to create surfaces that undergo specific interactions with cells without promoting nonspecific fouling. This work reports an innovative approach toward biomimetic surfaces based on the covalent immobilization of a carboxylate terminated PEGylated hyaluronan (HA-PEG) onto plasma functionalized NiTi alloy surfaces. The metal substrates were aminated via two different plasma functionalization processes. Hyaluronan, a natural glycosaminoglycan and the major constituent of the extracellular matrix, was grafted to the substrates by reaction of the surface amines with the carboxylic acid terminated PEG spacer using carbodiimide chemistry. The surface modification was monitored at each step by X-ray photoelectron spectroscopy (XPS). HA-immobilized surfaces displayed increased hydrophilicity and reduced fouling, compared to bare surfaces, when exposed to human platelets (PLT) in an in vitro assay with radiolabeled platelets (204.1 ( 123.8 × 10 3 PLT/cm 2 vs 538.5 ( 100.5 × 10 3 PLT/cm 2 for bare metal, p < 0.05). Using a robust plasma patterning technique, microstructured hyaluronan surfaces were successfully created as demonstrated by XPS chemical imaging. The bioactive surfaces described present unique features, which result from the synergy between the intrinsic biological properties of hyaluronan and the chemical composition and morphology of the polymer layer immobilized on a metal surface. Figure 6. XPS imaging overlay of oxygen (O 2p) and F 1s signal intensities (280 × 280 µm 2 ).

Langmuir, 2007

Several studies suggested that the cytotoxic effects of quantum dots (QDs) may be mediated by cad... more Several studies suggested that the cytotoxic effects of quantum dots (QDs) may be mediated by cadmium ions (Cd2+) released from the QDs cores. The objective of this work was to assess the intracellular Cd2+ concentration in human breast cancer MCF-7 cells treated with cadmium telluride (CdTe) and core/shell cadmium selenide/zinc sulfide (CdSe/ZnS) nanoparticles capped with mercaptopropionic acid (MPA), cysteamine (Cys), or N-acetylcysteine (NAC) conjugated to cysteamine. The Cd2+ concentration determined by a Cd2+-specific cellular assay was below the assay detection limit (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;5 nM) in cells treated with CdSe/ZnS QDs, while in cells incubated with CdTe QDs, it ranged from approximately 30 to 150 nM, depending on the capping molecule. A cell viability assay revealed that CdSe/ZnS QDs were nontoxic, whereas the CdTe QDs were cytotoxic. However, for the various CdTe QD samples, there was no dose-dependent correlation between cell viability and intracellular [Cd2+], implying that their cytotoxicity cannot be attributed solely to the toxic effect of free Cd2+. Confocal laser scanning microscopy of CdTe QDs-treated cells imaged with organelle-specific dyes revealed significant lysosomal damage attributable to the presence of Cd2+ and of reactive oxygen species (ROS), which can be formed via Cd2+-specific cellular pathways and/or via CdTe-triggered photoxidative processes involving singlet oxygen or electron transfer from excited QDs to oxygen. In summary, CdTe QDs induce cell death via mechanisms involving both Cd2+ and ROS accompanied by lysosomal enlargement and intracellular redistribution.

Journal of Thermal Analysis and Calorimetry, 2010

The interaction of chitosan and its N-dodecyl and poly(ethylene glycol) derivatives with 1,2-dipa... more The interaction of chitosan and its N-dodecyl and poly(ethylene glycol) derivatives with 1,2-dipalmitoylsn-glycero-3-phosphocholine (DPPC) vesicles was studied to evaluate the influence of molecular architecture of the polymers on the liposomes. The study was carried out in aqueous solution using differential scanning microcalorimetry (DSC) and dynamic light scattering. The interaction of these polymers with DPPC vesicles altered the gel-liquid crystalline phase transition temperature and decreased both the enthalpy (DH) and cooperativity of the phase transition. The results obtained indicate that perturbations in the vesicles surface and the incorporation of chitosan and its derivatives into the lipid bilayer upon polysaccharides interaction are responsible for the formation of large vesicles.

Journal of the American Chemical Society, 2003

Journal of the American Chemical Society, 2005

We report the design of a platform for the delivery of hydrophobic drugs via a macromolecular pro... more We report the design of a platform for the delivery of hydrophobic drugs via a macromolecular prodrug approach combined with LbL-assembled polyelectrolyte multilayers. A hyaluronan ester prodrug of the chemotherapeutic drug paclitaxel has been synthesized. Conjugation of the drug to hyaluronan through a labile succinate ester did not inhibit its activity. Using quartz crystal microbalance, atomic force microscopy, and UV spectroscopy, we have shown that the presence of the hydrophobic paclitaxel moieties does not prohibit the layer-by-layer construction of the multilayers. Release of the drug from the paclitaxel-loaded multilayers upon hydrolysis of the ester linkage resulted in a drastic cell death. Application of this delivery platform to substrates such as colloids, biomedical implants, or vascular tissues may lead to new therapeutic strategies.

Journal of Colloid and Interface Science, 2009

The interactions between phosphorylcholine-substituted chitosans (PC-CH) and calf-thymus DNA (ct-... more The interactions between phosphorylcholine-substituted chitosans (PC-CH) and calf-thymus DNA (ct-DNA) were investigated focusing on the effects of the charge ratio, the pH, and phosphorylcholine content on the size and stability of the complexes using the ethidium bromide fluorescence assay, gel electrophoresis, dynamic light scattering, and fluorescence microscopy. The size and colloidal stability of deacetylated chitosan (CH/DNA) and PC-CH/DNA complexes were strongly dependent on phosphorylcholine content, charge ratios, and pH. The interaction strengths were evaluated from ethidium bromide fluorescence, and, at N/P ratios higher than 5.0, no DNA release was observed in any synthesized PC-CH/DNA polyplexes by gel electrophoresis. The PC-CH/DNA polyplexes exhibited a higher resistance to aggregation compared to deacetylated chitosan (CH) at neutral pH. At low pH values highly charged chitosan and its phosphorylcholine derivatives had strong binding affinity with DNA, whereas at higher pH values CH formed large aggregates and only PC-CH derivatives were able to form small nanoparticles with hydrodynamic radii varying from 100 to 150 nm. Nanoparticles synthesized at low ionic strength with PC-CH derivatives containing moderate degrees of substitution (DS = 20% and 40%) remained stable for weeks. Photomicroscopies also confirmed that rhodamine-labeled PC 40 CH derivative nanoparticles presented higher colloidal stability than those synthesized using deacetylated chitosan. Accordingly, due to their improved physicochemical properties these phosphorylcholine-modified chitosans provide new perspectives for controlling the properties of polyplexes.

Biomaterials, 2006

Gene therapy using polymers such as chitosan shows good biocompatibility, but low transfection ef... more Gene therapy using polymers such as chitosan shows good biocompatibility, but low transfection efficiency. The mechanism of folic acid (FA) uptake by cells to promote targeting and internalization could improve transfection rates. The objective of this study was to synthesize and characterize FA-chitosan-DNA nanoparticles and evaluate their cytotoxicity in vitro. Chitosan-DNA and FA-Chitosan-DNA nanoparticles were prepared using reductive amidation and a complex coacervation process. The effect of charge ratio on the properties of these nanoparticles was monitored by laser scattering. DNA inclusion and integrity was evaluated by gel electrophoresis. Cell viability was illustrated with the MTT assay. Charge ratio (N/P) controlled the nanoparticles size and their zeta potential. Nanoparticles presented a mean size of 118 nm and 80% cellular viability compared to 30% cell viability using LipofectAMINE2000 controls. Gel electrophoresis showed intact DNA within the carriers.

Biomaterials, 2004

Catheter-based brachytherapy is one of the most effective modalities to inhibit hyperplasia follo... more Catheter-based brachytherapy is one of the most effective modalities to inhibit hyperplasia following revascularization procedures. Radioactive stents have failed, however, to prevent clinical hyperplasia due to excessive late lumen loss on the edge of the devices. Numerous strategies have been proposed to circumvent the drawbacks of irradiation therapies, such as the use of more appropriate radionuclides or the ''hot-end'' stents approach. This paper describes versatile radioactive devices obtained by coating plasma functionalized surfaces-stents or catheters-with a hyaluronan (HA)-diethylenetriamine pentaacetic acid (DTPA) conjugate (HA-DTPA) complexed with a g or b radionuclide. Yttrium and indium were used as radionuclide models, due to their suitability for endovascular radiotherapy. X-ray photoelectron microscopy and time-of-flight secondary ions mass spectrometry analyses confirmed the successful immobilization of the HA-DTPA conjugate on both the metallic (NiTi) and polymeric (Teflon) plasma functionalized surfaces. HA-DTPA-coated surfaces were significantly more hydrophilic than bare surfaces (39.5 vs. 67 on NiTi substrate and 29 vs. 128 on Teflon substrate). Therapeutic doses of yttrium and indium were easily loaded onto the surfaces and remained stable over 2 weeks with a radionuclide loss of about 6%. The HA-DTPA-coated Teflon surfaces presented significantly less fibrinogen adsorption than uncoated materials in an in vitro flow model. This approach, which combines the hemocompatibility of HA-coated surfaces and the anti-proliferative effects of an appropriate radiotherapy, constitutes a promising methodology to alleviate the restenosis induced by existing devices. r

Biomaterials, 2011

The aim of the present study was to develop a new biopolymer to increase endothelial progenitor c... more The aim of the present study was to develop a new biopolymer to increase endothelial progenitor cells (EPC) survival and amplification. As a cell culture platform, bone marrow-derived cells (BMDC) were used to investigate the biocompatibility of chitosanephosphorylcholine (CHePC). On CHePC, BMDC were found in colonies with a mortality rate similar to that of fibronectin (FN), the control matrix. Adhesion/proliferation assays demonstrated a greater number of BMDC on CHePC after 7 days with an amplification phase occurring during the second week. Difference in adhesion mechanisms between (CH ePC) and the control FN matrix suggest distinctive cell retention ability. Confocal microscopy analyses confirmed that (CHePC) supported the survival/differentiation of endothelial cells. Moreover, flow cytometry analyses demonstrated that, (CHePC) increased the percentage of progenitor cells (CD117 þ CD34 þ ) (7.1 AE 0.8%, FN: 4.1 AE 0.8%) and EPC (CD117 þ CD34 þ VEGFR-2 þ CD31 þ ) (2.33 AE 0.6%, FN: 0.25 AE 0.1%), while the mesenchymal stem cell fraction (CD44 þ CD106 þ CD90 þ ) was decreased (0.07 AE 0.01%, FN: 0.55 AE 0.22%). Polymeric substrate CHePC might provide a suitable surface to promote the amplification of EPC for future vascular therapeutic applications.

Biomacromolecules, 2003

Layer-by-layer self-assembly of two polysaccharides, hyaluronan (HA) and chitosan (CH), was emplo... more Layer-by-layer self-assembly of two polysaccharides, hyaluronan (HA) and chitosan (CH), was employed to engineer bioactive coatings for endovascular stents. A polyethyleneimine (PEI) primer layer was adsorbed on the metallic surface to initiate the sequential adsorption of the weak polyelectrolytes. The multilayer growth was monitored using a radiolabeled HA and shown to be linear as a function of the number of layers. The chemical structure, interfacial properties, and morphology of the self-assembled multilayer were investigated by time-of-flight secondary ions mass spectrometry (ToF-SIMS), contact angle measurements, and atomic force microscopy (AFM), respectively. Multilayer-coated NiTi disks presented enhanced antifouling properties, compared to unmodified NiTi disks, as demonstrated by a decrease of platelet adhesion in an in vitro assay (38% reduction; p ) 0.036). An ex vivo assay on a porcine model indicated that the coating did not prevent fouling by neutrophils. To assess whether the multilayers may be exploited as in situ drug delivery systems, the nitric-oxide-donor sodium nitroprusside (SNP) was incorporated within the multilayer. SNP-doped multilayers were shown to further reduce platelet adhesion, compared to standard multilayers (40% reduction). When NiTi wires coated with a multilayer containing a fluorescently labeled HA were placed in intimate contact with the vascular wall, the polysaccharide translocated on the porcine aortic samples, as shown by confocal microscopy observation of a treated artery. The enhanced thromboresistance of the self-assembled multilayer together with the antiinflammatory and wound healing properties of hyaluronan and chitosan are expected to reduce the neointimal hyperplasia associated with stent implantation.

Biomacromolecules, 2007

Films of hyaluronan (HA) and a phosphorylcholine-modified chitosan (PC-CH) were constructed by th... more Films of hyaluronan (HA) and a phosphorylcholine-modified chitosan (PC-CH) were constructed by the polyelectrolyte multilayer (PEM) deposition technique and their buildup in 0.15 M NaCl was followed by atomic force microscopy, surface plasmon resonance spectroscopy (SPR), and dissipative quartz crystal microbalance (QCM). The HA/PC-CH films were stable over a wide pH range (3.0-12.0), exhibiting a stronger resistance against alkaline conditions as compared to HA/CH films. The loss and storage moduli, G&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and G&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;, of the films throughout the growth of eight bilayer assemblies were derived from an impedance analysis of the QCM data recorded in situ. Both G&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and G&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; values were one order of magnitude lower than the moduli of HA/CH films. The fluid gel-like characteristics of HA/PC-CH multilayers were attributed to their high water content (50 wt %), which was estimated by comparing the surface coverage values derived from SPR and QCM measurements. Given the versatility of the PEM methodology, HA/PC-CH films are attractive tools for developing biocompatible surface coatings of controlled mechanical properties.

Biomacromolecules, 2009

The interaction of chitosan with plasmid DNA was investigated as a function of pH, buffer composi... more The interaction of chitosan with plasmid DNA was investigated as a function of pH, buffer composition, degree of deacetylation (DDA), and molecular weight (M n ) of chitosan, using isothermal titration microcalorimetry (ITC). The Single Set of Identical Sites model was used to obtain the enthalpy of interaction, the binding constant, and the stoichiometry of binding. The chitosan-DNA interaction was shown to be coupled with proton transfer from the buffer to chitosan, as revealed by the dependence of the measured heat release on the ionization enthalpy of the buffer. The measured enthalpy of binding was almost entirely due to proton transfer, because it was accounted for by the enthalpy of ionization of the buffer and of chitosan once the number of protons transferred was calculated. This proton transfer during binding resulted in the protonation of an additional 17, 37, and 58% of total glucosamine units at pH 5.5, 6.5, and 7.4, respectively. The strong polyanionic nature of DNA facilitates the ionization of glucosamines of chitosan upon complexation and is responsible for proton transfer. Interestingly, using the chitosan-DNA stoichiometry provided by ITC and the calculated degree of ionization of chitosan in the complex, the charge ratio of protonated amines to negative phosphate groups in the complex was nearly constant at 0.50-0.75 after saturation and was independent of the pH, buffer type and chitosan molecular characteristics. The chitosan-DNA binding constant was in the range of 10 9 -10 10 M -1 . The binding constant was pH-dependent and was greater at lower pH due to increased electrostatic attraction to DNA when chitosan is highly charged. Furthermore, the DDA and molecular weight of chitosan exerted a great influence on binding affinity which increased by almost an order of magnitude with an increase of the latter from 7 to 153 kDa. The binding affinity did not change significantly with DDA from 72 to 80% when the M n was kept constant near 80 kDa, but it increased substantially with DDA from 80 to 93% to reach a value similar to that obtained with chitosan of M n ) 153 kDa and 80% DDA. These results provide insight into the previously reported dependence of the transfection efficiency of DNA/chitosan complexes on chitosan DDA and molecular weight, where complex stability and chitosan-DNA binding strength play a critical role.

Biomacromolecules, 2005

Vitamin B12 (VB12)-modified dextran-g-polyethyleneoxide cetyl ether (DEX-g-PEO-C16) was synthesiz... more Vitamin B12 (VB12)-modified dextran-g-polyethyleneoxide cetyl ether (DEX-g-PEO-C16) was synthesized by linking VB12 residues to a DEX-g-PEO-C16 copolymer via a 2,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-(ethylenedioxy)bis(ethylamine) spacer. The level of VB12 substitution on the DEX-g-PEO-C16 copolymer reached 1.68% (w/w). In aqueous solution, DEX-based copolymers form micelles that can entrap within their hydrophobic core up to 8.5% w/w of cyclosporin A (CsA), a poorly water soluble immunosuppressant. The permeability of Caco-2 cell membranes to CsA incorporated in VB12 modified and unmodified polymeric micelles was monitored in the presence and absence of intrinsic factor (IF). The apical (AP) to basolateral (BL) permeation of CsA through Caco-2 cell monolayers after 24 h of transport was significantly higher (1.8 and 2.3 times in absence and presence of IF, respectively) in the case of CsA loaded in VB12-modified polymeric micelles, compared to CsA in unmodified micelles. The results point to possible improvement in the application of polysaccharide-based polymeric micelles as targeted polymeric drug carriers for the oral delivery of poorly water soluble drugs.

Bioconjugate Chemistry, 2002

Folate conjugates (PNIPAM-NH-FA) of a copolymer of N-isopropylacrylamide (NIPAM) and amino-N&... more Folate conjugates (PNIPAM-NH-FA) of a copolymer of N-isopropylacrylamide (NIPAM) and amino-N&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-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.

Biochemistry, 1981

Four glycopeptides have been purified by Dowex and Bio-Gel P2 chromatography from Pronase digests... more Four glycopeptides have been purified by Dowex and Bio-Gel P2 chromatography from Pronase digests of hen ovalbumin. The high-resolution proton magnetic resonance spectra of these glycopeptides and various products of their enzymatic digestion have been obtained at 360 MHz. By use of information derived from the spectra of a number of model compounds, an unambiguous assignment of all C1-H and Man C2-H resonances in the spectra can be made. On this basis structures are proposed for the four glycopeptides which are identical with those structures previously deduced from destructive chemical methods.