Aurélie Malzert-freon - Academia.edu (original) (raw)

Papers by Aurélie Malzert-freon

Pharmaceutics, 2021

Background and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable... more Background and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide. Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in ...

Pharmaceutics, 2020

Among advanced formulation strategies, nanoemulsions are considered useful drug-delivery systems ... more Among advanced formulation strategies, nanoemulsions are considered useful drug-delivery systems allowing to improve the solubility and the bioavailability of lipophilic drugs. To select safe excipients for nanoemulsion formulation and to discard any haemolytic potential, an in vitro miniaturized test was performed on human whole blood. From haemolysis results obtained on eighteen of the most commonly used excipients, a medium chain triglyceride, a surfactant, and a solubilizer were selected for formulation assays. Based on a design of experiments and a ternary diagram, the feasibility of nanoemulsions was determined. The composition was defined to produce monodisperse nanodroplets with a diameter of either 50 or 120 nm, and their physicochemical properties were optimized to be suitable for intravenous administration. These nanoemulsions, stable over 21 days in storage conditions, were shown to be able to encapsulate with high encapsulation efficiency and high drug loading, up to 16...

International Journal of Pharmaceutics, 2003

In the present paper, different spectroscopic methods were applied to evaluate conformational cha... more In the present paper, different spectroscopic methods were applied to evaluate conformational changes of hen egg-white lysozyme (HEWL) in various solvents and in the presence of poly(ethylene glycol) (PEG). In citrate (0.007M, pH=6), or in Tris (0.1M, pH=7.4), no conformational change of the protein was measured across the range of concentrations tested. In addition, HEWL in ultra-pure water revealed no irreversible conformational change and no activity loss, at least at low concentrations (< or =0.2mg/ml). Whereas PEG can induce a reorganization of water molecules, no change of the secondary and tertiary protein conformations was observed in the presence of PEG. In addition, in the presence of PEG of various molecular weights, no change of enzymatic activity of the HEWL was observed across the range of concentrations tested.

Langmuir, 2002

The dilational rheological properties of interfacial films of poly(ethylene glycol) (PEG2000) and... more The dilational rheological properties of interfacial films of poly(ethylene glycol) (PEG2000) and hen egg-white lysozyme (HEWL) were studied respectively at the dichloromethane (DCM)-water and airwater interfaces by means of the pendant drop method. In both cases, the observed interfacial behaviors were approached by a model corresponding to a two-dimensional viscoelastic solid. The interfacial layers were characterized by three physical constants: Ee, the equilibrium elasticity, Ene, the nonequilibrium elasticity, and τ, the relaxation time. Because the interfacial dilational properties of the films were studied by using a ramp type perturbation approach or a sinusoidal variations approach, identical rheological physical constants values were obtained for PEG2000 and HEWL. From these studies, the interactions within the interfacial layer and those between the interfacial film and adjacent phases can be indirectly accessed and estimated.

Langmuir, 2001

The dilational properties of monolayers are analyzed using the classical linear approximation. In... more The dilational properties of monolayers are analyzed using the classical linear approximation. In most cases, the observed interfacial behavior can be approached by a model corresponding to a two-dimensional viscoelastic solid. The monolayer is characterized by two dilational elasticity terms (Ee, equilibrium elasticity, and Ene, nonequilibrium elasticity) and by one relaxation time (τ). These three physical constants are obtained from the responses of a ramp type perturbation, or from the responses (as a function of the frequencies) after sinusoidal area variations. Using axisymmetric drop shape analysis experiments, a dipalmitoyl phosphatidylcholine (DPPC) layer at the dichloromethane/water interface is characterized. Measurements of the surface pressure variations as the response to linear or sinusoidal variations of surface area are performed. Identical rheological physical constants (equilibrium elasticity, nonequilibrium elasticity, and relaxation time) are obtained using both methods. Dilational behavior of DPPC monolayer can be attributed to the molecular diffusion between the DPPC layer and the adjacent phases.

Langmuir, 2001

In this paper, we compared the interfacial behaviors of spread films of poly(ethylene glycol) (PE... more In this paper, we compared the interfacial behaviors of spread films of poly(ethylene glycol) (PEG2000), poly(D,L-lactide) (PLA50), and a mixture of PEG2000 and PLA50, to understand the properties of a PEG2000-PLA50 diblock copolymer at the air/water interface. This was achieved (i) by analyzing the surface pressuresurface area curves obtained on a Langmuir trough and (ii) by modeling the dilatational properties of the films according to a modified Maxwell model. The properties of the films composed of a mixture of PEG2000 and PLA50 showed the influence of PEG2000 before the nucleation transition of PLA50. Then, increasing the lateral compression of the mixed monolayer led to the expulsion of PEG2000 segments with presumably their irreversible desorption into the bulk. In the case of the copolymer, the covalently bound PEG2000 segments were segregated at low surface coverage forming a stable film with the PEG corona oriented toward the water phase. This situation was conserved until high surface coverage (10-15 mN/m). Afterward, compression led to the penetration of PEG2000 into the tridimensional layer oriented toward the air/ phase. These results allow better understanding and modulation of the composition and the hydrophilic character of interfaces formed during emulsion processes and thus improvement of the control of the surface properties of drug delivery systems.

Journal of Pharmaceutical Sciences, 2010

Lipidic nanoparticles (NP), formulated from a phase inversion temperature process, have been stud... more Lipidic nanoparticles (NP), formulated from a phase inversion temperature process, have been studied with chemometric techniques to emphasize the influence of the four major components (Solutol®, Labrasol®, Labrafac®, water) on their average diameter and their distribution in size. Typically, these NP present a monodisperse size lower than 200 nm, as determined by dynamic light scattering measurements. From the application of the partial least squares (PLS) regression technique to the experimental data collected during definition of the feasibility zone, it was established that NP present a core-shell structure where Labrasol® is well encapsulated and contributes to the structuring of the NP. Even if this solubility enhancer is regarded as a pure surfactant in the literature, it appears that the oil moieties of this macrogolglyceride mixture significantly influence its properties. Furthermore, results have shown that PLS technique can be also used for predictions of sizes for given relative proportions of components and it was established that from a mixture design, the quantitative mixture composition to use in order to reach a targeted size and a targeted polydispersity index (PDI) can be easily predicted. Hence, statistical models can be a useful tool to control and optimize the characteristics in size of NP.

Journal of Colloid and Interface Science, 2003

Adsorption kinetics of films of poly(ethylene glycol) (PEG2000) studied by the dynamic pendant dr... more Adsorption kinetics of films of poly(ethylene glycol) (PEG2000) studied by the dynamic pendant drop method showed that PEG2000 was more tensioactive at the dichloromethane (DCM)-water interface than at the air-water interface. When initially solubilized into DCM, PEG2000 segments would form an adsorbed layer with hydrophobic segments buried into the polymer chains turned toward the organic phase. Compression of this layer, accompanied by viscoelastic effects, led to expulsion of some hydrophilic tails toward the water phase. When initially dissolved in water, adsorption of PEG2000 segments led to an elastic PEG2000 layer organized on both sides of the interface. Results showed that when the PEG2000-PLA50 (poly(D,L-lactide)) copolymer film was adsorbed at the DCM-water interface, it resulted in a mixed layer exclusively turned toward DCM and its rheological properties were governed by PLA50. When adsorption at the DCM-water interface resulted from a physical mixture of PEG2000 and PLA50, rheological properties of the film were influenced by the initial localization of PEG2000 in the bulk phases. In the case of a mixed film formed by the adsorption of PLA50 from DCM and PEG2000 from water, results showed that PEG2000 segments totally pushed those of PLA50 away from the interface and exclusively influenced the behavior of the mixed film.

European Journal of Pharmaceutics and Biopharmaceutics, 2010

The objective of the present paper is to develop lipidic nanoparticles (NP) able to encapsulate d... more The objective of the present paper is to develop lipidic nanoparticles (NP) able to encapsulate drugs presenting limited solubility in both water and lipids, with high loading rates, and without using organic solvents. In this goal, a solubility enhancer, a macrogolglyceride (Labrasol Ò), was incorporated in a formulation process based on a low-energy phase inversion temperature method. From electrical conductivity through the temperature scans, it appears that presence of Labrasol Ò does not prevent the phase inversion, and it takes part in the microemulsion structuring, probably of bicontinuous type. After screening pseudo-ternary diagrams, the feasibility of NP was established. From results of a partial least square analysis, it appears that these NP present a core-shell structure where Labrasol Ò is well encapsulated and contributes to the formation of the oily liquid core of the NP. The diameter of the NP, assessed by dynamic light scattering, remains kinetically stable. These NP, smaller than 200 nm, spherical in shape as attested by cryo-transmission electron micrographs, are able to encapsulate a tripentone, a new anticancer agent, with drug loading rates up to 6.5% (w/w). So highly drug-loaded lipidic nanocarriers were developed without using the slightest organic solvent trace, and making it easily possible dose adjustment.

Colloids and Surfaces B: Biointerfaces, 2003

ABSTRACT The mechanism of the hydrolysis by cutinase and the progressive fragmentation of lactic ... more ABSTRACT The mechanism of the hydrolysis by cutinase and the progressive fragmentation of lactic chains in diblock copolymers of PLA with various sizes attached to PEG were studied in a 2D monolayers model system. The hydrolysis kinetics was followed by measuring simultaneously the decrease of the surface area and evolution of the surface potential with time at barostatic conditions. The decrease of the surface area is due to the solubilization of the copolymers as well as of their hydrolytic products: detached PEG blocks and small soluble PLA fragments. The evolution of the surface potential detects the transient interfacial accumulation of charged insoluble PLA fragments. A kinetic model describing the enzymatic hydrolysis was developed and the values for the global hydrolytic kinetic constant were obtained without any fitting parameter. It was found that the global kinetic constant no practically depend on the length of the lactic and the presence of polyethylene–glycol chains.

Colloids and Surfaces B: Biointerfaces, 2002

ABSTRACT The role of the polyethylene glycol (PEG) on the mechanisms of hydrolysis of poly(d,l-la... more ABSTRACT The role of the polyethylene glycol (PEG) on the mechanisms of hydrolysis of poly(d,l-lactide-co-glycolide) (PLAGA) in mixed monolayers at alkaline pH and under the enzymatic action of cutinase was studied by use of a Langmuir balance. The obtained decreases in the surface area at constant surface pressure are interpreted as a result of solubilization of PEG and the progressively obtained small soluble fragments of PLAGA during the interfacial hydrolysis. In the framework of the random scission mode of fragmentation, the values for the degree of completion of the hydrolysis and specific activity of enzyme were obtained numerically. A small surface dilution effect of the PEG in respect to the degradable polyester molecules PLAGA in their mixed monolayers was found.

Biomaterials, 2013

Ovarian cancer is the leading cause of death from gynecological malignancies worldwide. Although ... more Ovarian cancer is the leading cause of death from gynecological malignancies worldwide. Although the majority of tumors initially respond to standard treatments combining surgery and chemotherapy with platinum based chemotherapy, frequent recurrence and subsequent acquired chemoresistance are responsible for the therapeutic failure, leading to an overall 5 years survival rate of 30%. Considering the usual initial sensitivity of the ovarian tumors to chemotherapy, over the past decade efforts have been focused over the past decade to cure ovarian cancer using the currently available chemotherapeutic agents in various combinations, dosages, schedules (durations and/or routes of administration). However, with such a systemic chemotherapeutic approach, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. Considerable efforts are implemented to engineer systems capable of ferrying large doses of cytotoxic agents specifically into targeted malignant cells while sparing healthy cells. The purpose of the present review is to index the main targeted colloidal systems used for drug delivery to ovarian tumors. These nanocarriers will be analyzed by citing examples of their use in preclinical development.

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUP (751062107) / SudocLYON1-BU Santé (69388... more CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUP (751062107) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Http Www Theses Fr, 2002

Dans le cadre de cette etude, les proprietes interfaciales de polymeres d'interet therapeutiq... more Dans le cadre de cette etude, les proprietes interfaciales de polymeres d'interet therapeutique ont ete caracterisees. Des films de poly(α-hydroxy acide)s (PAHA), le PLA50 et le PLA37,5GA25, et des poly(ethylene glycol)s, en particulier le PEG2000 et le PEG4000, formes par etalement ou par adsorption, separement , sous forme de melanges ou de copolymere dibloc, ont ete etudies a des interfaces fluide/liquide, en presence ou non d'une proteine, le lysozyme du blanc d'oeuf de poule. Pour ce faire, differentes techniques de tensiometrie (balance de Langmuir, tensiometre a goutte), l'AFM, la reflectivite des rayons X et l'application d'un modele rheologique de type Maxwell ont ete utilises. Il a ete montre que selon la nature des polymeres, les segments de PEG restent enchevetres avec ceux de PAHA dans le plan de l'interface ou desorbent. Par ailleurs, les interactions entre PEG et lysozyme ont ete caracterisees par differentes methodes spectrophotometriques en volume, tout comme l'a ete l'influence de la force ionique sur la stabilite conformationnelle de la proteine. Il a ete montre que l'empechement de l'adsorption interfaciale du lysozyme est dependant de la densite de segments de PEG ancres a l'interface. L'ensemble de ces resultats a permis de determiner les interactions interfaciales existant entre les polymeres impliques dans la formulation de systemes particulaires et d'expliquer experimentalement les strategies utilisees pour empecher l'adsorption proteique.

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-... more An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC 50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC 50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E°= −0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.

ChemMedChem, 2019

Pyridoclax is considered a promising anticancer drug, acting as a protein‐protein interaction dis... more Pyridoclax is considered a promising anticancer drug, acting as a protein‐protein interaction disruptor, with potential applications in the treatment of ovarian, lung, and mesothelioma cancers. Eighteen sensibly selected structural analogues of Pyridoclax were synthesized, and their physicochemical properties were systematically assessed and analyzed. Moreover, considering that drug‐membrane interactions play an essential role in understanding the mode of action of a given drug and its eventual toxic effects, membrane models were used to investigate such interactions in bulk (liposomes) and at the air‐water interface. The measured experimental data on all original oligopyridines allowed the assessment of relative differences in terms of physicochemical properties, which could be determinant for their druggability, and hence for drug development.

International Journal of Pharmaceutics, 2002

According to our results concerning the behavior of lysozyme at interfaces, its secondary structu... more According to our results concerning the behavior of lysozyme at interfaces, its secondary structure and its enzymatic activity, successful protein encapsulation would need to maintain a pH value far from the enzyme isoelectric point value during the formulation to reduce, in particular, the adsorption of lysozyme molecules at the created interfaces. Moreover, buffers or salt solution must be used in order to keep intact the native secondary conformation of lysozyme, and preserve its enzymatic activity.

ChemMedChem, Jan 25, 2017

Herein we describe the drug design steps developed to increase the radical scavenging and β-amylo... more Herein we describe the drug design steps developed to increase the radical scavenging and β-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease.

European Journal of Medicinal Chemistry, 2016

This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrroli... more This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid β (βA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate βA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation.

Pharmaceutics, 2021

Background and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable... more Background and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide. Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in ...

Pharmaceutics, 2020

Among advanced formulation strategies, nanoemulsions are considered useful drug-delivery systems ... more Among advanced formulation strategies, nanoemulsions are considered useful drug-delivery systems allowing to improve the solubility and the bioavailability of lipophilic drugs. To select safe excipients for nanoemulsion formulation and to discard any haemolytic potential, an in vitro miniaturized test was performed on human whole blood. From haemolysis results obtained on eighteen of the most commonly used excipients, a medium chain triglyceride, a surfactant, and a solubilizer were selected for formulation assays. Based on a design of experiments and a ternary diagram, the feasibility of nanoemulsions was determined. The composition was defined to produce monodisperse nanodroplets with a diameter of either 50 or 120 nm, and their physicochemical properties were optimized to be suitable for intravenous administration. These nanoemulsions, stable over 21 days in storage conditions, were shown to be able to encapsulate with high encapsulation efficiency and high drug loading, up to 16...

International Journal of Pharmaceutics, 2003

In the present paper, different spectroscopic methods were applied to evaluate conformational cha... more In the present paper, different spectroscopic methods were applied to evaluate conformational changes of hen egg-white lysozyme (HEWL) in various solvents and in the presence of poly(ethylene glycol) (PEG). In citrate (0.007M, pH=6), or in Tris (0.1M, pH=7.4), no conformational change of the protein was measured across the range of concentrations tested. In addition, HEWL in ultra-pure water revealed no irreversible conformational change and no activity loss, at least at low concentrations (< or =0.2mg/ml). Whereas PEG can induce a reorganization of water molecules, no change of the secondary and tertiary protein conformations was observed in the presence of PEG. In addition, in the presence of PEG of various molecular weights, no change of enzymatic activity of the HEWL was observed across the range of concentrations tested.

Langmuir, 2002

The dilational rheological properties of interfacial films of poly(ethylene glycol) (PEG2000) and... more The dilational rheological properties of interfacial films of poly(ethylene glycol) (PEG2000) and hen egg-white lysozyme (HEWL) were studied respectively at the dichloromethane (DCM)-water and airwater interfaces by means of the pendant drop method. In both cases, the observed interfacial behaviors were approached by a model corresponding to a two-dimensional viscoelastic solid. The interfacial layers were characterized by three physical constants: Ee, the equilibrium elasticity, Ene, the nonequilibrium elasticity, and τ, the relaxation time. Because the interfacial dilational properties of the films were studied by using a ramp type perturbation approach or a sinusoidal variations approach, identical rheological physical constants values were obtained for PEG2000 and HEWL. From these studies, the interactions within the interfacial layer and those between the interfacial film and adjacent phases can be indirectly accessed and estimated.

Langmuir, 2001

The dilational properties of monolayers are analyzed using the classical linear approximation. In... more The dilational properties of monolayers are analyzed using the classical linear approximation. In most cases, the observed interfacial behavior can be approached by a model corresponding to a two-dimensional viscoelastic solid. The monolayer is characterized by two dilational elasticity terms (Ee, equilibrium elasticity, and Ene, nonequilibrium elasticity) and by one relaxation time (τ). These three physical constants are obtained from the responses of a ramp type perturbation, or from the responses (as a function of the frequencies) after sinusoidal area variations. Using axisymmetric drop shape analysis experiments, a dipalmitoyl phosphatidylcholine (DPPC) layer at the dichloromethane/water interface is characterized. Measurements of the surface pressure variations as the response to linear or sinusoidal variations of surface area are performed. Identical rheological physical constants (equilibrium elasticity, nonequilibrium elasticity, and relaxation time) are obtained using both methods. Dilational behavior of DPPC monolayer can be attributed to the molecular diffusion between the DPPC layer and the adjacent phases.

Langmuir, 2001

In this paper, we compared the interfacial behaviors of spread films of poly(ethylene glycol) (PE... more In this paper, we compared the interfacial behaviors of spread films of poly(ethylene glycol) (PEG2000), poly(D,L-lactide) (PLA50), and a mixture of PEG2000 and PLA50, to understand the properties of a PEG2000-PLA50 diblock copolymer at the air/water interface. This was achieved (i) by analyzing the surface pressuresurface area curves obtained on a Langmuir trough and (ii) by modeling the dilatational properties of the films according to a modified Maxwell model. The properties of the films composed of a mixture of PEG2000 and PLA50 showed the influence of PEG2000 before the nucleation transition of PLA50. Then, increasing the lateral compression of the mixed monolayer led to the expulsion of PEG2000 segments with presumably their irreversible desorption into the bulk. In the case of the copolymer, the covalently bound PEG2000 segments were segregated at low surface coverage forming a stable film with the PEG corona oriented toward the water phase. This situation was conserved until high surface coverage (10-15 mN/m). Afterward, compression led to the penetration of PEG2000 into the tridimensional layer oriented toward the air/ phase. These results allow better understanding and modulation of the composition and the hydrophilic character of interfaces formed during emulsion processes and thus improvement of the control of the surface properties of drug delivery systems.

Journal of Pharmaceutical Sciences, 2010

Lipidic nanoparticles (NP), formulated from a phase inversion temperature process, have been stud... more Lipidic nanoparticles (NP), formulated from a phase inversion temperature process, have been studied with chemometric techniques to emphasize the influence of the four major components (Solutol®, Labrasol®, Labrafac®, water) on their average diameter and their distribution in size. Typically, these NP present a monodisperse size lower than 200 nm, as determined by dynamic light scattering measurements. From the application of the partial least squares (PLS) regression technique to the experimental data collected during definition of the feasibility zone, it was established that NP present a core-shell structure where Labrasol® is well encapsulated and contributes to the structuring of the NP. Even if this solubility enhancer is regarded as a pure surfactant in the literature, it appears that the oil moieties of this macrogolglyceride mixture significantly influence its properties. Furthermore, results have shown that PLS technique can be also used for predictions of sizes for given relative proportions of components and it was established that from a mixture design, the quantitative mixture composition to use in order to reach a targeted size and a targeted polydispersity index (PDI) can be easily predicted. Hence, statistical models can be a useful tool to control and optimize the characteristics in size of NP.

Journal of Colloid and Interface Science, 2003

Adsorption kinetics of films of poly(ethylene glycol) (PEG2000) studied by the dynamic pendant dr... more Adsorption kinetics of films of poly(ethylene glycol) (PEG2000) studied by the dynamic pendant drop method showed that PEG2000 was more tensioactive at the dichloromethane (DCM)-water interface than at the air-water interface. When initially solubilized into DCM, PEG2000 segments would form an adsorbed layer with hydrophobic segments buried into the polymer chains turned toward the organic phase. Compression of this layer, accompanied by viscoelastic effects, led to expulsion of some hydrophilic tails toward the water phase. When initially dissolved in water, adsorption of PEG2000 segments led to an elastic PEG2000 layer organized on both sides of the interface. Results showed that when the PEG2000-PLA50 (poly(D,L-lactide)) copolymer film was adsorbed at the DCM-water interface, it resulted in a mixed layer exclusively turned toward DCM and its rheological properties were governed by PLA50. When adsorption at the DCM-water interface resulted from a physical mixture of PEG2000 and PLA50, rheological properties of the film were influenced by the initial localization of PEG2000 in the bulk phases. In the case of a mixed film formed by the adsorption of PLA50 from DCM and PEG2000 from water, results showed that PEG2000 segments totally pushed those of PLA50 away from the interface and exclusively influenced the behavior of the mixed film.

European Journal of Pharmaceutics and Biopharmaceutics, 2010

The objective of the present paper is to develop lipidic nanoparticles (NP) able to encapsulate d... more The objective of the present paper is to develop lipidic nanoparticles (NP) able to encapsulate drugs presenting limited solubility in both water and lipids, with high loading rates, and without using organic solvents. In this goal, a solubility enhancer, a macrogolglyceride (Labrasol Ò), was incorporated in a formulation process based on a low-energy phase inversion temperature method. From electrical conductivity through the temperature scans, it appears that presence of Labrasol Ò does not prevent the phase inversion, and it takes part in the microemulsion structuring, probably of bicontinuous type. After screening pseudo-ternary diagrams, the feasibility of NP was established. From results of a partial least square analysis, it appears that these NP present a core-shell structure where Labrasol Ò is well encapsulated and contributes to the formation of the oily liquid core of the NP. The diameter of the NP, assessed by dynamic light scattering, remains kinetically stable. These NP, smaller than 200 nm, spherical in shape as attested by cryo-transmission electron micrographs, are able to encapsulate a tripentone, a new anticancer agent, with drug loading rates up to 6.5% (w/w). So highly drug-loaded lipidic nanocarriers were developed without using the slightest organic solvent trace, and making it easily possible dose adjustment.

Colloids and Surfaces B: Biointerfaces, 2003

ABSTRACT The mechanism of the hydrolysis by cutinase and the progressive fragmentation of lactic ... more ABSTRACT The mechanism of the hydrolysis by cutinase and the progressive fragmentation of lactic chains in diblock copolymers of PLA with various sizes attached to PEG were studied in a 2D monolayers model system. The hydrolysis kinetics was followed by measuring simultaneously the decrease of the surface area and evolution of the surface potential with time at barostatic conditions. The decrease of the surface area is due to the solubilization of the copolymers as well as of their hydrolytic products: detached PEG blocks and small soluble PLA fragments. The evolution of the surface potential detects the transient interfacial accumulation of charged insoluble PLA fragments. A kinetic model describing the enzymatic hydrolysis was developed and the values for the global hydrolytic kinetic constant were obtained without any fitting parameter. It was found that the global kinetic constant no practically depend on the length of the lactic and the presence of polyethylene–glycol chains.

Colloids and Surfaces B: Biointerfaces, 2002

ABSTRACT The role of the polyethylene glycol (PEG) on the mechanisms of hydrolysis of poly(d,l-la... more ABSTRACT The role of the polyethylene glycol (PEG) on the mechanisms of hydrolysis of poly(d,l-lactide-co-glycolide) (PLAGA) in mixed monolayers at alkaline pH and under the enzymatic action of cutinase was studied by use of a Langmuir balance. The obtained decreases in the surface area at constant surface pressure are interpreted as a result of solubilization of PEG and the progressively obtained small soluble fragments of PLAGA during the interfacial hydrolysis. In the framework of the random scission mode of fragmentation, the values for the degree of completion of the hydrolysis and specific activity of enzyme were obtained numerically. A small surface dilution effect of the PEG in respect to the degradable polyester molecules PLAGA in their mixed monolayers was found.

Biomaterials, 2013

Ovarian cancer is the leading cause of death from gynecological malignancies worldwide. Although ... more Ovarian cancer is the leading cause of death from gynecological malignancies worldwide. Although the majority of tumors initially respond to standard treatments combining surgery and chemotherapy with platinum based chemotherapy, frequent recurrence and subsequent acquired chemoresistance are responsible for the therapeutic failure, leading to an overall 5 years survival rate of 30%. Considering the usual initial sensitivity of the ovarian tumors to chemotherapy, over the past decade efforts have been focused over the past decade to cure ovarian cancer using the currently available chemotherapeutic agents in various combinations, dosages, schedules (durations and/or routes of administration). However, with such a systemic chemotherapeutic approach, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. Considerable efforts are implemented to engineer systems capable of ferrying large doses of cytotoxic agents specifically into targeted malignant cells while sparing healthy cells. The purpose of the present review is to index the main targeted colloidal systems used for drug delivery to ovarian tumors. These nanocarriers will be analyzed by citing examples of their use in preclinical development.

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUP (751062107) / SudocLYON1-BU Santé (69388... more CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUP (751062107) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Http Www Theses Fr, 2002

Dans le cadre de cette etude, les proprietes interfaciales de polymeres d'interet therapeutiq... more Dans le cadre de cette etude, les proprietes interfaciales de polymeres d'interet therapeutique ont ete caracterisees. Des films de poly(α-hydroxy acide)s (PAHA), le PLA50 et le PLA37,5GA25, et des poly(ethylene glycol)s, en particulier le PEG2000 et le PEG4000, formes par etalement ou par adsorption, separement , sous forme de melanges ou de copolymere dibloc, ont ete etudies a des interfaces fluide/liquide, en presence ou non d'une proteine, le lysozyme du blanc d'oeuf de poule. Pour ce faire, differentes techniques de tensiometrie (balance de Langmuir, tensiometre a goutte), l'AFM, la reflectivite des rayons X et l'application d'un modele rheologique de type Maxwell ont ete utilises. Il a ete montre que selon la nature des polymeres, les segments de PEG restent enchevetres avec ceux de PAHA dans le plan de l'interface ou desorbent. Par ailleurs, les interactions entre PEG et lysozyme ont ete caracterisees par differentes methodes spectrophotometriques en volume, tout comme l'a ete l'influence de la force ionique sur la stabilite conformationnelle de la proteine. Il a ete montre que l'empechement de l'adsorption interfaciale du lysozyme est dependant de la densite de segments de PEG ancres a l'interface. L'ensemble de ces resultats a permis de determiner les interactions interfaciales existant entre les polymeres impliques dans la formulation de systemes particulaires et d'expliquer experimentalement les strategies utilisees pour empecher l'adsorption proteique.

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-... more An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC 50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC 50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E°= −0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.

ChemMedChem, 2019

Pyridoclax is considered a promising anticancer drug, acting as a protein‐protein interaction dis... more Pyridoclax is considered a promising anticancer drug, acting as a protein‐protein interaction disruptor, with potential applications in the treatment of ovarian, lung, and mesothelioma cancers. Eighteen sensibly selected structural analogues of Pyridoclax were synthesized, and their physicochemical properties were systematically assessed and analyzed. Moreover, considering that drug‐membrane interactions play an essential role in understanding the mode of action of a given drug and its eventual toxic effects, membrane models were used to investigate such interactions in bulk (liposomes) and at the air‐water interface. The measured experimental data on all original oligopyridines allowed the assessment of relative differences in terms of physicochemical properties, which could be determinant for their druggability, and hence for drug development.

International Journal of Pharmaceutics, 2002

According to our results concerning the behavior of lysozyme at interfaces, its secondary structu... more According to our results concerning the behavior of lysozyme at interfaces, its secondary structure and its enzymatic activity, successful protein encapsulation would need to maintain a pH value far from the enzyme isoelectric point value during the formulation to reduce, in particular, the adsorption of lysozyme molecules at the created interfaces. Moreover, buffers or salt solution must be used in order to keep intact the native secondary conformation of lysozyme, and preserve its enzymatic activity.

ChemMedChem, Jan 25, 2017

Herein we describe the drug design steps developed to increase the radical scavenging and β-amylo... more Herein we describe the drug design steps developed to increase the radical scavenging and β-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease.

European Journal of Medicinal Chemistry, 2016

This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrroli... more This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid β (βA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate βA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation.