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Micro / nanoparticles

Controlled release of protein from degradable multi-block copolymer microspheres.

About the project:

Contact:

Xavier Garric
Xavier Garric
Cédric Paniagua
Cédric Paniagua
Jean Coudane
Jean Coudane

Collaborations:

Pr Venier and Dr Montero-Venei (Micro et Nanomédecines Translationnelles , MINT UMR 1066-CNRS 6021)

Funding:

None

Pharmacologically active microcarriers delivering BDNF within a hydrogel: Novel strategy for human bone marrow-derived stem cells neural neuronal differentiation guidance and therapeutic secretome enhancement

Acta Biomater. 49, 167–180 (2017)

Kandalam, S., Sindji, L., Delcroix, G. J.-R., Violet, F., Garric, X., Andre, E. M., Schiller, P. C., Venier-Julienne, M.-C., des Rieux, A., Guicheux, J. & Montero-Menei, C. N.

ABSTRACT

Stem cells combined with biodegradable injectable scaffolds releasing growth factors hold great promises in regenerative medicine, particularly in the treatment of neurological disorders. We here integrated human marrow-isolated adult multilineage-inducible (MIAMI) stem cells and pharmacologically active microcarriers (PAMs) into an injectable non-toxic silanized-hydroxypropyl methylcellulose (Si-HPMC) hydrogel. The goal is to obtain an injectable non-toxic cell and growth factor delivery device. It should direct the survival and/or neuronal differentiation of the grafted cells, to safely transplant them in the central nervous system, and enhance their tissue repair properties. A model protein was used to optimize the nanoprecipitation conditions of the neuroprotective brain-derived neurotrophic factor (BDNF). BDNF nanoprecipitate was encapsulated in fibronectin-coated (FN) PAMs and the in vitro release profile evaluated. It showed a prolonged, bi-phasic, release of bioactive BDNF, without burst effect. We demonstrated that PAMs and the Si-HPMC hydrogel increased the expression of neural/neuronal differentiation markers of MIAMI cells after 1 week. Moreover, the 3D environment (PAMs or hydrogel) increased MIAMI cells secretion of growth factors (b-NGF, SCF, HGF, LIF, P1GF-1, SDF-1 alpha, VEGF-A & D) and chemokines (MIP-la & RANTES, IL-8). These results show that PAMs delivering BDNF combined with Si-HPMC hydrogel represent a useful novel local delivery tool in the context of neurological disorders. It not only provides neuroprotective BDNF but also bone marrow-derived stem cells that benefit from that environment by displaying neural commitment and an improved neuroprotective/reparative secretome. It provides preliminary evidence of a promising pro-angiogenic, neuroprotective and axonal growth-promoting device for the nervous system. Statement of Significance Combinatorial tissue engineering strategies for the central nervous system are scarce. We developed and characterized a novel injectable non-toxic stem cell and protein delivery system providing regenerative cues for central nervous system disorders. BDNF, a neurotrophic factor with a wide-range effect, was nanoprecipitated to maintain its structure and released in a sustained manner from novel polymeric microcarriers. The combinatorial 3D support, provided by fibronectin-microcarriers and the hydrogel, to the mesenchymal stem cells guided the cells towards a neuronal differentiation and enhanced their tissue repair properties by promoting growth factors and cytokine secretion. The long-term release of physiological doses of bioactive BDNF, combined to the enhanced secretion of tissue repair factors from the stem cells, constitute a promising therapeutic approach.

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Offre de position post-doctorale « Projet DECAP, Hydrogels pour la décontamination corporelle d’actinides à base de polymères biocompatibles »

Offre de position post-doctorale

« Projet DECAP, Hydrogels pour la décontamination corporelle d’actinides à base de polymères biocompatibles »

Montpellier France

Laboratoire d’accueil : Département « Biopolymères Artificiels », Institut des Biomolécules Max Mousseron (UMR 5247), Université de Montpellier, France

Durée du projet : 8 mois

Date de début du contrat souhaité : février/mars 2021

Financement : ANR

 

Projet :

Le projet DECAP concerne le développement d’hydrogels à base de polymères originaux en vue de la décontamination corporelle externe d’actinides. L’objectif est de synthétiser et de formuler sous forme d’hydrogel de nouveaux polymères chélatants de radionucléides. La mise au point de ces systèmes à base de polymères sera réalisée selon un cahier des charges précis. Ce projet pluridisciplinaire va de la synthèse et la polymérisation de monomères fonctionnels à l’étude biologique des formulations, en passant par les études des propriétés de complexation. Dans ce cadre, un consortium pluridisciplinaire a été élaboré associant l’Institut des Biomolécules Max Mousseron (IBMM) et l’Institut Charles Gerhardt (ICG) de Montpellier, l’Institut de Chimie Séparative de Marcoule (ICSM) et Institut Galien Paris-Sud (IGPS). Le candidat devra faire le lien entre les différentes équipes impliquées.

Des détails supplémentaires seront donnés aux candidats intéressés par ce projet.

 

Profil du candidat recherché :

Le(la) candidat(e) devra être titulaire d’un doctorat en chimie organique ou en chimie des polymères. Il(elle) devra posséder de solides compétences en chimie organique et/ou macromoléculaire. Une expérience dans le domaine des procédés de séparation et/ou sorption serait un plus. Il(elle) devra avoir le goût pour aborder un sujet de recherche expérimental et pluridisciplinaire. Il(elle) devra avoir d’excellentes capacités pour le travail en équipe et être à l’aise dans la communication. Il(elle) devra faire preuve d’autonomie dans son organisation et d’esprit d’initiative.

Modalités de candidature :

Merci de postuler obligatoirement sur le site emploi.cnrs.fr (Référence UMR5247-MORJOL-007) et d’envoyer votre CV et votre lettre de motivation par courrier électronique à Vincent DARCOS et à Sophie MONGE-DARCOS au plus tard le 18 janvier 2021 minuit.

Emails : vincent.darcos@umontpellier.fr et sophie.monge-darcos@umontpellier.fr

Modulation of protein release from penta-block copolymer microspheres European Journal of Pharmaceutics and Biopharmaceutics 152, 175–182 (2020)

European Journal of Pharmaceutics and Biopharmaceutics 152, 175–182 (2020).

Minh-Quan Le, Jean-Christophe Gimel, Xavier Garric, Thao-Quyen Nguyen-Pham, Cédric Paniagua, Jérémie Riou, Marie-Claire Venier-Julienne,

 

ABSTRACT

Releasing a protein according to a zero-order profile without protein denaturation during the polymeric microparticle degradation process is very challenging. The aim of the current study was to develop protein-loaded microspheres with new PLGA based penta-block copolymers for a linear sustained protein release. Lysozyme was chosen as model protein and 40 µm microspheres were prepared using the solid-in-oil-in-water solvent extraction/evaporation process. Two types of PLGA-P188-PLGA penta-block copolymers were synthetized with two PLGA-segments molecular weight (20 kDa or 40 kDa). The resulting microspheres (50P20-MS and 50P40-MS) had the same size, an encapsulation efficiency around 50–60% but different porosities. Their protein release profiles were complementary: linear but non complete for 50P40-MS, non linear but complete for 50P20-MS. Two strategies, polymer blending and microsphere mixing, were considered to match the release to the desired profile. The (1:1) microsphere mixture was successful. It induced a bi-phasic release with a moderate initial burst (around 13%) followed by a nearly complete linear release for 8 weeks. This study highlighted the potential of this penta-block polymer where the PEO block mass ratio influence clearly the Tg and consequently the microsphere structure and the release behavior at 37 °C. The (1:1) mixture was a starting point but could be finely tuned to control the protein release.

In Vivo Evaluation of the Efficacy and Safety of a Novel Degradable Polymeric Film for the Prevention of Intrauterine Adhesions.

Journal of Minimally Invasive Gynecology (2020)

Stéphanie Huberlant, Salomé Leprince, Lucie Allegre, Sophie Warembourg, Isabelle Leteuff, Hubert Taillades, Xavier Garric., Renaud de Tayrac, Vincent Letouzey.

ABSTRACT

To study the safety of a degradable polymeric film (DPF) and its efficacy on reducing the risk of intrauterine-adhesion (IUA) formation in a rat model.A series of case-control studies relying on random allocation, where feasible.The animal models comprised female and male Oncins France Strain A and female Wistar rats.The Oncins France Strain A rats were used for in vivo evaluation of the impact of the DPF on endometrial thickness and its effect on fertility. For in vivo evaluation of the biologic response, 40 Wistar rats were randomly allocated to intervention and control groups, with matched sampling time after surgery. Finally, for the in vivo evaluation of the DPF’s efficacy on IUA prevention, a total of 24 Wistar rats were divided into 3 groups: 1 treated with the DPF, 1 treated with hyaluronic acid gel, and a sham group. The DPF did not have a significant impact on endometrial thickness, and there were no significant differences in the number of conceived or prematurely terminated pregnancies, confirming its noninferiority to no treatment. The DPF did not induce irritation at 5 days and 28 days. Finally, the DPF significantly reduced the likelihood of complete IUA formation compared with hyaluronic acid gel– and sham-implanted animals, where only 27% of the animals had their uterine cavity obliterated compared with 80% and 100%, respectively.The DPF is a safe film that is effective in preventing IUA formation after intrauterine curettage in rats.

Hyaluronic Acid-Poly(N-acryloyl glycinamide) Copolymers as Sources of Degradable Thermoresponsive Hydrogels for Therapy

Gels 2020, 6(4), 42

Mahfoud Boustta and Michel Vert

 

ABSTRACT

One-pot free-radical polymerization of N-acryloyl glycinamide in the presence of hyaluronic acid as transfer-termination agent led to new copolymers in high yields without any chemical activation of hyaluronic acid before. All the copolymers formed thermoresponsive hydrogels of the Upper Critical Solution Temperature-type in aqueous media. Gel properties and the temperature of the reversible gel ↔ sol transition depended on feed composition and copolymer concentration. Comparison with mixtures of hyaluronic acid-poly(N-acryloyl glycinamide) failed in showing the expected formation of graft copolymers conclusively because poly(N-acryloyl glycinamide) homopolymers are also thermoresponsive. Grafting and formation of comb-like copolymers were proved after degradation of inter-graft hyaluronic acid segments by hyaluronidase. Enzymatic degradation yielded poly(N-acryloyl glycinamide) with sugar residues end groups as shown by NMR. In agreement with the radical transfer mechanism, the molar mass of these released poly(N-acryloyl glycinamide) grafts depended on the feed composition. The higher the proportion of hyaluronic acid in the feed, the lower the molar mass of poly(N-acryloyl glycinamide) grafts was. Whether molar mass can be made low enough to allow kidney filtration remains to be proved in vivo. Last but not least, Prednisolone was used as model drug to show the ability of the new enzymatically degradable hydrogels to sustain progressive delivery for rather long periods of time in vitro.DPF is a safe film that is effective in preventing IUA formation after intrauterine curettage in rats.

Novel Biopolymers for Sustained Delivery of Drugs to the Eye

About the project:

The objective of this project is to design novel biopolymers for sustained delivery of drugs to the eye

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Vincent Darcos
Vincent Darcos

Students:

Floriane Bahuon
Floriane Bahuon

Collaborations:

Dr. G. Schwach & Dr. S. Patel (Hoffmann – La Roche)

Funding:

Hoffmann – La Roche

Jump to other drug delivery related subjects >>> Micro/nanoparticles >>> Hydrogels

Micelles:

Multifunctional polyesters for stimuli-responsive drug delivery systems

About the project:

This project is dedicated to the design and synthesis of multifunctional and degradable amphiphilic copolymers for drug delivery applications. Original architectures are in particular investigated and compared to classical linear copolymers.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Audrey Bethry
Audrey Bethry
Sylvie Hunger
Sylvie Hunger

Students:

Assala Al Samad
Assala Al Samad
Ayman El Jundi
Ayman El Jundi

Collaborations:

Prof. Bakkour (Lebanese University, Lebanon) Dr. Etrych, Dr. Koziolova, Dr. Janouskova (Institute of Macromolecular Chemistry, Czech Republic), Dr. Coll (University Grenoble-Alpes), Prof. Subra (IBMM-peptides, UMR 5247), Dr. Pound-Lana & Prof. Mosqueira⁠ (Federal University of Ouro Preto, Brazil)

Funding:

Doctoral grants for LASER and Azm & Saade Associations

Double hydrophilic block copolymers self-assemblies in biomedical applications

Adv. Colloid Interface Sci 283, 102213, (2020)

A. El Jundi, S. Buwalda, Y. Bakkour, X. Garric, B. Nottelet

 

ABSTRACT

Double-hydrophilic block copolymers (DHBCs), consisting of at least two different water-soluble blocks, are an alternative to the classical amphiphilic block copolymers and have gained increasing attention in the field of biomedical applications. Although the chemical nature of the two blocks can be diverse, most classical DHBCs consist of a bioeliminable non-ionic block to promote solubilization in water, like poly(ethylene glycol), and a second block that is more generally a pH-responsive block capable of interacting with another ionic polymer or substrate. This second block is generally non-degradable and the presence of side chain functional groups raises the question of its fate and toxicity, which is a limitation in the frame of biomedical applications. In this review, following a first part dedicated to recent examples of non-degradable DHBCs, we focus on the DHBCs that combine a biocompatible and bioeliminable non-ionic block with a degradable functional block including polysaccharides, polypeptides, polyesters and other miscellaneous polymers. Their use to design efficient drug delivery systems for various biomedical applications through stimuli-dependent self-assembly is discussed along with the current challenges and future perspectives for this class of copolymers.

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Degradable double hydrophilic block copolymers and tripartite polyionic complex micelles thereof for small interfering ribonucleic acids (siRNA) delivery

J. Colloid Interface 580, 449, (2020)

A. El Jundi, M. Morille, N. Bettache, A. Bethry, J. Berthelot, J. Salvador, S. Hunger, Y. Bakkour, E. Belamie, B. Nottelet

 

ABSTRACT

Polymer vectors for gene therapy have been largely investigated as an alternative to viral vectors. In particular, double hydrophilic block copolymers (DHBCs) have shown potential in this domain, but to date studies mainly focus on non-degradable copolymers, which may be a restriction for further development. To overcome this limitation, we synthesized a DHBC (PEG43-b-PCL12(COOH)6.5) composed of a poly(ethylene glycol) (PEG) non-ionic and bioeliminable block and a degradable carboxylic acid-functionalized poly(e-caprolactone) (PCL) block. The potential of this DHBC as an original vector for small interfering ribonucleic acids (siRNA) to formulate tripartite polyionic complex (PIC) micelles with poly(lysine) (PLL) was evaluated. We first studied the impact of the charge ratio (R) on the size and the zeta potential of the resulting micelles. With a charge ratio R=1, one formulation with optimized physico-chemical properties showed the ability to complex 75 % of siRNA. We showed a stability of the micelles at pH 7.4 and a disruption at pH 5, which allowed a pH-triggered siRNA release and proved the pH-stimuli responsive character of the tripartite micelles. In addition, the tripartite PIC micelles were shown to be non-cytotoxic below 40 µg/mL. The potential of these siRNA vectors was further evaluated in vitro: it was found that the tripartite PIC micelles allowed siRNA internalization to be 3 times higher than PLL polyplexes in murine mesenchymal stem cells, and were able to transfect human breast cancer cells. Overall, this set of data pre-validates the use of degradable DHBC as non-viral vectors for the encapsulation and the controlled release of siRNA, which may therefore constitute a sound alternative to non-degradable and/or cytotoxic polycationic vectors.

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Role of Polymer Micelles in the Delivery of Photodynamic Therapy Agent to Liposomes and Cells

Cancers. 12, 384 (2020)

Gibot L., Demazeau M., Pimienta V., Mingotaud A-F., Vicendo P., Collin F., Martins-Froment N., Dejean S., Nottelet B., Roux C.,Lonetti B.

 

ABSTRACT

The use of nanocarriers for hydrophobic photosensitizers in the context of photodynamic therapy (PDT) to improve pharmacokinetics and biodistribution is well established. However, the mechanisms at play in the internalization of nanocarriers are not well elucidated despite being crucial to inspiring nanocarrier design. Here we focus on the mechanisms involved in copolymer PEO-PCL and PEO-PS micelles – membrane interactions through complementary physico-chemical studies on biomimetic membranes and biological experiments on 2D and 3D cell cultures. Förster Resonance Energy Transfer measurements on fluorescently labelled lipid vesicles and flow cytometry on two cancerous cell lines allowed evaluation of the uptake of a photosensitizer, Pheophorbide a (Pheo), and copolymer chains towards model membranes and cells respectively. The effects of calibrated light illumination for PDT treatment on lipid vesicle membranes, i.e. leakage and formation of oxidized lipids, and cell viability, were assessed. No significant differences were observed between the ability of PEO-PCL and PEO-PS micelles to deliver Pheo to model membranes, but Pheo was found in higher concentrations in cells in the case of PEO-PCL. These higher Pheo concentrations did not correspond to better performances in PDT treatment. We thus highlighted subtle differences in PEO-PCL and PEO-PS micelles for the delivery of Pheo.

Double-hydrophilic block copolymers based on functional poly(ε-caprolactone)s for pH-dependent controlled drug delivery

Biomacromolecules 21, 397, (2020)

Ayman El Jundi, Sytze Buwalda, Audrey Bethry, Sylvie Hunger, Jean Coudane, Youssef Bakkour, Benjamin Nottelet

 

ABSTRACT

The use of double-hydrophilic block copolymers (DHBCs) in biomedical applications is limited by their lack of degradability. This additional functionality has been obtained in the past through multistep chemical strategies associated with low yields. In this work, a series of DHBCs composed of a bioeliminable poly(ethylene glycol) (PEG) block and hydrolysable functional poly(e-caprolactone) (PCL) blocks bearing carboxylic (PEG-b-PCL(COOH)), amino (PEG-b-PCL(NH2)) or hydroxyl side groups (PEG-b-PCL(OH)) is synthesized in only 3 steps. DHBCs with 50% substitution degree with respect to the CL units are obtained for all functional groups. The pH-dependent self-assembly behavior of the DHBCs is studied showing critical micelle concentration (CMC) variations by a factor 2 upon pH changes and micellar mean diameter variations of 20-30%. The potential of these partly degradable DHBCs as drug-loaded polyion complex micelles is further exemplified with the PEG-b-PCL(COOH) series that is associated with the positively charged anticancer drug doxorubicin (DOX). Encapsulation efficiencies, drug loadings, pH-controlled release and cytotoxicity of the DOX-loaded micelles towards cancer cells are demonstrated. This set of data confirms the interest of the proposed straightforward chemical strategy to generate fully bioeliminable and partly degradable DHBCs with potential as pH-responsive drug delivery systems.

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Stabilized micelles for prolonged drug delivery

About the project:

In this project, we take advantage of weak interactions (Pi-Pi stacking, hydrogen bonding, coordination) to stabilize micellar systems in order to increase their therapeutic benefice.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Audrey Bethry
Audrey Bethry

Students:

Sytze Buwalda
Sytze Buwalda
Assala Al Samad
Assala Al Samad
Ayman El Jundi
Ayman El Jundi

Collaborations:

Dr. Kok (Utrecht University)

Funding:

Marie Skłodowska-Curie grant, doctoral grants for LASER and Azm & Saade Associations

Reversibly core-crosslinked PEG-P(HPMA) micelles: Platinum coordination chemistry for competitive-ligand-regulated drug delivery

J. Colloid Interface Sci. 535, 505–515 (2019)

Buwalda, S., Nottelet, B., Bethry, A., Kok, R. J., Sijbrandi, N. & Coudane, J.

ABSTRACT

Hypothesis. The presence of pendant thioether groups on poly(ethylene glycol)-poly(N(2-hydroxypropyl) methacrylamide) (PEG-P(HPMA)) block copolymers allows for platinum-mediated coordinative micellar core-crosslinking, resulting in enhanced micellar stability and stimulus-responsive drug delivery.

Experiments. A new PEG-P(HPMA) based block copolymer with pendant 4-(methylthio)benzoyl (MTB) groups along the P(HPMA) block was synthesized by free radical polymerization of a novel HPMA-MTB monomer using a PEG based macro-initiator. As crosslinker the metal-organic linker [ethylenediamineplatinum(II)]2+ was used, herein called Lx, which is a coordinative linker molecule that has been used for the conjugation of drug molecules to a number of synthetic or natural carrier systems such as hyperbranched polymers and antibodies.

Findings. The introduction of Lx in the micellar core results in a smaller size, a lower critical micelle concentration and a better retention of the hydrophobic drug curcumin thanks to coordination bonds between the central platinum atom of Lx and thioether groups on different polymer chains. The drug release from Lx crosslinked micelles is significantly accelerated under conditions mimicking the intracellular environment due to competitive coordination and subsequent micellar de-crosslinking. Because of their straightforward preparation and favorable drug release characteristics, core-crosslinked Lx PEG-P(HPMA) micelles hold promise as a versatile nanomedicine platform.

Stabilization of poly(ethylene glycol)-poly(epsilon-caprolactone) star block copolymer micelles via aromatic groups for improved drug delivery properties

Colloid Interface Sci. 514, 468–478 (2018)

Buwalda, S., Al Samad, A., El Jundi, A., Bethry, A., Bakkour, Y., Coudane, J. & Nottelet, B

ABSTRACT

Hypothesis

The functionalization of poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) block copolymers with moieties allowing for core-crosslinking is expected to result in improved micellar stability and drug delivery properties.

Experiments

PEG-(PCL)8 star block copolymers were functionalized with pendant benzylthioether (BTE) groups by applying an anionic post-polymerization modification technique followed by photoradical thiol-yne addition of benzyl mercaptan. The micellar properties of PEG-(PCL)8 and PEG-(PCL-BTE)8 were studied and compared in terms of critical micelle concentration (CMC), size, morphology, drug loading and release and in vitro cytotoxicity.

Findings

In comparison with unmodified PEG-(PCL)8 micelles, PEG-(PCL-BTE)8 micelles exhibited a 15-fold lower CMC, a 15-fold smaller size and a 50% higher drug loading and encapsulation efficiency thanks to the presence of pendant benzyl groups which provide the possibility for micellar core-crosslinking via supramolecular π-π stacking and additional hydrophobic interactions. Whereas the PEG-(PCL)8 micelles showed significant aggregation during in vitro cytotoxicity experiments, the PEG-(PCL-BTE)8 micelles showed no signs of aggregation and were capable of solubilizing high concentrations of curcumin, resulting in a significant decrease in MCF-7 cell viability after 48 h. Their ease of synthesis combined with promising results regarding drug delivery make the PEG-(PCL-BTE)8 micelles appealing for application in the field of encapsulation.

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Polyester-g-oligosaccharide micelles for cancer therapy

About the project:

Contact:

Hélène Van Den Berghe
Hélène Van Den Berghe
Jean Coudane
Jean Coudane
Stéphane Dejean
Stéphane Dejean
Sylvie Hunger
Sylvie Hunger

Students:

Victor Demorme
Victor Demorme

Collaborations:

Dr. Magali Gary-Bobo, Pr Alain Morère Kok (« Glyco and nanovectors for therapeutic targeting » team, IBMM, University of Montpellier), Dr. Ghislain David (IAM team, ICGM, University of Montpellier)

Funding:

“Emergence project” funding from the “Cancéropôle Grand Sud Ouest”, Doctoral Grant from the French Ministry

Offre de position post-doctorale « Projet DECAP, Hydrogels pour la décontamination corporelle d’actinides à base de polymères biocompatibles »

Offre de position post-doctorale

« Projet DECAP, Hydrogels pour la décontamination corporelle d’actinides à base de polymères biocompatibles »

Montpellier France

Laboratoire d’accueil : Département « Biopolymères Artificiels », Institut des Biomolécules Max Mousseron (UMR 5247), Université de Montpellier, France

Durée du projet : 8 mois

Date de début du contrat souhaité : février/mars 2021

Financement : ANR

 

Projet :

Le projet DECAP concerne le développement d’hydrogels à base de polymères originaux en vue de la décontamination corporelle externe d’actinides. L’objectif est de synthétiser et de formuler sous forme d’hydrogel de nouveaux polymères chélatants de radionucléides. La mise au point de ces systèmes à base de polymères sera réalisée selon un cahier des charges précis. Ce projet pluridisciplinaire va de la synthèse et la polymérisation de monomères fonctionnels à l’étude biologique des formulations, en passant par les études des propriétés de complexation. Dans ce cadre, un consortium pluridisciplinaire a été élaboré associant l’Institut des Biomolécules Max Mousseron (IBMM) et l’Institut Charles Gerhardt (ICG) de Montpellier, l’Institut de Chimie Séparative de Marcoule (ICSM) et Institut Galien Paris-Sud (IGPS). Le candidat devra faire le lien entre les différentes équipes impliquées.

Des détails supplémentaires seront donnés aux candidats intéressés par ce projet.

 

Profil du candidat recherché :

Le(la) candidat(e) devra être titulaire d’un doctorat en chimie organique ou en chimie des polymères. Il(elle) devra posséder de solides compétences en chimie organique et/ou macromoléculaire. Une expérience dans le domaine des procédés de séparation et/ou sorption serait un plus. Il(elle) devra avoir le goût pour aborder un sujet de recherche expérimental et pluridisciplinaire. Il(elle) devra avoir d’excellentes capacités pour le travail en équipe et être à l’aise dans la communication. Il(elle) devra faire preuve d’autonomie dans son organisation et d’esprit d’initiative.

Modalités de candidature :

Merci de postuler obligatoirement sur le site emploi.cnrs.fr (Référence UMR5247-MORJOL-007) et d’envoyer votre CV et votre lettre de motivation par courrier électronique à Vincent DARCOS et à Sophie MONGE-DARCOS au plus tard le 18 janvier 2021 minuit.

Emails : vincent.darcos@umontpellier.fr et sophie.monge-darcos@umontpellier.fr

Modulation of protein release from penta-block copolymer microspheres European Journal of Pharmaceutics and Biopharmaceutics 152, 175–182 (2020)

European Journal of Pharmaceutics and Biopharmaceutics 152, 175–182 (2020).

Minh-Quan Le, Jean-Christophe Gimel, Xavier Garric, Thao-Quyen Nguyen-Pham, Cédric Paniagua, Jérémie Riou, Marie-Claire Venier-Julienne,

 

ABSTRACT

Releasing a protein according to a zero-order profile without protein denaturation during the polymeric microparticle degradation process is very challenging. The aim of the current study was to develop protein-loaded microspheres with new PLGA based penta-block copolymers for a linear sustained protein release. Lysozyme was chosen as model protein and 40 µm microspheres were prepared using the solid-in-oil-in-water solvent extraction/evaporation process. Two types of PLGA-P188-PLGA penta-block copolymers were synthetized with two PLGA-segments molecular weight (20 kDa or 40 kDa). The resulting microspheres (50P20-MS and 50P40-MS) had the same size, an encapsulation efficiency around 50–60% but different porosities. Their protein release profiles were complementary: linear but non complete for 50P40-MS, non linear but complete for 50P20-MS. Two strategies, polymer blending and microsphere mixing, were considered to match the release to the desired profile. The (1:1) microsphere mixture was successful. It induced a bi-phasic release with a moderate initial burst (around 13%) followed by a nearly complete linear release for 8 weeks. This study highlighted the potential of this penta-block polymer where the PEO block mass ratio influence clearly the Tg and consequently the microsphere structure and the release behavior at 37 °C. The (1:1) mixture was a starting point but could be finely tuned to control the protein release.

In Vivo Evaluation of the Efficacy and Safety of a Novel Degradable Polymeric Film for the Prevention of Intrauterine Adhesions.

Journal of Minimally Invasive Gynecology (2020)

Stéphanie Huberlant, Salomé Leprince, Lucie Allegre, Sophie Warembourg, Isabelle Leteuff, Hubert Taillades, Xavier Garric., Renaud de Tayrac, Vincent Letouzey.

ABSTRACT

To study the safety of a degradable polymeric film (DPF) and its efficacy on reducing the risk of intrauterine-adhesion (IUA) formation in a rat model.A series of case-control studies relying on random allocation, where feasible.The animal models comprised female and male Oncins France Strain A and female Wistar rats.The Oncins France Strain A rats were used for in vivo evaluation of the impact of the DPF on endometrial thickness and its effect on fertility. For in vivo evaluation of the biologic response, 40 Wistar rats were randomly allocated to intervention and control groups, with matched sampling time after surgery. Finally, for the in vivo evaluation of the DPF’s efficacy on IUA prevention, a total of 24 Wistar rats were divided into 3 groups: 1 treated with the DPF, 1 treated with hyaluronic acid gel, and a sham group. The DPF did not have a significant impact on endometrial thickness, and there were no significant differences in the number of conceived or prematurely terminated pregnancies, confirming its noninferiority to no treatment. The DPF did not induce irritation at 5 days and 28 days. Finally, the DPF significantly reduced the likelihood of complete IUA formation compared with hyaluronic acid gel– and sham-implanted animals, where only 27% of the animals had their uterine cavity obliterated compared with 80% and 100%, respectively.The DPF is a safe film that is effective in preventing IUA formation after intrauterine curettage in rats.

Hyaluronic Acid-Poly(N-acryloyl glycinamide) Copolymers as Sources of Degradable Thermoresponsive Hydrogels for Therapy

Gels 2020, 6(4), 42

Mahfoud Boustta and Michel Vert

 

ABSTRACT

One-pot free-radical polymerization of N-acryloyl glycinamide in the presence of hyaluronic acid as transfer-termination agent led to new copolymers in high yields without any chemical activation of hyaluronic acid before. All the copolymers formed thermoresponsive hydrogels of the Upper Critical Solution Temperature-type in aqueous media. Gel properties and the temperature of the reversible gel ↔ sol transition depended on feed composition and copolymer concentration. Comparison with mixtures of hyaluronic acid-poly(N-acryloyl glycinamide) failed in showing the expected formation of graft copolymers conclusively because poly(N-acryloyl glycinamide) homopolymers are also thermoresponsive. Grafting and formation of comb-like copolymers were proved after degradation of inter-graft hyaluronic acid segments by hyaluronidase. Enzymatic degradation yielded poly(N-acryloyl glycinamide) with sugar residues end groups as shown by NMR. In agreement with the radical transfer mechanism, the molar mass of these released poly(N-acryloyl glycinamide) grafts depended on the feed composition. The higher the proportion of hyaluronic acid in the feed, the lower the molar mass of poly(N-acryloyl glycinamide) grafts was. Whether molar mass can be made low enough to allow kidney filtration remains to be proved in vivo. Last but not least, Prednisolone was used as model drug to show the ability of the new enzymatically degradable hydrogels to sustain progressive delivery for rather long periods of time in vitro.DPF is a safe film that is effective in preventing IUA formation after intrauterine curettage in rats.

Thermo-responsive poly(lactic acid)-base micelles for drug delivery

About the project:

Contact:

Vincent Darcos
Vincent Darcos
Jean Coudane
Jean Coudane

Students:

Fanny Coumes
Fanny Coumes
Yanfei Hu

Collaborations:

Prof. Sébastien Lecommendoux (LCPO, Bordeaux)

Funding:

CNRS

Thermo-responsive drug release from self-assembled micelles of brush-like PLA/PEG analogues block copolymers

Int. J. Pharm. 491, 152–161 (2015)

Hu, Y., Darcos, V., Monge, S. & Li, S.

 

ABSTRACT

Thermo-responsive brush-like amphiphilic poly[2-(2-methoxyethoxy) ethyl methacrylate-co-oligo(ethylene glycol) methacrylate]-b-poly(l-lactide)-b-poly[2-(2-methoxyethoxy) ethyl methacrylate-co-oligo(ethylene glycol) methacrylate] [P(MEO2MA-co-OEGMA)-b-PLLA-b-P(MEO2MA-co-OEGMA)] triblock copolymers were synthesized by atom transfer radical polymerization of MEO2MA and OEGMA co-monomers using a α,ω-Bromopropionyl poly(l-lactide) (Br-PLLA-Br) macroinitiator. The resulting copolymers with MEO2MA/OEGMA molar ratio ranging from 79/21 to 42/58 were characterized by 1H nuclear magnetic resonance and size exclusion chromatography. Thermo-responsive micelles were obtained by self-assembly of copolymers in aqueous medium. The micelles are spherical in shape with sizes varying from 20.7 to 102.5 nm. A hydrophobic anticancer drug, curcumin, was encapsulated in micelles by using membrane hydration method. The properties of drug loaded micelles were determined by dynamic light scattering, transmission electron microscopy and lower critical solution temperature (LCST) measurements. The micelles size decreases from 102.5 nm for blank micelles to 37.6 nm with 10.8% drug loading, suggesting that the drug plays an important role in the micellization procedure. The LCST decreases from 45.1 °C for blank micelles to 40.6 and 38.3 °C with 5.9 and 10.8% drug loading, respectively. In vitro drug release was performed in pH 7.4 PBS at different temperatures. Data show that the release rate was significantly enhanced above the LCST comparing with that below the LCST. The amount of released drug at 41 °C was ca. 20% higher than that at 37 °C. Burst-like release was depressed due to enhanced interaction between drug with hydrophobic PLA and PMA chains.

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Biocompatibility of thermo-responsive PNIPAAm-PLLA-PNIPAAm triblock copolymer as potential drug carrier.

Polym. Adv. Technol. 26, 1567–1574 (2015)

Su, F., Shen, X., Hu, Y., Darcos, V. & Li, S

 

ABSTRACT

This work aims to evaluate the cytocompatibility and hemocompatibility of thermo‐responsive polymers as potential drug carrier. Thermo‐responsive poly(N‐isopropyl acrylamide) (PNIPAAm) and poly(N‐isopropyl acrylamide)‐poly(l‐lactide)‐poly(N‐isopropyl acrylamide) (PNIPAAm‐PLLA‐PNIPAAm) triblock copolymer were synthesized by atom transfer radical polymerization using ethyl α‐bromoisobutyrate or Br‐PLLA‐Br as initiator under mild conditions. The self‐assembly and thermo‐responsive properties of the copolymer in aqueous medium were investigated by critical micelle concentration, dynamic light scattering, transmission electron microscopy, and lower critical solution temperature measurements. The critical micelle concentration was 0.014 mg ml−1. Dynamic light scattering and transmission electron microscopy results show that the micelles are spherical in shape with sizes between 20 and 40 nm. The lower critical solution temperature of PNIPAAm and PNIPAAm‐PLLA‐PNIPAAm is 34.8°C and 32.8°C, respectively. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay was carried out to evaluate the cytotoxicity of polymers, and the hemocompatibility was assessed from hemolysis ratio and plasma recalcification time measurements. The results show that PNIPAAm‐PLLA‐PNIPAAm presents outstanding biocompatibility and could be promising for applications in targeted drug delivery.

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Hydrogels:

Robust, fast gelling and tunable degradable hydrogels for drug delivery

About the project:

In this project we synthesize hydrogels based on degradable polymers. Our aim is to improve gelation times and/or gel mechanical properties by either adjusting the copolymers compositions/architectures, or by introducing moeities that ensure fast gelations.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Audrey Bethry
Audrey Bethry

Students:

Sytze Buwalda
Sytze Buwalda

Collaborations:

Funding:

Marie Skłodowska-Curie grant

Ultrafast in situ forming poly(ethylene glycol)-poly(amido amine) hydrogels with tunable drug release properties via controllable degradation rates

Eur. J. Pharm. Biopharm. 139, 232-239 (2019)

Buwalda S., Bethry A., Hunger S., Kandoussi S., Coudane J., Nottelet B.

ABSTRACT

Fast in situ forming, chemically crosslinked hydrogels were prepared by the amidation reaction between N-succinimidyl ester end groups of multi-armed poly(ethylene glycol) (PEG) and amino surface groups of poly(amido amine) (PAMAM) dendrimer generation 2.0. To control the properties of the PEG/PAMAM hydrogels, PEGs were used with different arm numbers (4 or 8) as well as different linkers (amide or ester) between the PEG arms and their terminal N-succinimidyl ester groups. Oscillatory rheology measurements showed that the hydrogels form within seconds after mixing the PEG and PAMAM precursor solutions. The storage moduli increased with crosslink density and reached values up to 2.3 kPa for hydrogels based on 4-armed PEG. Gravimetrical degradation experiments demonstrated that hydrogels with ester linkages between PEG and PAMAM degrade within 2 days, whereas amide-linked hydrogels were stable for several months. The release of two different model drugs (fluorescein isothiocyanate-dextran with molecular weights of 4·103 and 2·106 g/mol, FITC-DEX4K and FITC-DEX2000K, respectively) from amide-linked hydrogels was characterized by an initial burst followed by diffusion-controlled release, of which the rate depended on the size of the drug. In contrast, the release of FITC-DEX2000K from ester-containing hydrogels was governed mainly by degradation of the hydrogels and could be modulated via the ratio between ester and amide linkages. In vitro cytotoxicity experiments indicated that the PEG/PAMAM hydrogels are non-toxic to mouse fibroblasts. These in situ forming PEG/PAMAM hydrogels can be tuned with a broad range of mechanical, degradation and release properties and therefore hold promise as a platform for the delivery of therapeutic agents.

Robust & thermosensitive poly(ethylene glycol)-poly(e-caprolactone) star block copolymer hydrogels

Polym. Degrad. Stabil. 137, 173–183 (2017)

Buwalda, S. J., Nottelet, B. & Coudane, J.

ABSTRACT

Novel 8-armed poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) star block copolymers, possessing an amide or an ester group between the PEG core and the PCL arms (PEG20K-(NHCO)-(PCL9)8 and PEG20K-(OCO)-(PCL9)8), are synthesized by ring opening polymerization of ε-caprolactone in toluene at 110 °C initiated by 8-armed star PEG20K-(NH2)8 and PEG20K-(OH)8, respectively. Compared to linear triblock copolymers with a similar hydrophilic/hydrophobic balance and molecular weight, star block copolymers show better aqueous solubility and yield more homogeneous and transparent hydrogels. PEG20K-(NHCO)-(PCL9)8 hydrogels exhibit a significantly higher storage modulus and in vitro stability in comparison with PEG20K-(OCO)-(PCL9)8 hydrogels of similar concentration and molecular weight. 1H NMR analysis of degrading hydrogel samples clearly demonstrates different degradation mechanisms for the ester and amide type star block copolymers. Their robust mechanical properties, the possibility to be formed in situ and their excellent resistance against hydrolytic degradation make these PEG-PCL star block copolymer hydrogels, especially those based on PEG20K-(NHCO)-(PCL9)8, appealing for various biomedical applications.

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Biopolymers based hydrogels for drug delivery

About the project:

In this project coordinated by our colleagues of the AO Research Institute Davos, the objective is to investigate how antibiotics can affect the physico-chemical characteristics of alginate gels, which could help in elucidating the problem of antibiotic tolerance.

Contact:

Xavier Garric
Xavier Garric
Benjamin Nottelet
Benjamin Nottelet
Hélène Van Den Berghe
Hélène Van Den Berghe

Students:

Sytze Buwalda
Sytze Buwalda

Collaborations:

Dr. D’Este, Dr. Richards, Dr. Moriarty, Dr. Eglin, Dr. Guillaume (AO Research Institute, Switzerland)

Funding:

Marie Skłodowska-Curie grant

Interaction of gentamicin sulfate with alginate and consequences on the physico-chemical properties of alginate-containing biofilms

Int. J. Biol. Macromol. 121, 390–397 (2019)

Heriot, M., Nottelet, B., Garric, X., D’Este, M., Richards, G. R., Moriarty, F. T., Eglin, D. & Guillaume, O.

ABSTRACT

Background: Alginate is one of the main extracellular polymeric substances (EPS) in biofilms of Cystic Fibrosis (CF) patients suffering frompulmonary infections. Gentamicin sulfate (GS) can strongly bind to alginate resulting in loss of pharmacological activity; however neither the mechanism nor its repercussion is fully understood. In this study, we investigated how GS modifies the alginate macromolecular network and its microenvironment. Material and methods: Alginate gels of two different compositions (either enriched in guluronate units (G) or enriched inmannuronate units(M))were crosslinkedwith Ca2+ and exposed to GS at varying times and concentrations.

The complexes formed were characterized via turbidimetry, mechanical tests, swelling assay, calorimetry techniques, nuclear magnetic resonance, Ca2+ displacement, macromolecular probe diffusion and pH alteration.

Results: In presence of GS, the alginate network and its environment undergo a tremendous reorganization in terms of gel density, stiffness, diffusion property, presence and state of the water molecules. We noted that the intensity of those alterations is directly dependent on the polysaccharide motif composition (ratio M/G).

Conclusion: Our results underline the importance of alginate as biofilm component, its pernicious role during antibiotherapy and could represent a potential macromolecular target to improve anti-infectious

therapies.

A method to slow down the ionization-dependent release of risperidone loaded in a thermoresponsive poly(N-acryloyl glycinamide) hydrogel

ABSTRACT

Poly(N-acryloyl glycinamide) polymers are soluble in hot aqueous media that gel rapidly on cooling. This gelatin-like behavior was previously compared with drug delivery requirements. Slow releases were demonstrated in vitro using different model molecules and macromolecules and in vivo using methylene blue. Risperidone is a weak basic drug sparingly soluble in water frequently used to treat patients suffering of schizophrenia. A standard risperidone-poly(N-acryloyl glycinamide) hydrogel formulation was selected from which the drug was allowed to release comparatively in buffered and non-buffered isotonic media at 37 °C under pseudo sink conditions. Linear release was observed in pH = 7.4 phosphate buffer whereas in buffer-free 0.15 M NaCl, the release was initially faster than in the buffer but became rapidly slower as the pH increased from 6.8 to 8.2. These features were related to the ionization-dependent solubility of risperidone. In order to minimize the ionization and thus the solubility of the drug inside the hydrogel despite outside buffering at 7.4, Mg(OH2), a sparingly soluble mineral base, was added to the standard formulation. This addition resulted in a c.a. threefold increase of the zero-order release duration. The method should be applicable to other sparingly soluble weakly basic drugs.

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