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Benjamin Nottelet

Benjamin Nottelet

Professor, Faculty of pharmacy, University of Montpellier

Benjamin initially graduated as a chemical engineer from the Ecole Nationale Supérieure de Chimie of Montpellier (ENSCM), France before completing an industrial PhD on degradable polymers from the University of Montpellier (UM) in 2005 in contract with RHODIA in the group of Prof. Vert. He then worked in the Macromolecular Engineering and Architectures group of ENSCM in the group of Prof. Boutevin before joining the Department of Pharmaceutics and Biopharmaceutics of Prof. Gurny at the University of Geneva (UNIGE) to develop scaffolds for tissue engineering and drug delivery systems. In 2008, he became Associate Professor in the Faculty of Pharmacy at UM and joined the Department of Artificial Biopolymers of IBMM of Prof. Coudane, where he was appointed Full Professor in 2018.  His research activities focus on the synthesis and modification of degradable polymers for advanced biomedical applications and include hybrid biomaterials, bioactive surfaces, and multifunctional polymers.

Part of his recent work focuses on the synthesis and design of (1) innovative multifunctional degradable polymers for use in the field of drug delivery with smart and stimuli-responsive systems or (2) macromolecular contrast agents in the field of diagnostic allowing for MRI or X-ray imaging in of medical devices, or of theranostic approaches.

Another part of his research focuses on (3) hybrid biomaterials including peptide-based polymers or nanocomposites,  and degradable elastomers for tissue engineering applications, as well as the development of  (4) surface modification strategies to yield active surfaces in the frame of antibacterial and of imaging applications.

Benjamin is member of the editorial board of Multifunctional Materials and is co-author of over 58 papers and 3 patents.

Contact:

Benjamin.nottelet(a)umontpellier.fr
+33(0)4-11-75-96-97
Orcid n°: 0000-0002-8577-9273

5 publications récentes:

Anita Schulz, Laurent Lemaire, Audrey Bethry, Lucie Allègre, Maïda Cardoso, Florence Bernex, Florence Franconi, Christophe Goze-Bac, Hubert Taillades, Xavier Garric, Benjamin Nottelet. UV-triggered photoinsertion of contrast agent onto polymer surface for in vivo MRI-visible medical devices. Multifunctional Materials 2019

Louis Gangolphe, Stéphane Déjean, Audrey Bethry, Sylvie Hunger, Coline Pinese, Xavier Garric, Frédéric Bossard, Benjamin Nottelet. Degradable multi(aryl-azide) star copolymer as universal photo-crosslinker for elastomeric scaffolds Mat. Today Chem. 2019

Schulz, A. Stocco, A. Bethry, J-P. Lavigne, J. Coudane, B. Nottelet*. Direct Photomodification of Polymer Surfaces: Unleashing the Potential of Aryl-Azide Copolymers Adv. Funct. Mater. 2018 28, 1800976

Buwalda, A. Al Samad, A. El Jundi, A. Bethry, Y. Bakkour, J. Coudane, B. Nottelet. Stabilization of poly(ethylene glycol)-poly(ε-caprolactone) star block copolymer micelles via aromatic groups for improved drug delivery properties. J. Colloid. Interface Sci. 2018, 514, 468-478

A. Al Samad, A. Bethry, O Janouskova, J Ciccione, C Wenk, J-L Coll, G Subra, T Etrych, F El Omar, Y Bakkour, J Coudane, B. Nottelet. Iterative Photoinduced Chain Functionalization as a Generic Platform for Advanced Polymeric Drug Delivery Systems. Macromol Rapid Commun 2018, 39, 1700502

From in vitro evaluation to human post-mortem pre-validation of a radiopaque and resorbable internal biliary stent for liver transplantation applications

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Acta Biomaterialia. XX, XXX–XXX (2020)

Girard E., Chagnon G., Broisat A., Dejean S., Soubies A., Gil H., Sharkawi T., Boucher F. Roth G.S., Trilling B., Nottelet B.

 

Girard E. et al. Acta Biomaterialia 2020

ABSTRACT

The implantation of an internal biliary stent (IBS) during liver transplantation has recently been shown to reduce biliary complications. To avoid a potentially morbid ablation procedure, we developed a resorbable and radiopaque internal biliary stent (RIBS). We studied the mechanical and radiological properties of RIBS upon in vivo implantation in rats and we evaluated RIBS implantability in human anatomical specimens.

For this purpose, a blend of PLA50-PEG-PLA50 triblock copolymer, used as a polymer matrix, and of X-ray-visible triiodobenzoate-poly(e-caprolactone) copolymer (PCL-TIB), as a radiopaque additive, was used to design X-ray-visible RIBS. Samples were implanted in the peritoneal cavity of rats. The radiological, chemical, and biomechanical properties were evaluated during degradation. Further histological studies were carried out to evaluate the degradation and compatibility of the RIBS. A human cadaver implantability study was also performed.

The in vivo results revealed a decline in the RIBS mechanical properties within 3 months, whereas clear and stable X-ray visualization of the RIBS was possible for up to 6 months. Histological analyses confirmed compatibility and resorption of the RIBS, with a limited inflammatory response. The RIBS could be successfully implanted in human anatomic specimens. The results reported in this study will allow the development of trackable and degradable IBS to reduce biliary complications after liver transplantation.

Biomechanical behaviour of human bile duct wall and impact of cadaveric preservation processes.

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J. Mech. Behav. Biomed. 98, 291–300 (2019)

Girard E., Chagnon G., Gremen E., Calvez M., Boutonnat J., Trilling B., Nottelet B.

 

ABSTRACT

Biliary diseases are the third most common cause of surgical digestive disease. There is a close relationship between the mechanical performance of the bile duct and its physiological function. Data of biomechanical properties of human main bile duct are scarce in literature. Furthermore, mechanical properties of soft tissues are affected by these preservation procedures. The aim of the present work was, on the one hand, to observe the microstructure of the human bile duct by means of histological analysis, on the other hand, to characterize the mechanical behavior and describe the impact of different preservation processes. A mechanical study in a controlled environment consisting of cyclic tests was made. The results of the mechanical tests are discussed and explained using the micro-structural observations. The results show an influence of the loading direction, which is representative of an anisotropic behavior. A strong hysteresis due to the viscoelastic properties of soft tissues was also observed. Embalming and freezing preservation methods had an impact on the biomechanical properties of human main bile duct, with fiber network deterioration. That may further provide a useful quantitative baseline for anatomical and surgical training using embalming and freezing.

Degradable multi(aryl-azide) star copolymer as universal photo-crosslinker for elastomeric scaffolds

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Mater. Today Chem. 12, 209-221, (2019)

Gangolphe L., Déjean S., Bethry A., Hunger S., Pinese C., Garric X., Bossard F., Nottelet B.

ABSTRACT

Degradable elastomers with elastic properties close to those of soft-tissues are necessary for tissue-engineering. Most degradable elastomers developed so far are based on functional low molecular weight pre-polymers that are combined with molecular crosslinkers to yield the elastomeric 3D networks. To overcome this limitation, we present in this work the concept of star-shaped macromolecular multi(aryl-azide) photo-crosslinker that has the ability to efficiently crosslink any polymer containing C-H bonds independently of its molecular weight and without the need for pre-functionalization. This concept of universal crosslinking agent is illustrated with a star-shaped block copolymer composed of an 8-arm poly(ethylene glycol) core and poly(lactide) side arms functionalized with aryl-azide moieties (PEG8arm-PLA-fN3). It was selected due to its macromolecular nature that allows for an easy processing of electrospun photo-crosslinked scaffolds while making it possible to adapt its chemical nature with the one of the polymer matrix. A parameter study is first carried out on PEG8arm-PLA-fN3 / PLA-Pluronic®-PLA films to evaluate the impact of the polymers molecular weight, PEG/PLA ratios, and UV irradiation conditions on the crosslinking efficiency. This study confirms that high crosslinking efficiencies can be obtained with PEG8arm-PLA-fN3 (60%) compared to commercially availabe bis(aryl-azide) photo-crosslinker (below 15%). Optimal conditions are then used to yield electrospun microfibers (1-2 µm) crosslinked with PEG8arm-PLA-fN3 resulting in biocompatible and highly elastomeric scaffolds (ε_y>100%) compared to uncrosslinked scaffolds(ε_y<10%). In addition, we show that the degradation rate can be controlled over time depending on the blend content of PEG8arm-PLA-fN3. Taken together, these results demonstrate the potential of macromolecular multi(aryl-azide) photo-crosslinkers to develop original degradable elastomeric scaffolds for soft-tissue reconstruction.

Controlled Anchoring of Iron Oxide Nanoparticles on Polymeric Nanofibers: Easy Access to Core@Shell Organic−Inorganic Nanocomposites for Magneto-Scaffolds

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ACS Appl. Mater. Interfaces 11, 9519–9529 (2019)

Awada H., Al Samad A., Laurencin D., Gilbert R., Dumail X., El Jundi A., Bethry A., Pomrenke R., Johnson C., Lemaire L., Franconi F., Félix G., Larionova J., Guari Y., Nottelet B.

ABSTRACT

Composites combining superparamagnetic iron oxide nanoparticles (SPIONs) and polymers are largely present in modern (bio)materials. However, while SPIONs embedded in polymer matrices are classically reported, the mechanical and degradation properties of the polymer scaffold are impacted by the SPIONs. Therefore, the controlled anchoring of SPIONs onto polymer surfaces is still a major challenge. Herein, we propose an efficient strategy for the direct and uniform anchoring of SPIONs on the surface of functionalized-polylactide (PLA) nanofibers via a simple free ligand exchange procedure to design PLA@SPIONs core@shell nanocomposites. The resulting PLA@SPIONs hybrid biomaterials are characterized by electron microscopy (SEM and TEM) and EDXS analysis, to probe the morphology and detect elements present at the organic/inorganic interface, respectively. A monolayer of SPIONs with a complete and homogeneous coverage is observed on the surface of PLA nanofibers. Magnetization experiments show that magnetic properties of the nanoparticles are well-preserved after their grafting on the PLA fibers and that the size of the nanoparticles does not change. The absence of cytotoxicity, combined with a high sensitivity of detection in MRI both in vitro and in vivo make these hybrid nanocomposites attractive for the development of magnetic biomaterials for biomedical applications.

UV-triggered photoinsertion of contrast agent onto polymer surfaces for in vivo MRI-visible medical devices

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Multifunct. Mater. 2 0240012019 (2019)

Schulz A., Lemaire L., Bethry A.; Allegre L., Cardoso M., Bernex F., Franconi F., Goze-Bac C., Taillades H., Garric X., Nottelet B.

ABSTRACT

Polymeric materials are largely employed for the manufacturing of implants for various reasons, but they are typically invisible by conventional imaging methods. To improve surgical procedure and postoperative implant follow-up though, biomaterials are needed which allow an accurate and efficient imaging. Here, we present a direct and versatile strategy that allows to covalently immobilize T1 magnetic resonance imaging (MRI) contrast agents at the surface of various clinically relevant polymeric biomaterials. An aryl-azide bearing complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and gadolinium (Gd) has been synthesized for easy photografting onto polymer surfaces. Polycaprolactone (PCL), polylactide (PLA), polyurethane (PU), polyetheretherketone (PEEK) and polypropylene (PP) have been selected as clinically relevant substrates and successfully functionalized with the photosensitive MRI probe DOTA/Gd. Following in vitro assessment of their biocompatibility and MRI visibility, commercial MRI-visible PP hernia repair meshes (MRI-meshes) have been prepared. MRI-meshes have been implanted in rats for in vivo evaluation of their imaging capacities over 1 month. Histological evaluation and Gd biodistribution studies have been carried out confirming the potential of this straightforward approach to simply yield imageable medical devices.

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

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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.

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

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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.

Phthalocyanine photosensitizer in polyethylene glycol-block-poly(lactide-co-benzyl glycidyl ether) nanocarriers: Probing the contribution of aromatic donor-acceptor interactions in polymeric nanospheres

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Mater. Sci. Eng. C-Mater. Biol. Appl. 94, 220–233 (2019)

Pound-Lana, G. E. N., Garcia, G. M., Trindade, I. C., Capelari-Oliveira, P., Pontifice, T. G., Vilela, J. M. C., Andrade, M. S., Nottelet, B., Postacchini, B. B. & Mosqueira, V. C. F.

ABSTRACT

For best photosensitizer activity phthalocyanine dyes used in photodynamic therapy should be molecularly dispersed. Polyethylene glycol-block-polylactide derivatives presenting benzyl side-groups were synthesized to encapsulate a highly lipophilic phthalocyanine dye (AlClPc) and evaluate the effect of π-π interactions on the nanocarrier colloidal stability and dye dispersion. Copolymers with 0, 1, 2 and 6mol% of benzyl glycidyl ether (BGE) were obtained via polyethylene glycol initiated ring-opening copolymerization of D,l-lactide with BGE. The block copolymers formed stable, monodisperse nanospheres with low in vitro cytotoxicity. AlClPc loading increased the nanosphere size and affected their colloidal stability. The photo-physical properties of the encapsulated dye, studied in batch and after separation by field flow fractionation, demonstrated the superiority of plain PEG-PLA over BGE-containing copolymers in maintaining the dye in its monomeric (non-aggregated) form in aqueous suspension. High dye encapsulation and sustained dye release suggest that these nanocarriers are good candidates for photodynamic therapy.

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

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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.

N-(2-Hydroxypropyl)methacrylamide-Based Linear, Diblock, and Starlike Polymer Drug Carriers: Advanced Process for Their Simple Production

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Biomacromolecules 19, 4003–4013 (2018)

Koziolova, E., Kostka, L., Kotrchova, L., Subr, V., Konefal, R., Nottelet, B. & Etrych, T.

 

ABSTRACT

We developed a new simplified method for the synthesis of well-defined linear, diblock, or starlike N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer drug carriers using controlled reversible addition–fragmentation chain transfer polymerization. The prepared monodispersed polymers are after the drug attachment intended for enhanced anticancer therapy. This new approach significantly reduces the number of required synthetic steps and minimizes the consumption of organic solvents during the synthesis. As a result, highly defined linear, diblock, and starlike copolymers designed for pH-triggered drug activation/release in tumor tissue were formed in sufficient amounts for further physicochemical and biological studies. Within the synthesis, we also developed a new procedure for the selective deprotection of tert-butoxycarbonyl hydrazide and amine groups on hydrophilic HPMA copolymers, including the one-pot removal of polymer end groups. We studied and described in detail the kinetics and efficacy of the deprotection reaction. We believe the simplified synthetic approach facilitates the preparation of polymer conjugates bound by the pH-sensitive hydrazone bond and their application in tumor treatment.

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