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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

Poly(Aspartic Acid) Functionalized Poly(e-Caprolactone) Microspheres with Enhanced Hydroxyapatite Affinity as Bone Targeting Antibiotic Carriers

Pharmaceutics 12, 885 (2020)

Rotman S.G., Moriarty T.F., Nottelet B., Grijpma D.W., Eglin D., Guillaume O.

ABSTRACT

Bone infection is a feared complication for patients with surgically fixed bone fractures and local antibiotic delivery is important in prophylaxis and treatment of these infections. Recent studies indicated that Staphylococcus aureus can penetrate bone tissue through micron-sized canaliculi and evade systemic and currently available local antibiotic treatments. Targeting bacteria within the bone requires highly efficient delivery of antimicrobials to the infected bone tissue. In this work, a biodegradable microsphere carrier loaded with antibiotics and with specific affinity to bone mineral was developed. Two widely used antibiotics, i.e. Gentamicin-AOT (GM-AOT) and Ciprofloxacin (CF) were embedded in poly(ϵ-caprolactone) (PCL) microspheres fabricated by oil-in-water emulsion techniques with carboxylated poly(vinyl alcohol) (cPVA) as surfactant. The carboxylic acid groups present at the PCL/cPVA microsphere surface were functionalized with aspartic acid oligomers (ASP) granting bone targeting properties. We report on cPVA synthesis, microsphere formulation and antibiotic loading of PCL/cPVA-ASP microspheres. Antibiotic loaded PCL/cPVA-ASP microspheres show sustained release of its antibiotic load and can inhibit bacterial growth in vitro for up to 6 days. PCL/cPVA-ASP microspheres show enhanced affinity to mineralized substrates compared to non-functionalized PCL/cPVA microspheres. These findings support further development of these bone targeting antibiotic carriers for potential treatment of persistent bone infections.

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Evaluation of a biodegradable PLA–PEG–PLA internal biliary stent for liver transplantation: in vitro degradation and mechanical properties

J. Biomed. Mater. Res. 1-10, (2020)

Girard E., Chagnon G., Moreau-Gaudry A., Letoublon C., Favier D., Dejean S., Trilling B., Nottelet B.

 

ABSTRACT

Internal biliary stenting during biliary reconstruction in liver transplantation decrease anastomotic biliary complications. Implantation of a resorbable internal biliary stent (RIBS) is interesting since it would avoid an ablation gesture. The objective of present work was to evaluate adequacy of selected PLA-b-PEG-b-PLA copolymers for RIBS aimed to secure biliary anastomose during healing and prevent complications, such as bile leak and stricture. The kinetics of degradation and mechanical properties of a RIBS prototype were evaluated with respect to the main bile duct stenting requirements in liver transplantation. For this purpose, RIBS degradation under biliary mimicking solution versus standard phosphate buffer control solution was discussed. Morphological changes, mass loss, water uptake, molecular weight, permeability, pH variations, and mechanical properties were examined over time. The permeability and mechanical properties were evaluated under simulated biliary conditions to explore the usefulness of a PLA-b-PEG-b-PLA RIBS to secure biliary anastomosis. Results showed no pH influence on the kinetics of degradation, with degradable RIBS remaining impermeable for at least 8 weeks, and keeping its mechanical properties for 10 weeks. Complete degradation is reached at 6 months. PLA-b-PEG-b-PLA RIBS have the required in vitro degradation characteristics to secure biliary anastomosis in liver transplantation and envision in vivo applications

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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Graft Copolymers with Tunable Amphiphilicity tailored for Efficient Dual Drug Delivery via Encapsulation and pH-sensitive Drug Conjugation

Polymer Chemistry 11, 4438–4453 (2020)

Bláhová M., Randárová E., Konefał R., Nottelet B., Etrych T.

ABSTRACT

Polymer-based drug delivery systems may significantly improve cancer therapy. We developed amphiphilic poly(e-caprolactone)-graft-(poly-N-(2-hydroxypropyl) methacrylamide) copolymers (PCL-graft-pHPMA) with tunable amphiphilicity intended for efficient dual delivery via simultaneous encapsulation of hydrophobic drug, Bcl-2 inhibitor ABT-199, and pH-sensitive conjugation of other  chemotherapeutics, doxorubicin, to desired sites, e.g. tumors. Using controlled RAFT polymerization and click chemistry well-defined PCL-graft-pHPMA of diverse Mw and physical properties were prepared. By simple dissolution they self-assembled into highly stable micelles with Dh ≈ 25 nm and low critical micelle concentration (around 5 μg mL-1). The total drug payload reached 17 wt % while maintaining system solubility. The micelles exhibited long-term stability in buffers, while they were cleaved in the presence of lipase, thus proving degradation and drug release after uptake to lysosomes of cancer cells with minimal drug leakage during blood circulation. PCL-graft-pHPMA micelles may serve as a long-circulating drug depo for effective dual therapy of diverse malignancies.

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In Vivo Tissue-Engineered Vascular Grafts

Tissue-Engineered Vascular Grafts, Reference Series in
Biomedical Engineering

Walpoth B.H., de Valence S., Tille J-C., Mugnai D., Sologashvili T., Mrówczyński W.,
Cikirikcioglu M., Pektok E., Osorio S., Innocente F., Bochaton-Piallat M-L., Nottelet B., Kalangos A., Gurny R.

ABSTRACT

Vascular grafts are needed for coronary and peripheral vascular bypass surgeries as well as for access surgeries for hemodialysis and reconstruction of congenital heart defects. Despite good results in the large caliber, small caliber (<6 mm) show unsatisfactory clinical results. Tissue-engineered vascular grafts (TEVG) have been made using several approaches ranging from acellular synthetic or biologic polymer scaffolds to decellularized natural matrices, self-assembled cell-based bioreactor matured, or 3D cell-printed constructs. This chapter will focus mainly on in vivo tissue engineering which was used as first-in-man. This is based on an acellular, synthetic, degradable, polymer scaffold which is repopulated by the host cells after implantation to create a “neo-artery.” Advantages are shelf-readiness; simple, costeffective manufacturing; and avoidance of bioreactor cell maturation. Short-, mid-, and long-term experimental and clinical results show good cellular remodeling with extracellular matrix formation and endothelialization as well as patency and function. Thus, the approach of using an acellular, synthetic, biodegradable scaffold is an optimal clinical option for TEVG.

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Synergistic Anti-fouling and Bactericidal Poly(ether ether ketone) Surfaces via a One-step Photomodification

Mater Sci Eng C. 111,110811 (2020)

Buwalda S., Rotman S., Eglin D., Moriarty F., Bethry A., Garric X., Guillaume O., Nottelet B.

ABSTRACT

Implants of poly(ether ether ketone) (PEEK) are gaining importance in surgical bone reconstruction of the skull. As with any implant material, PEEK is susceptible to bacterial contamination and occasionally PEEK implants were removed from patients because of infection. To address this problem, a combination of anti-fouling and bactericidal polymers are grafted onto PEEK. The originality is that anti-fouling (modified poly(ethylene glycol)) and bactericidal (quaternized poly(dimethylaminoethyl acrylate)) moieties are simultaneously and covalently grafted onto PEEK via UV photoinsertion. The functionalized PEEK surfaces are evaluated by water contact angle measurements, FTIR, XPS and AFM. Grafting of anti-fouling and bactericidal polymers significantly reduces Staphylococcus aureus adhesion on PEEK surfaces without exhibiting cytotoxicity in vitro. This study demonstrates that grafting combinations of anti-fouling and bactericidal polymers synergistically prevents bacterial adhesion on PEEK implants. This approach shows clinical relevance as grafting is rapid, does not modify PEEK properties and can be conducted on pre-formed implants.

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.

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

Acta Biomaterialia 106, 66-81, (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.

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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