Peptide-based polymers and materials

Peptide-based polymers and materials

With their outstanding range of structures, structural and biological activities, peptides are highly attractive molecules to give a tailored function to an existing material but also to design innovative materials with unprecedented properties. Existing approaches to functionalise materials with biomolecules mostly relies on post-modification using conjugation chemistry (e.g. click reactions, activated esters). On the contrary, we envisioned innovative bottom-up approaches based on peptide building-blocks bearing functions for polymerisation or condensation. We investigated organic polymerisation using peptides bearing N-carboxyanhydride (NCA) moieties or lactame rings but also inorganic polymerisation methods, using sol-gel process relying on hydroxysilane-derivatized peptides.

Applications are numerous and some of them are currently investigated thought founded programs and collaborations :

• The functionalization of medical devices and dressing with wound-healing and/or antibacterial peptides and the design of smart ‘communicant’ dressings using RFID technology.
• The synthesis of multi-ligands nanoparticles for cancer treatment and imaging.
• The synthesis of polymers for cell targeting and vectorization.
• The design of biomimetic hydrogels for cell-based therapies that can be printed as 3D scaffolds.
From a fundamental point of view, the self-assembly of hybrid peptides is also studied for the design of new nanostructured materials.

APAPTIDE

APAPTIDE Organic / inorganic particles for the treatment of complex wounds with high risk of infection

Funding: Carnot Chimie Balard Institute
November 2019- November 2022

Open wounds are common in all health services, from emergencies to dermatology, maxillofacial, orthopedic and plastic surgery. In the case of deep wounds, infection is a major threat to the health of the patient, especially for the most fragile subjects such as the elderly, diabetic patients, immuno-depressed or burn victims. In addition, current solutions are generally based on general antibiotic therapy, but microbial resistance is becoming a major public health problem, and alternative solutions are needed.

In this context, APAPTIDE aims to design an alternative solution to conventional dressings and systemic antibiotic treatments through the development of sub-micron peptide-apatite hybrid particles for the controlled release of active agents. Such anti-inflammatory or antibacterial agents will be associated with apatitic particles by ion doping (ex: ions Cu2 +, Zn2 +), and placed on the organic corona stabilizing apatite particles in colloidal solution. In this project and for the first time, this organic corona will be constituted by bio active peptides displaying antimicrobial, pro-angiogenic (promoting neovascularization) and wound healing properties. The innovative aspect of the project is based on the very nature of the hybrid objects.

This project is developed in collaboration between IBMM (Montpellier) and CIRIMAT (Toulouse).

THE TEAM

Gilles Subra
Mathilde Guérin
MATHILDE GUÉRIN
CHRISTOPHE DROUET
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PEPTIMPRINT

PEPTIMPRINT PEPTIDE-LIKE MATERIALS AS HIGHLY SPECIFIC MOLECULAR IMPRINTS

Funding: ANR-18-CE19-023-02
January 2019- June 2022

The concept of ‘molecular imprinting’ emerged in the 1930’s and thanks to its conceptual simplicity, it always attracted a tremendous interest of many scientific communities. The goal is to obtain the hollow shape of a molecule (i.e. ‘template ‘) in a three-dimensional matrix. The template is then removed from the material to give the empty cavities, which are now able to selectively capture the initial object (i.e. the template molecule). These molecular imprints were obtained either inside a material (e.g. hydrogel, macroporous matrix etc.) or on the surface of a substrate. Both organic or inorganic polymerization of monomeric precursors have been used to prepare imprinted materials. However, most of precursors (monomers) commonly used for molecular imprinting are organic ones that react between them by free radical polymerization.

In this sense, the objective of Peptimprint is to set-up a ground-breaking technology to prepare highly specific tridimensional and functionalized imprints of biomolecules (peptides, proteins) by template-assembly, but in this case following the inorganic polymerization by sol-gel process. For that, a variety of original hybrid building blocks mimicking amino acids (diketopiperazine) will be synthetised and developed to be used as precursors (functional monomers) in the MIP synthesis. Unfunctionalized blocks (e.g. tetraethoxysilane (TEOS), methyltriethoxysilane, dimethyldiethoxysilane, bis(triethoxysilyl) ethylene, mono-silylated PEG or bis-silylated PEG) will be also used concomitantly to create the network. Once the template molecule removed, the hollow cavities will be able to capture the biomolecule which was previously imprinted with very high selectivity and affinity. Indeed, unlike classical molecular imprint polymers (MIPs), the resulting inorganic/bioorganic hybrid material will recapitulate not only the shape but also the complementary functions of the biomolecular template.

This project is developed in collaboration with team “Analytic Sciences of Biomolecules & Molecular Modelling” of the Institute of Biomolecules Max Mousseron (IBMM), the team “Molecular Chemistry and Solid-state Organization (CMOS)” of the Institute Charles Gerhardt (ICG), the team “Optomicrofluidique (POMM)” from the Charles Coulomb laboratory of the University of Montpellier, and the team interactions of the “Institut de Recherche en Cancérologie de Montpellier” (IRCM).

THE TEAM

Gilles Subra
Ahmad Mehdi
AHMAD MEHDI
CATHERINE PERRIN
YOANN LADNER
Pascal Verdier
PASCAL VERDIÉ
PASCAL ETIENNE
Pierre Martineau
PIERRE MARTINEAU
Martine Pugniere
MARTINE PUGNIÈRE
RAQUEL GUTIÉRREZ-CLIMENTE
JÉRÉMIE GOUYON
Giang NGO
GIANG NGO
MARGAUX CLAVIÉ

Development of Amino Acids Functionalized SBA-15 for the Improvement of Protein Adsorption

Molecules 202126(19), 6085; https://doi.org/10.3390/molecules26196085

Abstract

Ordered mesoporous materials and their modification with multiple functional groups are of wide scientific interest for many applications involving interaction with biological systems and biomolecules (e.g., catalysis, separation, sensor design, nano-science or drug delivery). In particular, the immobilization of enzymes onto solid supports is highly attractive for industry and synthetic chemistry, as it allows the development of stable and cheap biocatalysts. In this context, we developed novel silylated amino acid derivatives (Si-AA-NH2) that have been immobilized onto SBA-15 materials in biocompatible conditions avoiding the use of toxic catalyst, solvents or reagents. The resulting amino acid-functionalized materials (SBA-15@AA) were characterized by XRD, TGA, EA, Zeta potential, nitrogen sorption and FT-IR. Differences of the physical properties (e.g., charges) were observed while the structural ones remained unchanged. The adsorption of the enzyme lysozyme (Lyz) onto the resulting functionalized SBA-15@AA materials was evaluated at different pHs. The presence of different functional groups compared with bare SBA-15 showed better adsorption results, for example, 79.6 nmol of Lyz adsorbed per m2 of SBA-15@Tyr compared with the 44.9 nmol/m2 of the bare SBA-15.

Sol-gel process – the inorganic approach in protein imprinting

J. Mater. Chem. B, 2021 Jan. https://doi.org/10.1016/j.xphs.2020.10.019

Abstract

Proteins play a central role for the signal transmission in living systems since they are able to recognize specific biomolecules acting as cellular receptors, antibodies or enzymes; or being themselves recognized by other proteins in protein/protein interactions, or displaying epitopes suitable for antibody binding. In this context, the specific recognition of a given protein, unlocks a range of interesting applications in diagnosis and in targeted therapies. Obviously, this role is already fulfilled with antibodies with unquestionable success. However, the design of synthetic artificial systems able to endorse this role is still challenging with a special interest to overcome limitations of antibodies, in particular their production and their stability. Molecular Imprinted Polymers (MIPs) are attractive recognition systems which could be an alternative for the specific capture of proteins in complex biological fluids. MIPs can be considered as biomimetic receptors or antibodies mimics displaying artificial paratopes. However, MIPs of proteins remains a challenge due to their large size and conformational flexibility, their complex chemical nature with multiple recognition sites and their low solubility in most organic solvents. Classical MIP synthesis conditions result in large polymeric cavities with and unspecific binding sites on the surface. In this review, the potentiality of sol-gel process as inorganic polymerization strategy to overcome the drawbacks of protein imprinting is highlighted. Thanks to the mild and biocompatible experimental conditions required and the use of water as solvent, the inorganic polymerization approach suits better to proteins than organic polymerization. Through numerous examples and applications of MIPs, we proposed a critical evaluation of the parameters that must be carefully controlled to achieve sol-gel protein imprinting (SGPI), including the choice of the monomers taking part in the polymerization.

Date Congress Type presentation Title presentation
15-18 June 2021 Balard Chemistry Conferences 2021 Oral Communication Biomimetic protein imprinting on magnetic particles using amino acid-based hybrid blocks
18 June 2021 aesap (Association des Enseignants de Sciences Analytiques de Pharmacie Flash Communication Silylated amino acids as hybrid precursors for protein-biomimetic surface coating: application to electrophoresis separation
22-24 June 2021 Affinity 2021 Flash Communication Amino acid-based hybrid blocks for biomimetic protein imprinting
5-7 July 2021 ISOS-2021 The 19th International Symposium on Silicon Chemistry Flash Communication
14 July 2021 e-MSB 2021 Boston Oral Communication Silylated amino acids as hybrid precursors for protein-biomimetic surface coating: application to electrophoresis separation
5-7 October 2021 SEP21- 14ème Congrès Francophone sur les Sciences Séparatives et les Couplages de l’AFSEP Oral communication Silylated amino acids as hybrid precursors for protein-biomimetic surface coating: application to electrophoresis separation

 

28-29 October 2021 JMJC2021 9èmes Journées Méditerranéennes des Jeunes Chercheur(e)s Poster Communication Applications of silylated amino acid in the development of hybrid materials
Oral Communication Silylated amino acids as hybrid precursors for molecularly
imprinted polymers
2-3 November 2021 QSense User Days – Biolin Scientific Oral Communication Using QCM-D to study the recognition of molecularly imprinted polymer particles toward their target proteins
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ORALCANCERPRINT

ORALCANCERPRINT
Biofabrication of an oral squamous cell carcinoma model by 3D bioprinting

Funding : Emergence, Cancéropôle Grand Sud-Ouest

June 2018 – June 2019

 

Nowadays, treatments of oral squamous cell carcinoma is principally based on excision surgery and can be associated with radiotherapy and chemotherapy. It is really important to have a better understanding of the neoplastic oral mucous membrane to develop less aggressive treatment. This project is a multidisciplinary project aiming at designing an oral squamous cell carcinoma model by 3D bioprinting, to help the development of cancer treatments.

The aim of the project is to develop an in vitro 3D organotipic model of oral mucous membrane with the help of 3D-bioprinting of cellularized layers. The use of two different 3D bioprinting technologies will allow to reproduce the architecture of cancer tissues at a macroscopic and a microscopic scale. Layers of hybrid collagenous peptide based hydrogel encapsulating gingival fibroblasts will be 3D printed by extrusion with layers of endothelial cells in the same hydrogel but 3D printed by a laser-assisted technology, to create a vascularized tissue. Finally, a layer of cancerous keratinocytes embedded into the hydrogel, printed by laser, will cover the model. The complexity of the model will give a better understanding of cellular communication in oral cancer and will be a platform for drug screening.

 

This project is developed in collaboration with BioTis Team ( Dr. Adrien Naveau and Dr. Raphael Devillar), Inserm 1026 : Tissular Bio-engineering team, Bordeaux.

THE TEAM

Gilles Subra
raphael devillard
RAPHAEL DEVILLAR (BioTis)
adrien naveau
ADRIEN NAVEAU (BioTis)
Ahmad Mehdi
AHMAD MEHDI
Laurine Valot
LAURINE VALOT
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E-dressing

E-dressing
The e-dressing project aims at developing a smart wound dressing able to detect an enzymatic activity and to transmit information by passive RFID (radio frequency identification)

Funding: MUSE research founding
Mar 2018- Feb 2021

E-dressing project

The e-dressing project aims at developing a smart wound dressing able to detect an enzymatic activity and to transmit information by passive RFID (radio frequency identification).

The cost of ineffective treatment of chronic wounds (diabetic foot, leg ulcers…) is estimated to be $20-25 billion annually. Efficient and simple wound diagnostic devices could reduce the complications associated with infection or excessive inflammation being able to target the right therapy, at the right time.

We chose to focus on the design of the RFID device which will be included into the dressing, in contact with the wound exudates. The antenna of RFID device, constituted of porous aluminum oxide, will be grafted by a layer of hybrid material, sensitive to the degradation by bacterial enzymes, virulence markers, or by enzymes related to the inflammation of wounds.

Hybrid material will be composed of hybrid silylated peptides whose sequences will be chosen to be enzyme substrates. Material will be synthesized by sol-gel process and will be degraded specifically by these chosen enzymes.

The first part of the work consists in the design and synthesis of hybrid peptides that will be modified by alkoxysilane groups. They will allow their immobilization by sol-gel process on aluminium oxide substrates.

The second part of the work aims the characterization of the hybrid material (AFM, XPS, SEM…) layer during its degradation. In vitro assays in the presence of isolated enzymes and with relevant bacterial strains will be performed.

The aim of the third part of project is to demonstrate that the degradation of hybrid material by enzymes will generate a detectable modification of electrical signal. Indeed, this electrical variation will impact on the RFID reading and the putative quantification of the targeted enzymes.

At last, the system will be assayed on infected exsudates of patients, collected at Montpellier University Hospital.

E-dressing is multidisciplinary project supported by Montpellier University Site of Excellence which also involves the Institute of Electronics and Systems (IES-team Brice Sorli), the University Hospital of Montpellier (CHU-teams Eric Renard and Luc Teot), Institute Charles Gerhart of Montpellier (ICG-team Ahmad Mehdi) and the Ecole des Mines d’Ales (EAM, team Ingrid Bazin)

THE TEAM

Gilles Subra
Ahmad Mehdi
AHMAD MEHDI
Amandine Sandoval
AMANDINE SANDOVAL
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LEGOGEL

LEGOGEL
A 'Lego'-like method to access multifunctional hydrogels for mesenchymal stem cell-based cartilage repair

Funding: ANR-16-CE18-0003-01
October 2016- September 2019

The LEGOGEL multidisciplinary project combines peptide chemistry and sol-gel inorganic polymerization to provide multifunctional hydrogels for full-thickness cartilage lesion repair using mesenchymal stem cells (MSC).

Treatment of cartilage injuries remains one of the most difficult challenges in regenerative medicine. Mesenchymal stem cell (MSC)-based therapies represent one possible innovative strategy. It is highly important that MSC will be associated with a support, to put the cells directly into the lesion to be repaired but also to avoid dissemination at the time of implantation. The support can be a scaffold shaped to fit the cartilage defect or a liquid that can be injected and can rapidly turn into a gel to fill the lesion. LEGOGEL is a multidisciplinary project aiming at designing cell therapy strategies for osteo-articular diseases.

Legogel Project

LEGOGEL aims at establishing a ground-breaking method to build modular and multifunctional hydrogels whose synthesis was too complex to be envisioned by existing methods. LEGOGEL relies on original ‘hybrid’ bioorganic-inorganic building blocks (peptides, biopolymers, dyes…) bearing alcoxysilane groups. Hydrolysis and condensation of these groups lead to the formation of a covalent hydrogel network. Interestingly, this sol-gel process occurs in water in physiological conditions, without the use of chemical cross-linkers, toxic reagents or catalysts. It is thus compatible with biomolecules (ligands, growth factors…) and the presence of cells. Moreover, the mixture of blocks is first obtained as a colloidal solution that can be either injected, or 3D-printed before complete gelation to get porous scaffolds. Taking advantage of this innovative ‘lego-like’ bottom-up approach, the complexity of extracellular matrices (ECM) composed of a huge variety of biological components, could be mimicked. Any type of bioactive peptide, biopolymer, dye or contrast agent can be combined in appropriate ratio to yield covalent hydrogel. Of course, any other component (as growth factors) can be added during the gel formation, in a non-covalent way.

Specific objectives of LEGOGEL project

  1. The first goal will be the synthesis of the different hybrid blocks (i.e. the ‘lego parts’). Bioactive peptide promoting cell migration and colonization, biopolymers (growth factors) and contrast agents will be specifically silylated. The synthesis of hybrid bioactive peptides is already mastered by the partners but the introduction of silyl groups on proteins is a challenge that will be tackled.
  2. The second objective will be to obtain multifunctional hydrogels whose biological and physicochemical properties (stiffness, porosity, degradability…) will be suitable for cell-based engineering. The obtainment of hydrogel substrates from liquid solution will be studied. The most challenging work will be the control of gelation conditions to transfer the soft polymerization method on the 3D printer for the biofabrication of cell-seeded porous scaffolds. If required, Peptide sequences sensitives to ECM degradation enzymes will be incorporated to tune the degradation rate of the matrix and to release the differentiation factors to induce the lineage commitment.

    3D printer used for the project
  3. The third objective will be to obtain optimized hydrogel substrates promoting in vitro and in vivo MSC colonization and differentiation into chondrocytes or osteoblasts. Different composition of hydrogels, containing differentiation factors tailored to mimic specific cartilage and subchondral bone environments will be assayed to obtain the ‘ideal’ substrate. It will be either 3D-printed as a scaffold or used as an injectable hydrogel. Ultimately, the scaffold will present a bilayer membrane composed of TGFβ3- hyaluronic acid upper layer to induce differentiation of MSCs into chondrocytes and secretion of the cartilage ECM; and BMP2-hydroxyapatite-collagen lower layer to favor the differentiation of MSC into osteoblasts.

THE TEAM

Gilles Subra
Ahmad Mehdi
AHMAD MEHDI
Laurine Valot
LAURINE VALOT
MM
MARIE MAUMUS
Luc Brunel
LUC BRUNEL
DANIÈLE NOËL
DANIÈLE NOËL
Pascal Verdier

PASCAL VERDIÉ

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CONTACT

Gilles Subra
Gilles Subra
Pascal Verdier
Pascal Verdier
Jean Martinez
Jean Martinez
Muriel Amblard
Muriel Amblard
Lubomir Vezenkov portrait
Lubomir Vezenkov

Hydrocarbon-Stapled Peptide Based-Nanoparticles for siRNA Delivery.

Nanomaterials (Basel). 2020 Nov 25;10(12):2334. doi: 10.3390/nano10122334

Simon M, Laroui N, Heyraud M, Laconde G, Ali LMA, Bourbiaux K, Subra G, Vezenkov LL, Legrand B, Amblard M, Bettache N.

 

Abstract

Small interfering RNAs (siRNAs) are promising molecules for developing new therapies based on gene silencing; however, their delivery into cells remains an issue. In this study, we took advantage of stapled peptide technology that has emerged as a valuable strategy to render natural peptides more structured, resistant to protease degradation and more bioavailable, to develop short carriers for siRNA delivery. From the pool of stapled peptides that we have designed and synthesized, we identified non-toxic vectors that were able to efficiently encapsulate siRNA, transport them into the cell and induce gene silencing. Remarkably, the most efficient stapled peptide (JMV6582), is composed of only eight amino-acids and contains only two cationic charges.

Nano-assemblies with core-forming hydrophobic polypeptide via polymerization-induced self-assembly (PISA)

Polym. Chem., 2021,12, 113-121 DOI: 10.1002/macp.202000311

Dao T, Vezenkov L, Subra G, Ladmiral V, Semsarilar M.

 

Abstract

The aim of this study is to produce self-assembled structures with hydrophobic polypeptide cores via Reversible Addition–Fragmentation chain Transfer (RAFT) – mediated Polymerisation-Induced Self-Assembly (PISA). Hydrophilic poly(glycerol monomethacrylate) macromolecular chain transfer agents (PGMA mCTAs) were used to polymerize the self-assembling peptide monomers, resulting in the formation of diblock copolymer nano objects. Methacrylamide derivatives containing self-assembling tripeptides MAm-GFF (MAm-Gly-Phe-Phe-NH2) and MAm-FGD (MAm-Phe-Gly-Asp-NH2) were used as hydrophobic monomers. The self-assembling behaviours of these monomers mainly derive from the interactions of the phenylalanine residues, however their difference in hydrophobicity required different polymerization conditions. MAm-GFF was polymerized in the presence of organic solvent (ethanol or acetonitrile), under either dispersion or emulsion polymerization, while MAm-FGD was polymerized under aqueous dispersion conditions. PGMA-b-P(MAm-FGD) obtained from aqueous PISA typically formed fibrous structures while a range of morphologies such as fibre-, flake-, and leaf-like or spherical vesicles were obtained for PGMA-b-P(MAm-GFF) depending on the copolymer composition and solvent used. In all cases the peptides self-assembling core had a crucial influence on the final morphologies.

Bottom-up strategies for the synthesis of peptide-based polymers

Progress in Polymer Science 115 (2021) 101377 https://doi.org/10.1016/j.progpolymsci.2021.101377

Martin J, Desfoux A, Martinez J, Amblard M, Mehdi A, Vezenkov L, Subra G

 

Abstract

Thanks to their wide range of biological activities, peptides have been extensively used to afford designed materials with tailored properties. Peptides can be associated to polymers combining the properties of various polymer backbones with those of bioactive peptide sequences. Such conjugates find promising applications in medical devices, tissue engineering, drug targeting and delivery. Improvement of existing polymers by post-modification peptide grafting is achieved through an extensive range of organic reactions, involving the prior preparation of functional polymers displaying suitable anchoring functions. Alternatively, peptides can be used as initiators of polymerization yielding a chimeric molecule bearing a single peptide at the end of macromolecular chains. Finally, novel polymer materials can be designed when the peptide itself is used as a macromonomer. In that case, the unmatched level of repetition of the peptide sequence or/and its self-assembly properties allow to access very high functionalization degree, original structures and bioactivities.

Self-Assembling Peptide—Polymer Nano-Objects via Polymerization-Induced Self-Assembly

Macromolecules 2020, 53, 16, 7034–7043 https://doi.org/10.1021/acs.macromol.0c01260

Dao T,  Vezenkov L, Subra G, Amblard M, In M, Le Meins J-F, Aubrit F, Moradi M-A, Ladmiral A, Semsarilar M*

 

Abstract

Self-assembling peptides (SAPs) have been extensively studied for their ability to form nanoscale ordered structures driven by noncovalent molecular interactions. Meanwhile, polymerization-induced self-assembly (PISA) has been exploited as a facile and efficient way to produce various amphiphilic block copolymer nano-objects, whose self-assembly was governed predominantly by the interactions of the different blocks with the polymerization medium. In this work, we combined PISA with SAPs to prepare novel peptide–polymer hybrid nano-objects, thus harnessing the advantages of PISA and the self-assembling driving force of SAPs. A tripeptide methacrylamide derivative (MAm-Gly-Phe-Phe-NH2, denoted as MAm-GFF, where MAm means methacrylamide) was copolymerized with glycerol monomethacrylate (GMA) to produce a P(GMA65stat-(MAm-GFF)7) macro-chain transfer agent (macro-CTA) by reversible addition–fragmentation chain transfer polymerization in dimethylformamide. This peptide-based macro-CTA was then successfully chain-extended with poly(2-hydroxypropyl methacrylate) (PHPMA) by aqueous dispersion PISA, forming P(GMA65stat-(MAm-GFF)7)-b-PHPMA28 self-assembled objects. Fibrous structures were observed by transmission electron microscopy (TEM) and Cryo-TEM, in agreement with depolarized dynamic light scattering, static light scattering, and small-angle X-ray scattering experiments that also revealed long anisotropic morphologies. Such structures have not been reported previously for PISA-prepared nano-objects. This confirms the decisive influence of the GFF SAP on the self-assembly. In addition, annealing the PISA suspension at different temperatures led to a significant size decrease in the self-assembled objects and to a morphological transition caused by the thermosensitivity of both the core-forming PHPMA block and the stabilizing P(GMA-stat-(MAm-GFF)) block.

Self-mineralization and assembly of a bis-silylated Phe–Phe pseudodipeptide to a structured bioorganic–inorganic material

Mater. Horiz., 2019, 6, 2040-2046   doi: 10.1039/C9MH00580C

Jebors S, Valot L, Echalier C, Legrand L, Mikhaleff R,Van Der Lee A, Arenal R, Dumy P, Amblard M, Martinez J, Mehdi A and Subra G.

Abstract

Self-mineralization of a trialkoxysilyl hybrid peptide yields in a single step a nanostructured hybrid material. A bis-silylated pseudodipeptide inspired from the Phe–Phe dipeptide was used to program the assembly by sol–gel polymerization under heterogeneous conditions, in water at pH 1.5 without any structure-directing agent. A mechanism deciphering the hybrid material assembly was proposed thanks to 1H NMR spectroscopy. First, water-insoluble hybrid building blocks were hydrolysed into their soluble silanol counterparts. Then, these transitional species, thanks to hydrogen bonding and π–π stacking, self-assembled in solution. Last, the proximity of the silanol moieties favoured their polycondensation into growing siloxane oligomers, which spontaneously precipitated to produce an ordered hybrid material.

Site-specific grafting on titanium surfaces with hybrid temporin antibacterial peptides

J. Mater. Chem. B, 2018,6, 1782-1790. doi 10.1039/C8TB00051D

Abstract

Relying on a membrane-disturbing mechanism of action and not on any intracellular target, antimicrobial peptides (AMP) are attractive compounds to be grafted on the surface of implantable materials such as silicone catheters or titanium surgical implants. AMP sequences often display numerous reactive functions (e.g. amine, carboxylic acid) on their side chains and straightforward conjugation chemistries could lead to uncontrolled covalent grafting, random orientation, and non-homogenous density. To achieve an easy and site specific covalent attachment of unprotected peptides on titanium surfaces, we designed hybrid silylated biomolecules based on the temporin-SHa amphipathic helical antimicrobial sequence. With the grafting reaction being chemoselective, we designed five analogues displaying the silane anchoring function at the N-ter, C-ter or at different positions inside the sequence to get an accurate control of the orientation. Grafting density calculations were performed by XPS and the influence of the orientation of the peptide on the surface was clearly demonstrated by the measure of antimicrobial activity. Temporin amphipathic helices are described to permeabilize the bacterial membrane by interacting in a parallel orientation with it. Our results move in the direction of this mechanism as the selective grafting of hybrid temporin 2 through a lysine placed at the center of the peptide sequence, resulted in better biofilm growth inhibition of E. coli and S. epidermis than substrates in which temporins were grafted via their C- or N-terminus.

Inorganic polymerization: an attractive route to biocompatible hybrid hydrogels

J. Mater. Chem. B, 2018,6, 3434-3448,  doi 10.1039/C8TB00456K

T

Abstract

As an intermediate state between liquid and solid materials, hydrogels display unique properties, opening a wide scope of applications, especially in the biomedical field. Organic hydrogels are composed of an organic network cross-linked via chemical or physical reticulation nodes. In contrast, hybrid hydrogels are defined by the coexistence of organic and inorganic moieties in water. Inorganic polymerization, i.e. the sol–gel process, is one of the main techniques leading to hybrid hydrogels. The chemoselectivity of this method proceeds through hydrolysis and condensation reactions of metal oxide moieties. In addition, the mild reaction conditions make this process very promising for the preparation of water-containing materials and their bio-applications.

Heteromultivalent targeting of integrin αvβ3 and neuropilin 1 promotes cell survival via the activation of the IGF-1/insulin receptors

Biomaterials 2018 Feb;155:64-79. doi: 10.1016/j.biomaterials.2017.10.042. Epub 2017 Oct 29.

Jia T, Choi J, Ciccione J, Henry M, Mehdi A, Martinez J, Eymin B, Subra G, Coll JL.

Abstract

Angiogenesis strongly depends on the activation of integrins, especially integrin αvβ3, and of neuropilin-1 (NRP-1), a co-receptor of VEGFR2. Dual-targeted molecules that simultaneously block both of them are expected have increased anti-angiogenic and antitumor activity. Toward this goal, we generated bifunctional 40 nm-sized silica nanoparticles (NPs) coated with controlled amounts of cRGD and ATWLPPR peptides and studied their affinity, selectivity and biological activity in HUVECs. Sub-nanomolar concentrations of NPs grafted either with ATWLPPR alone or in combination with cRGD exhibit potent and specific antagonist activity against VEGFR2/AKT signaling. However, a 1 nM concentration of the cRGD/ATWLPPR-heteromultivalent particles (RGD/ATW-NPs) also blocks the phosphorylation of VEGFR2 while co-inducing an unexpected long-lasting activation of AKT via IGF-1R/IR-AKT/GSK3β/eNOS signaling that stimulates cell survival and abrogates the intrinsic toxicity of silica-NPs to serum-starved HUVECs. We also showed that their repeated intravenous administration was associated with the proliferation of human U87MG tumor cells engrafted in nude mice and a dilatation of the tumor blood vessels. We present biochemical evidence for the complex cross-talk generated by the binding of the heteromultivalent NPs with αvβ3-integrin and with NRP1. In particular, we show for the first time that such heteromultivalent NPs can trans-activate IGF-1/insulin receptors and exert dose-dependent pro-survival activity. This study demonstrates the difficulties in designing targeted silica-based NPs for antiangiogenic therapies and the possible risks posed by undesirable side effects.

Sol-gel synthesis of collagen-inspired peptide hydrogel

 Materials Today , Pages: Ahead of Print, Journal, 2017,  DOI: 10.1016/j.mattod.2017.02.001

C. Echalier, S. Jebors, G. Laconde, B. Guillaume, V. Luc, C. Pascal, B. Lea, A. Bethry, B. Legrand, H. Van Den Berghe, X. Garric, D. Noel, J. Martinez, A. Mehdi, G. Subra

Abstract

Conceiving biomaterials able to mimic the specific environments of extracellular matrixes are a prerequisite for tissue engineering applications. Numerous types of polymers (PEG, PLA, etc.) have been used for the design of biocompatible scaffolds, but they are still less efficient than natural biopolymers such as collagen exts. Chem. modified and loaded with different bioactive factors, biopolymers afford an environment favorable to cell proliferation and differentiation. Unfortunately, they present several drawbacks, such as weak batch-to-batch reproducibility, potential immunogenicity and high cost of prodn. Herein we propose a fully synthetic covalent hydrogel obtained by sol-gel polymn. of a silylated peptide. We selected a short and low mol. building-block derived from the consensus collagen sequence [Pro-Hyp-Gly]. Interestingly, the sol-gel process occurs in physiol. buffer, enabling the embedment of stem cells. This collagen-inspired hydrogel provides a cell-friendly environment comparable to natural collagen substrates, demonstrating its potency as a biomimetic scaffold.

-Modular bioink for 3D printing of biocompatible hydrogels: sol-gel polymerization of hybrid peptides and polymers

RSC Advances, 2017, Volume: 7, Issue: 20, Pages: 12231-12235, DOI: 10.1039/C6RA28540F

C. Echalier, R. Levato, M. A. Mateos-Timoneda, O. Castano, S. Dejean, X. Garric, C. Pinese, D. Noel, E. Engel, J. Martinez, A. Mehdi, G.Subra

RCS materials

Abstract

An unprecedented generic system allowing the 3D printing of peptide-functionalized hydrogels by soft sol-gel inorg. polymn. is presented. Hybrid silylated inorg./bioorg. blocks are mixed in biol. buffer in an appropriate ratio, to yield a multicomponent bioink that can be printed as a hydrogel without using any photochem. or org. reagent. Hydrolysis and condensation of the silylated precursors occur during the printing process and result in a covalent network in which mols. are linked through siloxane bonds. The viscosity of the colloidal soln. used as bioink was monitored in order to set up the optimal conditions for extrusion printing. Grid-patterned hydrogel scaffolds contg. a hybrid integrin ligand were printed using a pressure-driven rapid prototyping machine. Finally, they were seeded with mesenchymal stem cells, demonstrating their suitability for cell culture. The versatility of the sol-gel process and its biocompatibility makes this approach highly promising for the prepn. of tailor-made cell-laden scaffolds.