Category: Peptide-based polymers and materials

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

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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.

Unambiguous and Controlled One-Pot Synthesis of Multifunctional Silica Nanoparticles

Chemistry of Materials, 2016, Volume: 28, Issue: 3, Pages: 885-889, DOI: 10.1021/acs.chemmater.5b04398

J. Ciccione, T. Jia, J .L. Coll, K. Parra, M. Amblard, S. Jebors, J. Martinez, A. Mehdi, G. Subra 

Abstract

A method for obtaining in a single step well-defined tunable multifunctional fluorescent particles having their surface functionalized with multiple covalently linked ligands is reported.  The strategy relies on the synthesis of hybrid bioorg.-inorg. peptide ligands, greatly simplifying the design of multifunctional nanoparticles.  It was possible to tune the ratio of two grafted ligands on the surface of the SiNPs simply by adjusting the relative concn. of hybrid species in the starting soln.  An original fluorine NMR method was applied to the dissolved SiNPs to demonstrate our hypothesis.

Easy Synthesis of Tunable Hybrid Bioactive Hydrogels

Chemistry of Materials, 2016, Volume: 28, Issue: 5, Pages: 1261-1265,  DOI: 10.1021/acs.chemmater.5b04881

C. Echalier, C. Pinese, X. Garric, H. Van Den Berghe, E. Jumas Bilak, J. Martinez, A. Mehdi, G. Subra 

Abstract

Hydrogels are raising an increasing interest in the biomedical field and have found applications in tissue engineering and regenerative medicine.  In order to mimic the complexity of natural tissues, functionalization of hydrogels with bioactive mols. is of first importance.  In this context, we developed a bottom-up approach based on the synthesis of hybrid silylated blocks that can be combined to obtain covalently functionalized gels.  In this study, hybrid silylated PEG and hybrid silylated bioactive peptides were synthesized and mixed in desired ratio before being simply dissolved in phosphate buff-er at physiol. pH to form a gel.  The soln. turns quickly into a covalent functional gel at 37 °C.  Mech. properties of these hydrogels were studied and their biocompatibility was demonstrated.  Depending on the type of bioactive peptides introduced within the gels, they exhibited either antibacterial or cell adhesion properties demonstrating the potency of this sol-gel modular strategy for fine tuning of gel properties.

Selective homodimerization of unprotected peptides using hybrid hydroxydimethylsilane derivatives

RSC Advances, 2016, Volume: 6, Issue: 39, Pages: 32905-32914, DOI: 10.1039/C6RA06075G

C. Echalier, A. Kalistratova, J. Ciccione, A. Lebrun, B. Legrand, E. Naydenova, D. Gagne, J. A. Fehrentz , J. Marie, M. Amblard, A. Mehdi, J. Martinez, G. Subra 

Abstract

We developed a simple and straightforward way to dimerize unprotected peptide sequences that relies on a chemoselective condensation of hybrid peptides bearing a hydroxydimethylsilyl group at a chosen position (either C-ter, N-ter or side-chain linked) to generate siloxane bonds upon freeze-drying. Interestingly, the siloxane bond sensitivity to hydrolysis is strongly pH-dependent. Thus, we investigated the stability of siloxane dimers in different exptl. conditions. For that purpose, 29Si, 13C and 1H NMR spectra were recorded to accurately quantify the ratio of dimer/monomer. More interestingly, we showed that 1H resonances of the methylene and Me groups connected to the Si can be used as sensitive probes to monitor siloxane hydrolysis and to det. the half-lives of the dimers. Importantly, we showed that the dimers were rather stable at pH 7.4 (t1/2 ≈ 400 h) and we applied the dimerization strategy to bioactive sequences. Once optimized, three dimers of the growth hormone releasing hexapeptide (GHRP-6) were prepd. Interestingly, their pharmacol. evaluation revealed that the activity of the dimeric ligands could be switched from agonist to inverse agonist depending on the position of dimerization.

A new way to silicone-based peptide polymers

Angewandte Chemie, 2015, Volume: 54, Issue: 12, Pages: 3778-3782,  DOI: 10.1002/anie.201411065

S. Jebors, J. Ciccione, S. Al-Halifa, B. Nottelet, C. Enjalbal, C. M’Kadmi,  M. Amblard, A. Mehdi, J. Martinez, G. Subra

Abstract

We describe a new class of silicone-contg. peptide polymers obtained by a straightforward polymn. in water using tailored chlorodimethylsilyl peptide blocks as monomeric units.  This general strategy is applicable to any type of peptide sequences, yielding linear or branched polymer chains composed of well-defined peptide sequences.

Engineered Adhesion Peptides for Improved Silicon Adsorption

Langmuir, 2015, Volume: 31, Issue: 43, Pages: 11868-11874,  DOI: 10.1021/acs.langmuir.5b02857

S. R.  Kumar; S. Jebors, M. Martin, T. Cloitre,  V. Agarwal, A. Mehdi, J. Martinez, G. Subra, C. Gergely 

Abstract

Engineering peptides that present selective recognition and high affinity for a material is a major challenge for assembly-driven elaboration of complex systems with wide applications in the field of biomaterials, hard-tissue regeneration, and functional materials for therapeutics.  Peptide-material interactions are of vital importance in natural processes but less exploited for the design of novel systems for practical applications because of our poor understanding of mechanisms underlying these interactions.  Here, we present an approach based on the synthesis of several truncated peptides issued from a silicon-specific peptide recovered via phage display technol.  We use the photonic response provided by porous silicon microcavities to evaluate the binding efficiency of 14 different peptide derivs.  We identify and engineer a short peptide sequence (SLVSHMQT), revealing the highest affinity for p+-Si.  The mol. recognition behavior of the obtained peptide fragment can be revealed through mutations allowing identification of the preferential affinity of certain amino acids toward silicon.  These results constitute an advance in both the engineering of peptides that reveal recognition properties for silicon and the understanding of biomol.-material interactions.