Colin V. Bonduelle

Synthetic Glycopolypeptides as Biomimetic Analogues of Natural Glycoproteins

Glycoproteins are naturally produced by protein glycosylation and are involved in a wide range of cellular functions. This Review aims to summarize the preparation of well-defined synthetic glycoproteins by using chemical routes as well as to highlight the preparation of ideal polymeric analogues of natural glycoproteins: glycopolypeptides. These macromolecules are simplified models of glycoproteins and are designed with the purpose of both mimicking the properties of natural glycoproteins as well as bringing innovative polymeric structures for materials science applications.

Synthesis and self-assembly of "tree-like" amphiphilic glycopolypeptides.

Novel synthetic tree-like oligosaccharides-grafted-polypeptides were prepared by using Huisgen 1,3-dipolar cycloaddition between poly(γ-benzyl-L-glutamate)-block-poly(propargylglycine) and two different oligosaccharides, dextran or hyaluronan. By direct solubilisation in water, these tree-like glycopeptides spontaneously form very small assemblies with sizes below 50 nm and low polydispersity.

Iminosugar-based glycopolypeptides: glycosidase inhibition with bioinspired glycoprotein analogue micellar self-assemblies.

Biomimetic nanoparticles prepared by self-assembly of iminosugar-based glycopolypeptides evidenced remarkable multivalency properties when inhibiting α-mannosidase activity. This approach paves the way to obtain biologically active drug delivery systems having glycosidase inhibition potency.

Dendritic Guanidines as Efficient Analogues of Cell Penetrating Peptides

The widespread application of cell penetrating agents to clinical therapeutics and imaging agents relies on the ability to prepare them on a large scale and to readily conjugate them to their cargos. Dendritic analogues of cell penetrating peptides, with multiple guanidine groups on their peripheries offer advantages as their high symmetry allows them to be efficiently synthesized, while orthogonal functionalities at their focal points allow them to be conjugated to cargo using simple synthetic methods. Their chemical structures and properties are also highly tunable as their flexibility and the number of guanidine groups can be tuned by altering the dendritic backbone or the linkages to the guanidine groups. This review describes the development of cell-penetrating dendrimers based on several different backbones, their structure-property relationships, and comparisons of their efficacies with those of known cell penetrating peptides. The toxicities of these dendritic guanidines are also reported as well as their application towards the intracellular delivery of biologically significant cargos including proteins and nanoparticles.

Preparation of antibacterial surfaces by hyperthermal hydrogen induced cross-linking of polymer thin films

The covalent immobilization of polymers on surfaces has the potential to impart new properties and functions to surfaces for a wide range of applications. However, most current methods for the production of these surfaces involve multiple chemical steps or do not impart a high degree of control over the chemical functionalities at the surface. Described here is the preparation of surfaces covalently functionalized with quaternized poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA), a known antibacterial polymer. PDMAEMA was coated onto octadecyltrimethoxysilane modified silicon wafers and was then cross-linked by the selective cleavage of C–H bonds using a hyperthermal hydrogen treatment. The surfaces were then quaternized with ethyl bromide. At each step the surfaces were characterized extensively using techniques including atomic force microscopy, contact angle measurements and X-ray photoelectron spectroscopy. These results demonstrated a high degree of functional group retention throughout the process. The antibacterial properties of the surfaces against Gram-positive S. aureus and Gram-negative E. coli were investigated using a “drop test” assay. Furthermore, the process was successfully applied to produce antibacterial butyl rubber surfaces, demonstrating the versatility of the method for grafting onto unfunctionalized hydrocarbon surfaces.

Preparation of Protein- and Cell-Resistant Surfaces by Hyperthermal Hydrogen Induced Cross-Linking of Poly(ethylene oxide)

The functionalization of surfaces with poly(ethylene oxide) (PEO) is an effective means of imparting resistance to the adsorption of proteins and the attachment and growth of cells, properties that are critical for many biomedical applications. In this work, a new hyperthermal hydrogen induced cross-linking (HHIC) method was explored as a simple one-step approach for attaching PEO to surfaces through the selective cleavage of C-H bonds and subsequent cross-linking of the resulting carbon radicals. In order to study the effects of the process on the polymer, PEO-coated silicon wafers were prepared and the effects of different treatment times were investigated. Subsequently, using an optimized treatment time and a modified butyl polymer with increased affinity for PEO, the technique was applied to butyl rubber surfaces. All of the treated surfaces exhibited significantly reduced protein adsorption and cell growth relative to control surfaces and compared favorably with surfaces that were functionalized with PEO using conventional chemical methods. Thus HHIC is a simple and effective means of attaching PEO to non-functional polymer surfaces.

Tuning polymersome surfaces: functionalization with dendritic groups

The conjugation of dendrons having varying peripheral functionalities to polymer vesicles, commonly referred to as polymersomes, provides an opportunity to significantly alter the polymersome surface chemistry in a single step while leaving intact the block copolymers responsible for assembly. In this work, polymersomes with surface azide groups were prepared from poly(1,2-butadiene)-poly(ethylene oxide) (PBD-PEO) and poly(e-caprolactone)-PEO (PCL-PEO) block copolymers and were functionalized with polyester dendrons having focal point alkyne moieties and peripheral hydroxyls, amines, or guanidines. The release rates of a small molecule rhodamine B and a rhodamine B-labeled protein from naked and functionalized polymersomes were investigated and the presence of dendritic groups was found to have a minimal effect. All of the naked and functionalized polymersomes were found to be nontoxic at all concentrations tested, except for the guanidine functionalized polymersomes which did impart some toxicity at the highest concentrations tested. The cell uptake of the different polymersomes was compared and it was found that the guanidine functionalized polymersomes exhibited increased cell uptake relative to all other materials. Further studies of this phenomenon suggested that the uptake is mediated by endocytosis and possibly direct translocation across the membrane.

Synthesis, Characterization, and Biological Interaction of Glyconanoparticles with Controlled Branching

Branched amphiphilic copolymers were synthesized through the reversible addition-fragmentation chain transfer (RAFT) chain extension of a poly(methyl acrylate) macro-chain transfer agent using a protected galactose monomer and a polymerizable chain transfer agent branching unit. After galactose deprotection, the copolymers were self-assembled via nanoprecipitation. The resultant nanoparticles were analyzed for their size, shape, and biological interaction with a galactose binding lectin. Using light scattering, the nanoparticles were determined to be solid spheres. Nanoparticles containing branched glycoblocks bound significantly more lectin than those containing comparable linear blocks. By adjusting the molecular weight and branching of the copolymer, the size of the self-assembled nanoparticle and the saccharide density on its surface can be varied.

Synthetic glycopolypeptides: synthesis and self-assembly of poly(γ-benzyl-L-glutamate)-glycosylated dendron hybrids

Nano-assemblies prepared from glycosylated macromolecules are promising systems for modulating or mimicking the interactions between natural carbohydrates and their receptors. In the current work, polyester dendrons bearing focal point alkynes and peripheral C-linked α-galactose moieties were synthesized and coupled to helical poly(γ-benzyl-L-glutamate) (PBLG) to afford synthetic linear-dendritic glycopolypeptides. Both the dendrimer generation and the length of the PBLG were varied to provide a small library of amphiphiles with hydrophilic mass fractions ranging from 0.07 to 0.54. The self-assembly of the copolymers in water using a solvent exchange method was optimized and studied in detail. While the linear-dendritic copolymers composed of lower generation dendrons tended to aggregate, a copolymer composed of a 4th generation galactose-functionalized dendron and PBLG with a degree of polymerization of 28 formed micellar nano-assemblies whose size could be tuned by varying the self-assembly process. Overall, this study provides new insights into the effects of polymer architecture on self-assembly properties, while at the same time introducing a new platform for the preparation of bioactive nanoparticles.