RESUMEN

The amphiphilic heterograft copolymers bearing biocompatible/biodegradable grafts [poly(2-methyl-2-oxazoline-co-2-pentyl-2-oxazoline)-g-poly(d-l-lactic acid)/poly(2-ethyl-2-oxazoline)] were synthesized successfully by the combination of cationic ring-opening polymerization and click chemistry via the ⟨"grafting to"⟩ approach. The challenge of this synthesis was to graft together hydrophobic and hydrophilic chains on a hydrophilic platform based on PMeOx. The efficiency of grafting depends on the chemical nature of the grafts and of the length of the macromolecular chains. The self-assembly of these polymers in aqueous media was investigated by DLS, cryo-TEM, and SANS. The results demonstrated that different morphologies were obtained from nanospheres and vesicles to filaments depending on the hydrophilic weight ratio in the heterograft copolymer varying from 0.38 until 0.84. As poly(2-ethyl-2-oxazoline) is known to be thermoresponsive, the influence of temperature rise on the nanoassembly stability was studied in water and in a physiological medium. SANS and DLS measurements during a temperature ramp allowed to show that nanoassemblies start to self-assemble in "raspberry like" primary structures at 50 °C, and these structures grow and get denser as the temperature is increased further. These amphiphilic heterograft copolymers may include hydrophobic drugs and should find important applications for biomedical applications which require stealth properties.

RESUMEN

Host-guest nanoassemblies made from spontaneous self-association of host and guest polymers in aqueous solutions have been studied. The specific motivation behind this work was to clarify the impact of the molecular design of the polymers on the interactions between them and on the inner structure of the resulting nanoassemblies. The polymers were composed of a dextran backbone, functionalized with either pendant ß-cyclodextrin (CD) or adamantyl (Ada). Those groups were connected to the backbone either directly or with hydrophilic polyethylene glycol (PEG) spacers. To study the impact of those spacers we have proposed a synthetic pathway to new guest polymers. The latter relied on the use of thiol-substituted dextrans as a scaffold, which is subsequently transformed into PEG-Ada grafted guest polymers via nucleophile-mediated thiol-click reaction. Surface plasmon resonance (SPR) studies evidenced strong mutual affinities between the host and guest polymers and showed that the stoichiometry was close to the ideal one (CD/Ada = 1/1) when PEG spacers were introduced. The structure of the nanoassemblies was studied by a combination of dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). The nature of the individual host or guest polymers has a strong impact on the size and internal structure of the resulting nanoassemblies. The presence of PEG spacers in the polymers led to smaller and less compact nanoassemblies, as evidenced by their large correlation length values (4-20nm compared to 2nm without PEG spacers). At the same time, all types of nanoassemblies appear to have radial density distribution with denser cores and pending polymer chains at the periphery. This study, centered on the influence of the molecular design on the host-guest interactions and structural ordering in polymeric nanoassemblies, will help to tailor host-guest nanoassemblies with attractive drug delivery profiles.

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RESUMEN

Stealth nanocarriers are a promising technology for the treatment of diseases. However, the preparation and characterization of well-defined soft nanoparticulate systems remain challenging. Here we describe a platform of amphiphilic graft copolymers leading to nanoparticles with multiple morphologies and the role of the hydrophilic backbone in their interaction with a model protein. The amphiphilic graft copolymers platform was composed of hydrophilic backbone poly(2-methyl-2-oxazoline-co-2-pentyl-2-oxazoline) (P(MeOx-co-PentOx)), prepared via cationic ring-opening polymerization. Hydrophobic poly(d,l-lactide) (PLA) chains were grafted on the backbone via Huisgen 1,3-dipolar cycloaddition. The "click" copper-catalyzed cycloaddition reactions of azides with alkynes (CuAAC) were successfully carried out, and a series of amphiphilic copolymers were prepared containing a backbone with a number-average molecular weight of 14.2 × 103 g mol-1 and different hydrophobic PLA grafts with various molecular weights (2.8 × 103-12.4 × 103 g mol-1). These original architectures of copolymers, when nanoprecipitated in water, the backbone-selective solvent, allowed us to obtain various structures of nanoparticles with a hydrodynamic diameter in the range of 65-99 nm. More interestingly, a plurality of morphologies going from unilamellar, multilamellar, and large compound vesicles to core-shell nanoparticles and depending on the PLA molecular weights were evidenced by combining cryo-transmission electron microscopy (cryo-TEM) and small-angle neutron scattering (SANS) studies. A first evaluation of their stealthiness by studying the stability and the interaction of these nano-objects with a model protein revealed the role played by the P(MeOx-co-PentOx) in these interactions, demonstrating the utility of this amphiphilic graft copolymers platform with well-defined architectures for the design of nanocarriers in drug delivery applications.

RESUMEN

The main goal of this work was to develop a supramolecular chemistry strategy to decorate interfaces with polyethylene glycol (PEG) grafts. A series of novel bifunctionalized dextrans, bearing 40-60 PEG pending chains and 12-24 hydrophobic adamantyl groups, have been prepared by copper(I)-catalyzed azide-alkyne cycloaddition. Their binding properties toward native ßCD and ßCD polymers were characterized both in solution and at interface using isothermal titration microcalorimetry and surface plasmon resonance. The polymers were found to form stable layers onto neutral and positively charged ßCD-polymer films pre-adsorbed on gold surfaces, due to multivalent interpolymer host-guest interactions. The thickness and stability of the layers could be tuned by varying the ratio between the degrees of substitution by PEG and adamantyl groups.

RESUMEN

The objective of this work is to develop an original method of polyoxazoline brush generation based on supramolecular chemistry onto silica nanoparticles. A first layer is realized by adsorption of a polymer bearing ß-cyclodextrin units (PßCD). This allows the anchoring of a second layer made of alkyl end-capped poly(2-methyl-2-oxazoline) (POXZ-C(n)) via host-guest interactions between the alkyl end groups and the ß-cyclodextrin units. The characteristics of the surface layers were studied by dynamic light scattering. A first study of PßCD adsorption allowed to define the conditions of homogeneous PßCD coverage onto the silica surfaces. Then the adsorption of the second polymer onto the PßCD coated nanoparticles was studied as a function of the POXZ-C(n) solution concentration. Brush layers with chains in extended conformation could be obtained above a critical POXZ-C(n) concentration. The large thickness sensitivity to the feeding POXZ-C(n) concentrations allowed to show that the POXZ-C(n) grafting ratio can be controlled by the POXZ-C(n) concentrations. In a limited concentration range, the nature of the anchoring end-group (C(12) or C(18)) does not influence the shape of the POXZ layer.

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RESUMEN

Associative networks have been elaborated by mixing in aqueous media a cyclodextrin polymer to a dextran bearing adamantyl groups. The two polymers interact mainly via inclusion complexes between adamantyl groups and cyclodextrin cavities, as evidenced by the high complexation constants determined by isothermal titration microcalorimetry (approximately 10(4) L mol(-1)). Additional interaction mechanisms participating in the strength of the network, mainly hydrogen bonding and electrostatic interactions, are sensitive to the pH and ionic strength of the medium, as shown by pH-dependent rheological properties. The loading and release of an apolar model drug, benzophenone, has been studied at two pH values and different cyclodextrin polymer content. Slow releases have been obtained (10-12 days) with slower kinetics at pH 2 than at pH 7. Analysis of the experiments at pH 7 shows that drug release is controlled both by diffusion in the network and by inclusion complex interactions with cyclodextrin cavities.

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RESUMEN

This paper presents a SANS study of hydrophobically end-modified poly(2-methyl-2-oxazoline) (POXZ-C(n)) micelles in aqueous solutions. Strong long-range repulsive interactions between the micelles are evidenced by correlation peaks present at concentrations as low as 0.5 wt %. Due to the dissymmetry in size between the hydrophobic and hydrophilic parts of the chains, the micelles have been analyzed using a model of star-like micelles. Large extension of the POXZ arms into the micelles can explain the original SANS behavior. The dissociation of the micellar structures by adding a complexing agent of the alkyl groups, hydroxypropy-beta-cyclodextrin (HPbeta-CD), has been followed by SANS. The micelles are progressively disrupted by the addition of increasing amounts of HPbeta-CD, and the SANS behavior of free chains is recovered in the presence of an excess of the complexing agent.