Dynamic Covalent Chemistry Enables Reconfigurable All-Polysaccharide Nanogels.

Dynamic covalent bonds are established upon molecular recognition of sugar derivatives by boronic acid molecules. These reversible links can be used in a cross-linking method to fabricate polymer-based responsive nanosystems. Herein, the design of the first dynamic nanogels made entirely of polysaccharides (PS) is reported. Based on PS chains alternately modified with phenyl boronic acid groups and sugar moieties, these colloids self-assemble in physiological conditions and combine the biocompatible nature of their PS backbone with the reconfiguration capacities of their cross-linking chemistry. These dynamic nanogels are easily prepared, stable for a long time, pH responsive, and efficiently internalized by cancer cells.

Designing multivalent probes for tunable superselective targeting.

Specific targeting is common in biology and is a key challenge in nanomedicine. It was recently demonstrated that multivalent probes can selectively target surfaces with a defined density of surface binding sites. Here we show, using a combination of experiments and simulations on multivalent polymers, that such "superselective" binding can be tuned through the design of the multivalent probe, to target a desired density of binding sites. We develop an analytical model that provides simple yet quantitative predictions to tune the polymer's superselective binding properties by its molecular characteristics such as size, valency, and affinity. This work opens up a route toward the rational design of multivalent probes with defined superselective targeting properties for practical applications, and provides mechanistic insight into the regulation of multivalent interactions in biology. To illustrate this, we show how the superselective targeting of the extracellular matrix polysaccharide hyaluronan to its main cell surface receptor CD44 is controlled by the affinity of individual CD44-hyaluronan interactions.

Influence of the interaction strength between supramolecular complexes on the topography of neutral polymer multilayer films.

Step-by-step polymer film buildup processes lead to polymer coatings, e.g., polyelectrolyte multilayers, of various structures ranging from continuous smooth films to droplet like discontinuous coatings. Yet, the origin of these different behaviors depending upon the system is not yet known. This study is a first attempt to rationalize the evolution of the coating structure as a function of the strength of the interactions between the polymers constituting the film. We investigated the influence of the strength of noncovalent host-guest interactions between cyclodextrin (CD) and pyrene (Py), ferrocene (Fc) or adamantane (Ad) on the structure of neutral poly(N-hydroxypropylmethacrylamide) (PHPMA) multilayers films formed in a step-by-step manner. In solution, the strength of the inclusion complex (measured by log K where K is the complex association constant) is increasing in the order Py/ß-CD < Fc/ß-CD < Ad/ß-CD and can be further varied in the presence of different sodium salts at different ionic strengths. Depending upon this strength, the buildup process is limited to the formation of isolated aggregates for PHPMA-CD/PHPMA-Py, leading to smooth continuous films for PHPMA-CD/PHPMA-Fc and to droplet-like films, not entirely covering the substrate, for PHPMA-CD/PHPMA-Ad. To study the influence of the strength of the host-guest interactions on the film topography, PHPMA-CD/PHPMA-Fc films were built in the presence of different sodium salts at different ionic strengths. For low host-guest interactions, only isolated aggregates are formed on the substrate. As the strength of the host-guest interactions increases (increase of log K), the formed films go through a droplet-like structure, before becoming continuous but rough for stronger interactions. When the interaction strength is further increased, the roughness of the films decreases, leading to a smooth continuous film before becoming rough again at still higher interaction strength. Smooth continuous multilayers seem thus to be obtained for an optimal range of the interaction strength.

Design of hyaluronan-based dopant for conductive and resorbable PEDOT ink.

Conformable biocompatible conductive materials are increasingly sought for the development of bioelectronics. If additionally resorbable, they could serve for the design of transient implantable electronic devices, opening the way to new healthcare applications. Hyaluronan (HA) derivatives including sulfate and aminophenylboronic acid (PBA) groups (HAS-PBA) were therefore designed to serve as dopants of poly(3,4-ethylenedioxy)thiophene (PEDOT). The optimized HA sulfation protocol allowed good control on polymer sulfation degree while minimizing polymer chain degradation. Sulfated HA was shown to be degradable in physiological conditions. A synergy was observed between the sulfate negative charges and the PBA aromatic groups promoting hydrophobic interactions and π-stacking between PEDOT and HAS-PBA, to boost the material conductivity that reached 1.6 ± 0.2 S/cm in physiological conditions. Moreover the PEDOT:HAS-PBA material was not cytotoxic and could be formulated for easy processing by inkjet printing, appearing as promising candidate for the design of soft transient electronics for in vivo applications.

α-Acetal, ω-alkyne poly(ethylene oxide) as a versatile building block for the synthesis of glycoconjugated graft-copolymers suited for targeted drug delivery.

α-Acetal, ω-alkyne poly(ethylene oxide) was synthesized as building block of glycoconjugated poly(ε-caprolactone)-graft-poly(ethylene oxide) (PCL-g-PEO) copolymers. The alkyne group is indeed instrumental for the PEGylation of a poly(α-azido-ε-caprolactone-co-ε-caprolactone) copolymer by the Huisgen's 1,3 dipolar cycloaddition, i.e., a click reaction. Moreover, deprotection of the acetal end-group of the hydrophilic PEO grafts followed by reductive amination of the accordingly formed aldehyde with an aminated sugar is a valuable strategy of glycoconjugation of the graft copolymer, whose micelles are then potential. A model molecule (fluoresceinamine) was first considered in order to optimize the experimental conditions for the reductive amination. These conditions were then extended to the decoration of the graft copolymer micelles with mannose, which is a targeting agent of dendritic cells and macrophages. The bioavailability of the sugar units at the surface of micelles was investigated by surface plasmon resonance (SPR). The same question was addressed to nanoparticles stabilized by the graft copolymer. Enzyme linked lectin assay (ELLA) confirmed the availability of mannose at the nanoparticle surface.

Synthesis of poly(lactide-co-glycolide-co-ε-caprolactone)-graft-mannosylated poly(ethylene oxide) copolymers by combination of "clip" and "click" chemistries.

Poly(lactide-co-glycolide) (PLGA) is extensively used in pharmaceutical applications, for example, in targeted drug delivery, because of biocompatibility and degradation rate, which is easily tuned by the copolymer composition. Nevertheless, synthesis of sugar-labeled amphiphilic copolymers with a PLGA backbone is quite a challenge because of high sensitivity to hydrolytic degradation. This Article reports on the synthesis of a new amphiphilic copolymer of PLGA grafted by mannosylated poly(ethylene oxide) (PEO). A novel building block, that is, α-methoxy-ω-alkyne PEO-clip-N-hydroxysuccinimide (NHS) ester, was prepared on purpose by photoreaction of a diazirine containing molecular clip. This PEO block was mannosylated by reaction of the NHS ester groups with an aminated sugar, that is, 2-aminoethyl-α-d-mannopyroside. Then, the alkyne ω-end-group of PEO was involved in a copper alkyne- azide coupling (CuAAC) with the pendent azides of the aliphatic copolyester. The targeted mannose-labeled poly(lactide-co-glycolide-co-ε-caprolactone)-graft-poly(ethylene oxide) copolymer was accordingly formed. Copolymerization of d,l-lactide and glycolide with α-chloro-ε-caprolactone, followed by substitution of chlorides by azides provided the azido-functional PLGA backbone. Finally, micelles of the amphiphilic mannosylated graft copolymer were prepared in water, and their interaction with Concanavalin A (ConA), a glyco-receptor protein, was studied by quartz crystal microbalance. This study concluded to the prospect of using this novel bioconjugate in targeted drug delivery.

Polysaccharide-blend multilayers containing hyaluronan and heparin as a delivery system for rhBMP-2.

It is shown that blend multilayers of hyaluronan (HA) and heparin (HEP) as polyanions and poly(L-lysine) (PLL) as a polycation can be used to prepare films with different thicknesses and chemical compositions. The amounts of recombinant human BMP-2 (rhBMP-2) loaded and the fraction initially released from the films depend on the film's chemical composition. The amounts of rhBMP-2 loaded in the films are much higher for HA mass fractions of more than 0.4. The bioactivity of the rhBMP-2-loaded films is investigated on C2C12 myoblasts, which differentiates into osteoblasts in contact with the films. The alkaline phosphatase expression for cells grown on nanoblend films of various compositions falls over a unique curve. This suggests that the cells "sensing" the rhBMP-2 are not influenced by the film's chemistry. The rhBMP-2 can sustain at least three successive culture sequences while remaining bioactive, thus confirming the important and protective effect of rhBMP-2. Altogether, these results indicate that crosslinked PLL/HA films have superior properties for the incorporation of rhBMP-2 and on its long-lasting bioactivity.

Liposome-based nanocarrier loaded with a new quinoxaline derivative for the treatment of cutaneous leishmaniasis.

The use of nanocarriers for drug delivery is a strategy aimed to improve therapeutic indices through changes in their pharmacokinetic and pharmacodynamic characteristics. Liposomes are well-investigated nanocarriers for drug delivery to macrophage-targeted therapy, the main hosts of intracellular pathogens of some infectious diseases, such as leishmaniasis. In this study, we developed hyaluronic acid (HA)-coated liposomes by different methods that can encapsulate a new quinoxaline derivative, the LSPN331, to increase its solubility and improve its bioavailability. The surface modification of liposomes and their physicochemical characteristics may depend on the coating method, which may be a critical parameter with regard to the route of administration of the antileishmanial drug. Liposomes with identical phospholipid composition containing the same drug were developed, and different biological responses were verified, and our hypothesis is that it is related to the type of modification of the surface. Different physicochemical characterization techniques (dynamic light scattering, transmission electron microscopy and UV-vis quantification of labeled-HA) were used to confirm the successful modification of liposomes as well as their stability upon storage. The encapsulation of LSPN331 was performed using HPLC method, and the entrapment efficiency (EE%) was satisfatory in all formulations, considering results of similar formulations in the literature. Furthermore, in vitro and in vivo studies were carried out to evaluate the efficacy against the parasite Leishmania amazonensis. The in vitro activity was maintained or even improved and HA-coated liposomes showed the ability to target to the site of action by the proposed routes of administration, topically and intravenously. Both formulations are promising for future tests of antileishmania activity in vivo.

Internal composition versus the mechanical properties of polyelectrolyte multilayer films: the influence of chemical cross-linking.

Different types of polyelectrolyte multilayer films composed of poly(L-lysine)/hyaluronan (PLL/HA), chitosan/hyaluronan (CHI/HA) and poly(allylamine hydrochloride)/poly(L-glutamic acid) (PAH/PGA) have been investigated for their internal composition, including water content, ion pairing, and ability to be covalently cross-linked, as well as for their mechanical properties. Film buildup under physiological conditions was monitored by the quartz crystal microbalance with dissipation monitoring (QCM-D) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), which allows unambiguous quantification of the different groups present in the polyelectrolytes. (PAH/PGA) films emerged as the most dense films with the lowest hydration (29%) and the highest COO(-) molar density. In addition, PAH is greatly in excess in these films (3 PAH monomers per PGA monomer). The formation of amide bonds during film cross-linking using the water-soluble carbodiimide EDC was also investigated. All of the films could be cross-linked in a tunable manner, but PAH/PGA exhibited the highest absolute number of amide bonds created, approximately 7 times more than for (PLL/HA) and (CHI/HA) films. The Young's modulus E of the films measured by AFM nanoindentation was shown to vary over 1 to 2 orders of magnitude for the different systems. Interestingly, a linear relationship between E and the density of the covalent cross-links created was observed for (PLL/HA) and (CHI/HA) films whereas (PGA/PAH) films exhibited biphasic behavior. The mean distance between covalent cross-links was estimated to be approximately 11 nm for (PLL/HA) and (CHI/HA) films and only approximately 6 nm for (PAH/PGA) films for the maximum EDC concentration tested (100 mg/mL).

Light induced functionalization of PCL-PEG block copolymers for the covalent immobilization of biomolecules.

Functionalized poly-epsilon-caprolactone-block-polyethyleneglycol (PCL-PEG) amphiphilic copolymers were prepared to be constituents of nanocarriers used for the targeting of specific cells. Hence, we conceived a smooth and simple photografting methodology on these copolymers using a bifunctional molecular clip (O-succinimidyl-4-(p-azido-phenyl)butanoate). We prepared PCL-PEGs with pendent N-hydroxysuccinimide esters and studied the grafting with 3H-lysine, which radioactivity was counted by LSC. Several parameters were investigated, such as behavior of homopolymers, initial concentrations, irradiation, and incubation durations. Evidences of a "PEG directed photografting" are discussed and this selectivity could be improved by a selective solvent technique. The photografting on different PCL-PEGs revealed a dependency of the rates to the crystallinity of the copolymers. Several controls by SEC, DLS, and TEM of the treated copolymers were realized. Lastly, the coupling of alpha-D-mannopyranoside ligand was performed, reaching amounts of 5400 nmol/g of PCL-PEG. This derivatized PCL-PEG enters in the preparation of nanocarriers used for the targeting of antigen presenting cells.

Polyester nanoparticles presenting mannose residues: toward the development of new vaccine delivery systems combining biodegradability and targeting properties.

We report the synthesis of fully biodegradable polymeric nanoparticles presenting mannose residues at their surface and their interaction with lectins. A simple and versatile method was used to reach the surface functionalization of poly(D,L-lactic acid) (PLA) nanoparticles by mannose moieties: It consists in using an amphiphilic mannosylated poly(ethylene oxide)-b-poly(E-caprolactone) (PEO-b-PCL) diblock copolymer as a bioresorbable surface modifier in a simple nanoprecipitation-evaporation procedure. The size and zeta potential of the nanoparticles were found to depend on the molar copolymer/PLA ratio, demonstrating the influence of the copolymer on the formation of the nanoparticles. The bioavailability of the mannose residues as specific recognition sites on the nanoparticle surface could be demonstrated by a modified enzyme-linked lectin assay (ELLA) using biotin-labeled lectins which interact specifically with alpha-D-mannopyrannoside derivatives. Besides specific interaction by lectin-mannose complex formation, nonspecific adsorption of the proteins on the nanoparticle surface was observed. These results were fully supported by isothermal titration calorimetry experiments which suggested that the balance between specific and nonspecific interactions can be controlled by the amount of glycosylated polymer used for the preparation of the nanoparticles. Such nanoparticles are expected to be specifically recognized by mannose receptors, which are highly expressed in cells of the immune system. The targeting properties of these carrier systems combined with their potential adjuvant effects due to their size in the range of 200-300 nm make them attractive candidates as vaccine delivery systems.

Heparosan as a potential alternative to hyaluronic acid for the design of biopolymer-based nanovectors for anticancer therapy.

Glycosaminoglycans (GAGs) are important components of the extracellular matrix that have attracted great interest for drug delivery and pharmaceutical applications due to their diverse biological functions. Among GAGs, heparosan (Hep), a biosynthetic precursor of heparin, has recently emerged as a promising building block for the design of nanoparticles with stealth properties. Though this non-sulfated polysaccharide has a chemical structure very close to that of hyaluronic acid (HA), it distinguishes from HA in that it is biologically inert in the extracellular spaces in the body. In this study, we designed Hep- and HA-based nanogels (NGs) that differ only in the chemical nature of the hydrophilic shell. The nanogels were prepared in a very straightforward way from Hep and HA modified with a thermoresponsive copolymer properly designed to induce self-assembly below room temperature. This versatile synthetic approach also enabled further shell-crosslinking allowing an increase in the colloidal stability. After careful characterization of the un-crosslinked and crosslinked Hep and HA NGs in terms of size (Z-average diameters of un-crosslinked and crosslinked NGs ∼110 and 150 nm) and morphology, they were injected intravenously into tumor-bearing mice for biodistribution experiments. Interestingly, these show that the liver uptake of Hep nanogels is remarkably reduced and tumor accumulation significantly improved as compared to HA nanogels (intensity ratios of tumor-to-liver of 2.2 and 1.4 for the un-crosslinked and crosslinked Hep NGs versus 0.11 for the un-crosslinked and crosslinked HA ones). These results highlight the key role played by the shell-forming GAGs on the in vivo fate of nanogels, which correlates with the specific biological properties of Hep and HA.

Design of interpenetrating chitosan and poly(ethylene glycol) sponges for potential drug delivery applications.

Semi-interpenetrating chitosan (CS)/poly(ethylene glycol) (PEG) sponges were designed by crosslinking PEG in the CS matrix via nucleophilic thiol-yne addition. This reaction does not require the use of any potentially cytotoxic catalytic species and offers possibilities to prepare materials with tunable properties. The molecular structure of the sponges was analyzed by FTIR spectroscopy, which provided evidence of intermolecular interactions between PEG and CS, and the presence of a cross-linked PEG network in the CS matrix. The crosslinked CS/PEG sponges displayed a structure with large interconnected pores (tens of micrometers) as demonstrated by scanning electron miscoscopy, in comparison to blended materials with irregular and smaller pores. The crosslinked sponges also exhibited improved mechanical properties (higher Young's modulus) and stability at physiological pH. All together, these interesting properties open the way for the application of this biomaterial in topical drug delivery.

Direct investigation of the vectorization properties of amphiphilic cyclodextrins in phospholipid films.

Recently, new cyclodextrin derivatives were synthesized and shown to exhibit strong amphiphilic properties. In this paper, we study the action of these new amphiphilic cyclodextrins on phospholipids. Mixed phospholipid/cyclodextrin derivative films were prepared and studied using X-ray reflectivity for various phospholipid/cyclodextrin ratios. A molar ratio of 3 provides a highly stable film the molecular structure of which has been investigated in detail. The cholesterol tail of the cyclodextrin molecule was found to be anchored into the phospholipid film. The cyclodextrin moieties exposed to the aqueous medium are prone to the addition of the guest molecule Dosulepin, making them of high interest for drug delivery. For this purpose and as an example of a potential application, this cyclodextrin molecular carrier property is also addressed to this complex film architecture.

Hydrogen bonded multilayer films based on poly(2-oxazoline)s and tannic acid.

In recent years, the layer-by-layer (LbL) assembly based on hydrogen bonding interactions is gaining popularity for the preparation of thin film coatings, especially for biomedical purposes, based on the use of neutral, non-toxic building blocks. The use of tannic acid (TA) as hydrogen bonding donor is especially interesting as it results in LbL films that are stable under physiological conditions. In this work, investigations on the LbL thin film preparation of TA with poly(2-oxazoline)s with varying hydrophilicity, namely poly(2-methyl-2-oxazoline) (PMeOx), poly(2-ethyl-2-oxazoline) (PEtOx) and poly(2-n-propyl-2-oxazoline) (PnPropOx), are reported. The LbL assembly process is investigated by quartz crystal microbalance and UV-vis spectroscopy revealing linear growth of the film thickness. Furthermore, isothermal titration calorimetry demonstrates the LbL assembly of TA, and PMeOx is found to be mostly enthalpy driven while the LbL assembly of TA with PEtOx and PnPropOx is mostly entropy driven. Finally, scanning electron microscopy and ellipsometry demonstrate the formation of smooth thin films for LbL assembly of TA with all three polymers. Such poly(2-oxazoline) coatings have high potential for use as anti-biofouling coatings.

Thermoresponsive hyaluronic acid nanogels as hydrophobic drug carrier to macrophages.

Delivery systems for macrophages are particularly attractive since these phagocytic cells play a important role in immunological and inflammatory responses, also acting as host cells for microorganisms that are involved in deadly infectious diseases, such as leishmaniasis. Hyaluronic acid (HA) is specifically recognized by macrophages that are known to express HA receptors. Therefore, in this study, we focused on HA-based nanogels as drug carriers for these cells. The drug delivery was validated in an in vivo study on mice using intravital two-photon laser scanning microscopy. HA derivatives were modified with a biocompatible oligo(ethylene glycol)-based thermoresponsive polymer to form nanogels. These HA conjugates were readily prepared by varying the molar mass of initial HA and the degree of substitution via radical-mediated thiol-ene chemistry in aqueous solution. The derivatives were shown to self-assemble into spherical gel particles with diameters ranging from 150 to 214 nm above 37 °C. A poorly water-soluble two-photon dye was successfully loaded into the nanogels during this self-assembly process. In vitro cellular uptake tests using a RAW 264.7 murine macrophage cell line showed successful intracellular delivery of the hydrophobic dye. After intravenous injection in mice, the nanogels circulated freely in the blood but were rapidly phagocytized within 13 min by circulating macrophages and stored in the liver and spleen, as observed by two-photon microscopy. Benefit can be thus expected in using such a delivery system for the liver and spleen macrophage-associated diseases.

Probing multivalent host-guest interactions between modified polymer layers by direct force measurement.

The adhesion behavior between modified polysaccharide layers capable of forming host-guest complexes has been determined by direct force measurements with the atomic force microscope (AFM). Polysaccharides bearing either host or guest moieties were obtained by derivatization of chitosan with pendant ß-cyclodextrin (CD) and adamantane (AD) moieties, respectively. These modified polysaccharides were covalently immobilized either to flat surfaces or to AFM-probes. The number of interacting polymer segments has been reduced significantly by covalently immobilizing chitosan to an AFM-tip with small radius and measuring the forces between the protruding polymer segments and a chitosan layer immobilized to a flat surface. By this approach, it was possible to determine the interaction between polymer layers on the level of single polymer strands. To separate contributions to the adhesion due to the formation of host-guest complexes from unspecific interactions, we performed measurements between various combinations of chitosan derivatives. With the same polymer probe of adamantane-modified chitosan, the interaction against a number of different chitosan layers has been determined, including ones that are not able to form host-guest complexes, such as unmodified chitosan or ß-cyclodextrin modified chitosan, which has been blocked previously by addition of adamantane. The resulting adhesion behavior has been analyzed in terms of the total work of adhesion, the number of rupture events, and the corresponding lengths of the polymer segments as well as rupture forces. A clear difference has been found for systems where the formation of host-guest complexes is possible in comparison to the absence of specific multivalent interaction between the polysaccharide layers. In particular, the work of adhesion is increasing up to an order of magnitude upon the formation of host-guest complexes between the chitosan layers.

Polymeric multilayer capsules delivering biotherapeutics.

Polymeric multilayer capsules have emerged as a novel drug delivery platform. These capsules are fabricated through layer-by-layer sequential deposition of polymers onto a sacrificial core template followed by the decomposition of this core yielding hollow capsules. The resulting nanometer thin membrane is permselective, allowing diffusion of water and ions but excluding larger molecules. Moreover, the sequential fabrication procedure allows a precise fine-tuning of the capsules' physicochemical and biological properties. These properties have put polymeric multilayer capsules under major attention in the field of drug delivery. In this review we focus on polymeric multilayer capsule mediated delivery of biotechnological macromolecular drugs such as peptides, proteins and nucleic acids.

A hydrophilic cyclodextrin duplex forming supramolecular assemblies by physical cross-linking of a biopolymer.

New beta-cyclodextrin (beta-CD) dimeric species have been synthesised in which the two CD moieties are connected by one or two hydrophilic oligo(ethylene oxide) spacers. Their complexation with sodium adamantylacetate (free adamantane) and adamantane-grafted chitosan (AD-chitosan) was then studied by different complementary techniques and compared with their hydrophobic counterparts that contain an octamethylene spacer. Isothermal titration calorimetry experiments have demonstrated that the use of hydrophilic spacers between the two CDs instead of aliphatic chains makes almost all of the CD cavities available for the inclusion of free adamantane. Investigation of the interaction of the CDs with AD-chitosan by viscosity measurements strongly suggests that the molecular conformation of the CD dimeric species plays a crucial role in their cross-linking with the biopolymer. The derivative doubly linked with hydrophilic arms, also called a duplex, has been shown to be a more efficient cross-linking agent than its singly bridged counterpart, referred to as a dimer. Hence, only 0.5 molar equivalents of the hydrophilic duplex with respect to adamantane was required to obtain the maximum viscosity, whereas in the case of the duplex with aliphatic spacers, the maximum viscosity was achieved with a [duplex]/[AD] ratio of about 1.7 (corresponding to a [CD]/[AD] ratio of 2.5), but with a higher value. To clarify the relationships between the molecular architecture and complexation properties, computational studies were also performed that clearly confirmed the importance of double bridging.

Mannosylated poly(ethylene oxide)-b-poly(epsilon-caprolactone) diblock copolymers: synthesis, characterization, and interaction with a bacterial lectin.

A novel bioeliminable amphiphilic poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) diblock copolymer end-capped by a mannose residue was synthesized by sequential controlled polymerization of ethylene oxide and epsilon-caprolactone, followed by the coupling of a reactive mannose derivative to the PEO chain end. The anionic polymerization of ethylene oxide was first initiated by potassium 2-dimethylaminoethanolate. The ring-opening polymerization of epsilon-caprolactone was then initiated by the omega-hydroxy end-group of PEO previously converted into an Al alkoxide. Finally, the saccharidic end-group was attached by quaternization of the tertiary amine alpha-end-group of the PEO-b-PCL with a brominated mannose derivative. The copolymer was fully characterized in terms of chemical composition and purity by high-resolution NMR spectroscopy and size exclusion chromatography. Furthermore, measurements with a pendant drop tensiometer showed that both the mannosylated copolymer and the non-mannosylated counterpart significantly decreased the dichloromethane/water interfacial tension. Moreover, these amphiphilic copolymers formed monodisperse spherical micelles in water with an average diameter of approximately 11 nm as measured by dynamic light scattering and cryo-transmission electron microscopy. The availability of mannose as a specific recognition site at the surface of the micelles was proved by isothermal titration microcalorimetry (ITC), using the BclA lectin (from Burkholderia cenocepacia), which interacts selectively with alpha-D-mannopyranoside derivatives. The thermodynamic parameters of the lectin/mannose interaction were extracted from the ITC data. These colloidal systems have great potential for drug targeting and vaccine delivery systems.