Degradable polyprodrugs: design and therapeutic efficiency.

Prodrugs are developed to increase the therapeutic properties of drugs and reduce their side effects. Polyprodrugs emerged as highly efficient prodrugs produced by the polymerization of one or several drug monomers. Polyprodrugs can be gradually degraded to release therapeutic agents. The complete degradation of polyprodrugs is an important factor to guarantee the successful disposal of the drug delivery system from the body. The degradation of polyprodrugs and release rate of the drugs can be controlled by the type of covalent bonds linking the monomer drug units in the polymer structure. Therefore, various types of polyprodrugs have been developed based on polyesters, polyanhydrides, polycarbonates, polyurethanes, polyamides, polyketals, polymetallodrugs, polyphosphazenes, and polyimines. Furthermore, the presence of stimuli-responsive groups, such as redox-responsive linkages (disulfide, boronate ester, metal-complex, and oxalate), pH-responsive linkages (ester, imine, hydrazone, acetal, orthoester, P-O and P-N), light-responsive (metal-complex, o-nitrophenyl groups) and enzyme-responsive linkages (ester, peptides) allow for a selective degradation of the polymer backbone in targeted tumors. We envision that new strategies providing a more efficient synergistic therapy will be developed by combining polyprodrugs with gene delivery segments and targeting moieties.

Confining the Sol-Gel Reaction at the Water/Oil Interface: Creating Compartmentalized Enzymatic Nano-Organelles for Artificial Cells.

Living organisms compartmentalize their catalytic reactions in membranes for increased efficiency and selectivity. To mimic the organelles of eukaryotic cells, we develop a mild approach for in situ encapsulating enzymes in aqueous-core silica nanocapsules. In order to confine the sol-gel reaction at the water/oil interface of miniemulsion, we introduce an aminosilane to the silica precursors, which serves as both catalyst and an amphiphilic anchor that electrostatically assembles with negatively charged hydrolyzed alkoxysilanes at the interface. The semi-permeable shell protects enzymes from proteolytic attack, and allows the transport of reactants and products. The enzyme-carrying nanocapsules, as synthetic nano-organelles, are able to perform cascade reactions when enveloped in a polymer vesicle, mimicking the hierarchically compartmentalized reactions in eukaryotic cells. This in situ encapsulation approach provides a versatile platform for the delivery of biomacromolecules.

Transparent and Self-Healing Elastomers for Reconfigurable 3D Materials.

Transparent soft materials are widely used in applications ranging from packaging to flexible displays, wearable devices, and optical lenses. Nevertheless, soft materials are susceptible to mechanical damage, leading to functional failure and premature disposal. Herein, a transparent self-healing elastomer that is able to repair the polymer network via exchange reactions of dynamic disulfide bonds is introduced. Due to its self-healing ability, the mechanical properties of the elastomer can be recovered as well as its transparency after multiple cycles of abrasion and healing. The self-healing polymer is fabricated into 3D structures by folding or modular origami assembly of planar self-healing polymer sheets. The 3D polymer objects are employed as storage containers of solid and liquid substances, reactors for photopolymerization, and cuvettes for optical measurements (exhibiting superior properties to those of commercial cuvettes). These dynamic polymers show outstanding mechanical, optical, and recycling properties that could potentially be further adapted in adaptive smart packaging, reconfigurable materials, optical devices, and recycling of elastomers.

Halochromic Polymer Nanosensors for Simple Visual Detection of Local pH in Coatings.

Replacing metallic structures before critical damage is beneficial for safety and for saving energy and resources. One simple approach consists in visually monitoring the early stage of corrosion, and related change of pH, of coated metals. We prepare smart nanoparticle additives for coatings which act as a pH sensor. The nanoparticles are formed with a terpolymer containing two dyes as side chains, acting as donor and acceptor for a FRET process. Real time monitoring of the extent of localized corrosion on metallic structures is then carried out with a smartphone camera. Colored pH mapping can be then manually retrieved by an operator or automatically recorded by a surveillance camera.

Brush Conformation of Polyethylene Glycol Determines the Stealth Effect of Nanocarriers in the Low Protein Adsorption Regime.

For nanocarriers with low protein affinity, we show that the interaction of nanocarriers with cells is mainly affected by the density, the molecular weight, and the conformation of polyethylene glycol (PEG) chains bound to the nanocarrier surface. We achieve a reduction of nonspecific uptake of ovalbumin nanocarriers by dendritic cells using densely packed PEG chains with a "brush" conformation instead of the collapsed "mushroom" conformation. We also control to a minor extent the dysopsonin adsorption by tailoring the conformation of attached PEG on the nanocarriers. The brush conformation of PEG leads to a stealth behavior of the nanocarriers with inhibited uptake by phagocytic cells, which is a prerequisite for successful in vivo translation of nanomedicine to achieve long blood circulation and targeted delivery. We can clearly correlate the brush conformation of PEG with inhibited phagocytic uptake of the nanocarriers. This study shows that, in addition to the surface's chemistry, the conformation of polymers controls cellular interactions of the nanocarriers.

Redox-Responsive Polymer with Self-Immolative Linkers for the Release of Payloads.

Previous couplings of corrosion inhibitors to redox-responsive polymers via covalent bonding suffer from several drawbacks. It is presented here novel redox-responsive polymer-corrosion inhibitor conjugates that contain self-immolative linkers in their side chains. Very fast redox-induced release of tryptamine, a drug and a corrosion inhibitor, is observed after applying a reductive trigger.

Directed Assembly of Soft Anisotropic Nanoparticles by Colloid Electrospinning.

Directed assembly of triblock copolymer worms to produce nanostructured fibers is achieved via colloid electrospinning. These copolymer worms are conveniently prepared by polymerization-induced self-assembly in concentrated aqueous dispersion. Addition of a second water-soluble component, poly(vinyl alcohol), is found to be critical for the production of well-defined fibers: trial experiments performed using the worms alone produce only spherical microparticles. Transmission electron microscopy studies confirm that the worm morphology survives electrospinning and the worms become orientated parallel to the main axis of the fibers during their generation. The average deviant angle (θdev ) between the worm orientation and fiber axis decreases from 17° to 9° as the worm/PVA mass ratio increases from 1.15:1 to 5:1, indicating a greater degree of worm alignment within fibers with higher worm contents and smaller fiber diameters. Thus triblock copolymer fibers of ≈300 ± 120 nm diameter can be readily produced that comprise aligned worms on the nanoscale.

Double Redox-Responsive Release of Encoded and Encapsulated Molecules from Patchy Nanocapsules.

Redox-responsive nanocapsules with surface regularities are presented. Two functional molecules are loaded in the nanocapsules. One molecule is chemically encoded in the capsule shell via a disulfide bond while the other one is physically entrapped in the capsule core. External reducing trigger can induce cascade release of the two payloads.

Nanocarrier for Oral Peptide Delivery Produced by Polyelectrolyte Complexation in Nanoconfinement.

The hydrophilic peptide YY (PYY) is a promising hormone-based antiobesity drug. We present a new concept for the delivery of PYY from pH-responsive chitosan-based nanocarriers. To overcome the drawbacks while retaining the merits of the polyelectrolyte complex (PEC) method, we propose a one-pot approach for the encapsulation of a hydrophilic peptide drug in cross-linked PEC nanocarriers. First, the hydrophilic peptide is encapsulated via polyelectrolyte complexation within water-in-oil miniemulsion droplets. In a second step, the PEC surface is reinforced by controlled interfacial cross-linking. PYY is efficiently encapsulated and released upon pH change. Such nanocarriers are promising candidates for the fight against obesity and, in general, for the oral delivery of protein drugs.

Self-healing, antibiofouling and anticorrosion properties enabled by designing polymers with dynamic covalent bonds and responsive linkages.

Coating metal structures with a protective material is a popular strategy to prevent their deterioration due to corrosion. However, maintaining the barrier properties of coatings after their mechanical damage is challenging. Herein, we prepared multifunctional coatings with self-healing ability to conserve their anticorrosion performance after damage. The coating was formed by blending synthesized redox-responsive copolymers with the ability to release a corrosion inhibitor upon the onset of corrosion with synthesized self-healing polyurethanes containing disulfide bonds. The corrosion rate of steel substrates coated with a blend is approximately 24 times lower than that of steel coated with only self-healing polyurethane. An exceptional healing efficiency, as high as 95%, is obtained after mechanical damage. The antibiofouling property against bacterial and microalgal attachments on coatings is facilitated by the repellent characteristic of fluorinated segments and the biocidal activity of the inhibitor moieties in the copolymer.

Fluorescence correlation spectroscopy directly monitors coalescence during nanoparticle preparation.

Dual color fluorescence cross-correlation spectroscopy (DC FCCS) experiments were conducted to study the coalescence and aggregation during the formation of nanoparticles. To assess the generality of the method, three completely different processes were selected to prepare the nanoparticles. Polymeric nanoparticles were formed either by solvent evaporation from emulsion nanodroplets of polymer solutions or by miniemulsion polymerization. Inorganic nanocapsules were formed by polycondensation of alkoxysilanes at the interface of nanodroplets. In all cases, DC FCCS provided fast and unambiguous information about the occurrence of coalescence and thus a deeper insight into the mechanism of nanoparticle formation. In particular, it was found that coalescence played a minor role for the emulsion-solvent evaporation process and the miniemulsion polymerization, whereas substantial coalescence was detected during the formation of the inorganic nanocapsules. These findings demonstrate that DC FCCS is a powerful tool for monitoring nanoparticles genesis.

Facile and large-scale fabrication of anisometric particles from fibers synthesized by colloid-electrospinning.

A new top-down approach is proposed to form large amounts of anisometric particles. Multicompartment fibers that present different domains composed of silica nanoparticles and larger polystyrene nanoparticles are fabricated by colloid-electrospinning and are subsequently calcinated and broken. The obtained fibers containing voids are subsequently cut via sonication to yield anisometric particles. It is shown that the majority of the fibers can be broken at the voids.

How shape influences uptake: interactions of anisotropic polymer nanoparticles and human mesenchymal stem cells.

Among several nanoparticle properties, shape is important for their interaction with cells and, therefore, relevant for uptake studies and applications. In order to further investigate such characteristics, fluorescently labeled spherical polymer nanoparticles are synthesized by free-radical polymerization via the miniemulsion process. The spherical nanoparticles are subsequently submitted to controlled mechanical deformation to yield quasi-ellipsoidal polymeric nanoparticles with different aspect ratios. The uptake behaviors of spherical and non-spherical particles with equal volume are investigated qualitatively and quantitatively by electron microscopy, confocal laser scanning microscopy, and flow cytometry measurements. Non-spherical particles show fewer uptake by cells than their spherical counterparts with a negative correlation between aspect ratio and uptake rate. This is attributed to the larger average curvature radius of adsorbed non-spherical particles experienced by the cells.

Colloid-electrospinning: fabrication of multicompartment nanofibers by the electrospinning of organic or/and inorganic dispersions and emulsions.

Solution-, melt-, and co-axial electrospinning are well-known methods for producing nano- and microfibers. The electrospinning of colloids (or colloid-electrospinning) is a new field that offers the possibility to elaborate multicompartment nanomaterials. However, the presence of colloids in the electrospinning feed further complicates theoretical predictions in a system that is dependent on chemical, physical, and process parameters. Herein, we give a summary of recent important results and discuss the perspectives of electrospinning of colloids for the synthesis and characterization of multicompartment fibers.

Marrying the incompatible for better: Incorporation of hydrophobic payloads in superhydrophilic hydrogels.

HYPOTHESIS: The entrapment of lyophobic in superhydrophilic hydrogels is challenging because of the intrinsic incompatibility between hydrophobic and hydrophilic molecules. To achieve such entrapment without affecting the hydrogel's formation, the electrospinning of nanodroplets or nanoparticles with a water-soluble polymer could reduce the incompatibility through the reduction of interfacial tension and the formation of a barrier film preventing coalescence or aggregation. EXPERIMENTS: Nanodroplets or nanoparticles dispersion are electrospun in the presence of a hydrophilic polymer in hydrogel precursors. The dissolution of the hydrophilic nanofibers during electrospinning allows a redispersion of emulsion droplets and nanoparticles in the hydrogel's matrix. FINDINGS: Superhydrophilic hydrogels with well-distributed hydrophobic nanodroplets or nanoparticles are obtained without detrimentally imparting the viscosity of hydrogel's precursors and the mechanical properties of the hydrogels. Compared with the incorporation of droplets without electrospinning, higher loadings of hydrophobic payload are achieved without premature leakage. This concept can be used to entrap hydrophobic agrochemicals, drugs, or antibacterial agents in simple hydrogels formulation.

Preparation of microporous melamine-based polymer networks in an anhydrous high-temperature miniemulsion.

We report the first example of a successful preparation of a microporous organic polymer within the droplet phase of an inverse non-aqueous miniemulsion. Stable nanoparticles with enhanced specific surface area could be obtained despite the harsh conditions regarding reaction temperature (180 °C) and time (72 h) needed for building melamine-based Schiff base networks. Our new flexible method can in principle be applied to other water-sensitive protocols suitable for the bulk synthesis of MOPs that are based on Friedel-Crafts, Sonogashira-Hagihara or Yamamoto chemistry.

Polymers with Hemiaminal Ether Linkages for pH-Responsive Antibacterial Materials.

Antibacterial materials containing biocides suffer from the fact that biocides are usually quickly released and hence display a limited antibacterial ability over a long period of time. To overcome this problem, the antibacterial agent 6-chloropurine is conjugated to a monomer via a hemiaminal ether linkage. The functional monomer is then reacted with a urethane acrylate by photopolymerization to yield thin polymer coatings. The release of the antibacterial agent from the coatings is sustained due to the slow kinetics of the hydrolysis of the hemiaminal ether linkage. Antibacterial performance is achieved against S. aureus and E. coli bacteria. This simple strategy can be applied for the rapid preparation of antibacterial coatings on various substrates and other applications such as antifouling or anticorrosion coatings.

Mapping the heterogeneity of protein corona by ex vivo magnetic levitation.

In the past decade, we witnessed limited success in the clinical translation of therapeutic nanoparticles (NPs). One of the main reasons for this limited success is our poor understanding of the biological identity of NPs. Herein, we report magnetic levitation (MagLev) as a complementary analytical tool to investigate the homogeneity of the created protein corona (PC) coated NPs through an ex vivo model. Our results demonstrate that the MagLev system not only has the capacity to separate corona coated NPs, but also enables us to study the homogeneity/heterogeneity of the PC. Our findings suggest that current ex vivo isolation methods cause a heterogeneous coverage of PC profiles at the surface of NPs. The MagLev technique, therefore, would be instrumental in identifying and separating fully PC coated NPs which, in turn, enables us to achieve more accurate information on protein corona composition. Ultimately, we believe that the MagLev technique can be used for the fast screening of the homogeneity of corona coated NPs before quantitative analysis of the corona profile/composition, hence definitely improving our fundamental understanding of nano-bio interfaces.

Synergy between polymer crystallinity and nanoparticles size for payloads release.

Drug delivery from polymer nanocarriers is usually achieved by designing polymers so that they release drugs by cleavage of labile bonds, or by preparing nanoparticles that swell or collapse in response to external stimuli. Herein, we unravel the importance of polymer crystallinity in release profiles of drugs encapsulated in polymer nanoparticles. Polycaprolactone, as a model biocompatible and biodegradable semi-crystalline polymer, was processed into nanoparticles by the miniemulsion-solvent evaporation technique. The crystallinity of the nanoparticles was controlled by the polymer concentration, size of nanoparticles, and the composition of mixtures with amorphous polymers such as poly(vinyl formal) and polystyrene. Crystallinity decreased significantly with decreasing nanoparticle diameter. Release profiles of drugs were found to be dependent on an interplay of nanoparticle size and crystallinity. Therefore, crystallinity can be used for tuning the release profiles of nanoparticles.

PEGylation of shellac-based nanocarriers for enhanced colloidal stability.

Shellac is a biomaterial obtained from secretion of lac insects. Nanoparticles based on shellac are prepared by nanoprecipitation and miniemulsion techniques. The corrosion inhibitor 2-mercaptobenzothiazole can be efficiently encapsulated in nanoparticles. Release kinetics of the inhibitor from the nanocarriers is controlled by pH of the surrounding environment as well as the introduction of other biopolymers such as lignin and zein. To overcome the low colloidal stability of shellac nanoparticles in saline conditions, shellac is conjugated with poly(ethylene glycol) moieties. After PEGylation, nanoparticles with higher critical aggregation concentration are obtained and provide release kinetics of 2-mercaptobenzothiazole similar to shellac nanoparticles.