J.C.M. van Hest

Polystyrene-dendrimer amphiphilic block copolymers with a generation-dependent aggregation.

A class of amphiphilic macromolecules has been synthesized by combining well-defined polystyrene (PS) with poly(propylene imine) dendrimers. Five different generations, from PS-dendr-NH2 up to PS-dendr-(NH2)32, were prepared in yields of 70 to 90 percent. Dynamic light scattering, conductivity measurements, and transmission electron microscopy show that in aqueous phases, PS-dendr-(NH2)32 forms spherical micelles, PS-dendr-(NH2)16 forms micellar rods, and PS-dendr-(NH2)8 forms vesicular structures. The lower generations of this class of macromolecules show inverted micellar behavior. The observed effect of amphiphile geometry on aggregation behavior is in qualitative agreement with the theory of Israelachvili et al. The amphiphiles presented here are similar in shape but different in size as compared with traditional surfactants, whereas they are similar in size but different in shape as compared with traditional block copolymers.

Elastin-like polypeptide based nanoparticles: design rationale toward nanomedicine

Elastin-like polypeptides (ELPs) are characterized by a high sequence control, temperature responsiveness and biocompatibility, which make them highly interesting as smart materials for application in nanomedicine. In particular the construction of ELP-based nanoparticles has recently become a focal point of attention in materials research. This review will give an overview of the ELP-based nanoparticles that have been developed until now and their underlying design principles. First a short introduction on ELPs and their stimulus-responsive behavior will be given. This characteristic has been applied for the development of ELP-based block copolymers that can self-assemble into nanoparticles. Both the fully ELP-based as well as several ELP hybrid materials that have been reported to form nanoparticles will be discussed, which is followed by a concise description of the promising biomedical applications reported for this class of materials.

Block copolymer vesicles

Amphiphilic block copolymers have the ability to assemble into multiple morphologies in solution. Depending on the length of the hydrophilic block, the morphology can vary from spherical micelles, rods, and vesicles to large compound micelles (LCMs). Vesicle formation is favored upon an increase in total molecular weight of the block copolymer, that is, an increasing bending modulus (K). Owing to the polymeric character of this type of vesicle (also called polymersomes), they possess remarkable properties. The diffusion of (polymeric) amphiphiles in these vesicles is very low compared to liposomes and for high-molecular-weight chain entanglements even lead to reptation-type motions, which make it possible to trap near-equilibrium and metastable morphologies. Additionally, in contrast to liposomes, membrane thicknesses can exceed 200 nm. As a consequence, this increased membrane thickness, in combination with the conformational freedom of the polymer chains, leads to a much lower permeability for water of block copolymer vesicles compared to liposomes. The enhanced toughness and reduced permeability of polymersomes makes them, therefore, very suitable as stable nanocontainers, which can be used, for example, as reactors or drug delivery vehicles.

Flash Chemistry Extensively Optimized: High-Temperature Swern–Moffatt Oxidation in an Automated Microreactor Platform

The generally accepted benefits of small lateral dimensions of microreactors (1 microm to 1 mm) enable a different way of performing synthetic chemistry: Extremely short contact times in the millisecond range can circumvent the need for performing highly exothermic and fast reactions at very low temperatures. In order to fully exploit this technology, such fast processes need to be redesigned and investigated for optimal reaction conditions, which can differ drastically from the ones traditionally applied. In a comprehensive study, we optimized the selective Swern-Moffatt oxidation of benzyl alcohol to benzaldehyde by varying five experimental parameters, including reaction time and temperature. Employing an ultrashort mixing and reaction time of only 32 ms, the optimal temperature was determined to be 70 degrees C, approximately 150 degrees C higher than in the conventional batch conditions. This remarkable difference shows both the potency of continuous-flow chemistry as well as the urgency of a paradigm shift in reaction design for continuous-flow conditions.

Permeability effects on the efficiency of antioxidant nanoreactors.

Enzyme-loaded polymeric vesicles, or polymersomes, can be regarded as nanoreactors, which, for example, can be applied as artificial organelles. We implemented a naturally occurring enzymatic cascade reaction in two types of polymersomes, which are known to possess different permeability properties. The selected cascade reaction involved the antioxidant enzymes superoxide dismutase (SOD1) and catalase (CAT) for combating oxidative stress. The activities of both enzymes were investigated by spectrophotometric and electrochemical assays. Whereas the SOD1 substrate (the radical anion superoxide, O2•-) was able to penetrate both membranes equally well, the CAT substrate (H2O2) showed different rates of diffusion. When O2•- was generated inside polymersomes filled with both SOD1 and CAT, the activities of the two systems were comparable again.

Site-specific immobilization of DNA in glass microchannels via photolithography

For the first time, a microchannel was photochemically patterned with a functional linker. This simple method was developed for the site-specific attachment of DNA via this linker onto silicon oxide surfaces (e.g., fused silica and borosilicate glass), both onto a flat surface and onto the inside of a fused silica microchannel. Sharp boundaries in the micrometer range between modified and unmodified zones were demonstrated by the attachment of fluorescently labeled DNA oligomers. Studies of repeated hybridization-dehybridization cycles revealed selective and reversible binding of cDNA strands at the explicit locations. On average, approximately 7 x 10(11) fluorescently labeled DNA molecules were hybridized per square centimeter. The modified surfaces were characterized with X-ray photoelectron spectroscopy, infrared microscopy, static contact angle measurements, confocal laser scanning microscopy, and fluorescence detection (to quantify the attachment of the fluorescently labeled DNA).

Biosynthesis of an amphiphilic silk-like polymer

An amphiphilic silk-like protein polymer was efficiently produced in the yeast Pichia pastoris. The secreted product was fully intact and was purified by solubilization in formic acid and subsequent precipitation of denatured host proteins upon dilution with water. In aqueous alkaline solution, the negatively charged acidic polymer assumed extended helical (silk III-like) and unordered conformations. Upon subsequent drying, it assumed a conformation rich in beta-turns. In water at low pH, the uncharged polymer aggregated and the solution became turbid. Concentrated solutions in 70% (v/v) formic acid slowly formed gels. Replacement of the formic acid-water mixture with methanol and subsequent drying resulted in beta-sheets, which stacked into fibril-like structures. The novel polymer instantaneously lowered the air-water interfacial tension under neutral to alkaline conditions and reversed the polarity of hydrophobic and hydrophilic solid surfaces upon adsorption.

Strain-Promoted Oxidation-Controlled Cyclooctyne–1,2-Quinone Cycloaddition (SPOCQ) for Fast and Activatable Protein Conjugation

A main challenge in the area of bioconjugation is to devise reactions that are both activatable and fast. Here, we introduce a temporally controlled reaction between cyclooctynes and 1,2-quinones, induced by facile oxidation of 1,2-catechols. This so-called strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) shows a remarkably high reaction rate when performed with bicyclononyne (BCN), outcompeting the well-known cycloaddition of azides and BCN by 3 orders of magnitude, thereby allowing a new level of orthogonality in protein conjugation.

Synthesis and self-assembly of well-defined elastin-like polypeptide–poly(ethylene glycol) conjugates

A series of stimulus-responsive elastin-like polypeptide-poly(ethylene glycol) (ELP-PEG) block copolymers was synthesized. The polymeric building blocks were conjugated via the efficient and specific strain-promoted alkyne-azide cycloaddition (SPAAC). For this purpose, ELP and PEG blocks were functionalized with azide and cyclooctyne moieties, respectively. Azides were introduced by applying a recently developed pH-controlled diazotransfer reaction on the primary amines present in ELP (N-terminus and lysine side chains). By varying pH, ELP-blocks with one or two azides were obtained, which subsequently allowed us to synthesize both ELP-PEG diblock copolymers and miktoarm star polymers. Triggering the phase transition of the ELP-block resulted in the formation of an amphiphilic block copolymer, which self-assembled into micelles. This is the first example of an ELP-containing hybrid block copolymer in which PEG as the hydrophilic corona-forming domain is combined with a stimulus-responsive ELP-block. The encapsulation of a hydrophobic fluorescent dye was shown to exemplify the potential of the micelles to serve as nanocarriers for hydrophobic drugs, with the PEG corona providing stealth and steric protection of encapsulated materials.

Polymersome magneto-valves for reversible capture and release of nanoparticles

Stomatocytes are polymersomes with an infolded bowl-shaped architecture. This internal cavity is connected to the outside environment via a small ‘mouth’ region. Stomatocytes are assembled from diamagnetic amphiphilic block-copolymers with a highly anisotropic magnetic susceptibility, which permits to magnetically align and deform the polymeric self-assemblies. Here we show the reversible opening and closing of the mouth region of stomatocytes in homogeneous magnetic fields. The control over the size of the opening yields magneto-responsive supramolecular valves that are able to reversibly capture and release cargo. Furthermore, the increase in the size of the opening is gradual and starts at fields below 10 T, which opens the possibility of using these structures for delivery and nanoreactor applications.