Daniela A. Wilson

Self-Assembly of Janus Dendrimers into Uniform Dendrimersomes and Other Complex Architectures

Janus Drug Delivery Vehicle Efficient drug delivery vehicles need to be produced in a limited size range and with uniform size distribution. The self-assembly of traditional small-molecule and polymeric amphiphiles has led to the production of micelles, liposomes, polymeric micelles, and polymersomes for use in drug delivery applications. Now, Percec et al. (p. 1009) describe the self-assembly of Janus-type (i.e., two-headed) dendrimers to produce monodisperse supramolecular constructs, termed “dendrimersomes,” and other complex architectures. The structures, which showed long-term stability as well as very narrow size distributions, were easily produced by the injection of an ethanolic solution of the dendrimer into water. The dendrimersomes could be loaded with the anticancer drug doxorubicin and exhibited controlled drug release with changing pH. Amphiphilic, spherically shaped polymers self-assemble into larger hollow complexes that could be used for drug delivery. Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biological membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise molecular arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepared by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mechanical strength obtainable from polymersomes with the biological function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chemical functionalization. This modular synthesis strategy provides access to systematic tuning of molecular structure and of self-assembled architecture.

Autonomous movement of platinum-loaded stomatocytes

Polymer stomatocytes are bowl-shaped structures of nanosize dimensions formed by the controlled deformation of polymer vesicles. The stable nanocavity and strict control of the opening are ideal for the physical entrapment of nanoparticles which, when catalytically active, can turn the stomatocyte morphology into a nanoreactor. Herein we report an approach to generate autonomous movement of the polymer stomatocytes by selectively entrapping catalytically active platinum nanoparticles within their nanocavities and subsequently using catalysis as a driving force for movement. Hydrogen peroxide is free to access the inner stomatocyte cavity, where it is decomposed by the active catalyst (the entrapped platinum nanoparticles) into oxygen and water. This generates a rapid discharge, which induces thrust and directional movement. The design of the platinum-loaded stomatocytes resembles a miniature monopropellant rocket engine, in which the controlled opening of the stomatocytes directs the expulsion of the decomposition products away from the reaction chamber (inner stomatocyte cavity).

Modular synthesis of amphiphilic Janus glycodendrimers and their self-assembly into glycodendrimersomes and other complex architectures with bioactivity to biomedically relevant lectins

The modular synthesis of 7 libraries containing 51 self-assembling amphiphilic Janus dendrimers with the monosaccharides D-mannose and D-galactose and the disaccharide D-lactose in their hydrophilic part is reported. These unprecedented sugar-containing dendrimers are named amphiphilic Janus glycodendrimers. Their self-assembly by simple injection of THF or ethanol solution into water or buffer and by hydration was analyzed by a combination of methods including dynamic light scattering, confocal microscopy, cryogenic transmission electron microscopy, Fourier transform analysis, and micropipet-aspiration experiments to assess mechanical properties. These libraries revealed a diversity of hard and soft assemblies, including unilamellar spherical, polygonal, and tubular vesicles denoted glycodendrimersomes, aggregates of Janus glycodendrimers and rodlike micelles named glycodendrimer aggregates and glycodendrimermicelles, cubosomes denoted glycodendrimercubosomes, and solid lamellae. These assemblies are stable over time in water and in buffer, exhibit narrow molecular-weight distribution, and display dimensions that are programmable by the concentration of the solution from which they are injected. This study elaborated the molecular principles leading to single-type soft glycodendrimersomes assembled from amphiphilic Janus glycodendrimers. The multivalency of glycodendrimersomes with different sizes and their ligand bioactivity were demonstrated by selective agglutination with a diversity of sugar-binding protein receptors such as the plant lectins concanavalin A and the highly toxic mistletoe Viscum album L. agglutinin, the bacterial lectin PA-IL from Pseudomonas aeruginosa, and, of special biomedical relevance, human adhesion/growth-regulatory galectin-3 and galectin-4. These results demonstrated the candidacy of glycodendrimersomes as new mimics of biological membranes with programmable glycan ligand presentations, as supramolecular lectin blockers, vaccines, and targeted delivery devices.

A comparative study of the SET-LRP of oligo(ethylene oxide) methyl ether acrylate in DMSO and in H2O

A comparative analysis of the SET-LRP of oligo(ethylene oxide) methyl ether acrylate (OEOMEA) in DMSO and in H2O at 25 °C is reported. Both the catalysis with activated Cu(0) wire/Me6-TREN and with mimics of “nascent” Cu(0) nanoparticles/Me6-TREN resulted in a higher rate of polymerization in water than in DMSO. This result is consistent with the acceleration expected for SET-LRP by a more polar reaction solvent, and with the difference between the equilibrium constants of disproportionation of CuBr in DMSO (Kd = 1.4–4.4) and in water (Kd = 106 to 107), both much higher in the presence of Me6-TREN. The inefficient access of the Cu(0) catalyst to the hydrophobic reactive centers of the monomer and initiator assembled in micellar structures explains the induction time observed in the SET-LRP of OEOMEA in water. This induction period is longer for Cu(0) wire. The use of “nascent” Cu(0) nanoparticles prepared by the disproportionation of CuBr in DMSO, in combination with 5 mol% CuBr2, led to an extremely efficient SET-LRP of OEOMEA in water. This SET-LRP in water is fast and follows first order kinetics to complete monomer conversion with linear dependence of experimental Mn on conversion, and narrow molecular weight distribution. Under the polymerization conditions investigated in both water and DMSO, no reduction in the absorbance of CuBr2/Me6-TREN was observed by online UV-vis spectroscopy. This excludes the formation of CuBr by reduction of CuBr2 by Cu(0) during the SET-LRP in DMSO and in water.

Neopentylglycolborylation of aryl mesylates and tosylates catalyzed by Ni-based mixed-ligand systems activated with Zn.

The mixed-ligand system NiCl(2)(dppp)/dppf is shown to be an effective catalyst for the neopentylglycolborylation of ortho-, meta-, and para-substituted electron-rich and electron-deficient aryl mesylates and tosylates. The addition of Zn powder as a reductant dramatically increases the reaction yield and reduces the reaction time by more than an order of magnitude, providing complete conversion in 1-3 h.

Self-Assembly of Dendritic Crowns into Chiral Supramolecular Spheres

The synthesis and structural and retrostructural analysis of a library of dendronized cyclotriveratrylene containing seven nonchiral and seven chiral self-assembling dendrons is reported. These dendronized cyclotriveratrylenes exhibit a crown conformation that we named dendritic crown. Selected examples of dendritic crowns self-assemble into helical pyramidal columns that self-organize into columnar crystals or into 2-D columnar hexagonal lattices with intracolumnar order. A second group of dendritic crowns self-assembles into helical pyramidal columns and spherical supramolecular dendrimers that self-organize into cubic and tetragonal lattices. A third group of dendritic crowns self-assembles only in spherical supramolecular dendrimers. The helical pyramidal columns and spherical supramolecular dendrimers assembled from dendronized cyclotriveratrylene containing nonchiral dendrons are chiral but racemic while those generated from chiral dendrons exhibit amplified chirality. Structural analysis by a combination of X-ray diffraction methods and CD experiments demonstrated a new mechanism for the assembly of chiral supramolecular spheres that involves an intramolecular structure containing short fragments of helical pyramidal columns.

Micro- and nano-motors for biomedical applications

Micro- and nano-motors are a class of miniaturized man-made machines that are able to convert chemical or external energy into mechanical motion. The past decade has witnessed significant progress in the design and fabrication of micro- and nano-motors as a future intelligent and comprehensive biomedical platform. In this review we will critically assess the challenges and limitations of micro- and nano-motors, their mechanism of propulsion and applications in the biomedical field. Important insights into the future development and direction of nano-motors for improved biocompatibility and design will be discussed.

Transfer, amplification, and inversion of helical chirality mediated by concerted interactions of C3-supramolecular dendrimers.

The synthesis, structural, and retrostructural analysis of two libraries containing 16 first and second generation C(3)-symmetric self-assembling dendrimers based on dendrons connected at their apex via trisesters and trisamides of 1,3,5-benzenetricarboxylic acid is reported. A combination of X-ray diffraction and CD/UV analysis methods demonstrated that their C(3)-symmetry modulates different degrees of packing on the periphery of supramolecular structures that are responsible for the formation of chiral helical supramolecular columns and spheres self-organizable in a diversity of three-dimensional (3D) columnar, tetragonal, and cubic lattices. Two of these periodic arrays, a 3D columnar hexagonal superlattice and a 3D columnar simple orthorhombic chiral lattice with P222(1) symmetry, are unprecedented for supramolecular dendrimers. A thermal-reversible inversion of chirality was discovered in helical supramolecular columns. This inversion is induced, on heating, by the change in symmetry from a 3D columnar simple orthorhombic chiral lattice to a 3D columnar hexagonal array and, on cooling, by the change in symmetry from a 2D hexagonal to a 2D centered rectangular lattice, both exhibiting intracolumnar order. A first-order transition from coupled columns with long helical pitch, to weakly or uncorrelated columns with short helical pitch that generates a molecular rotator, was also discovered. The torsion angles of the molecular rotator are proportional to the change in temperature, and this effect is amplified in the case of the C(3)-symmetric trisamide supramolecular dendrimers forming H-bonds along their column. The structural changes reported here can be used to design complex functions based on helical supramolecular dendrimers with different degree of packing on their periphery.

Two-step, one-pot Ni-catalyzed neopentylglycolborylation and complementary Pd/Ni-catalyzed cross-coupling with aryl halides, mesylates, and tosylates.

Two-step, one-pot neopentylglycolborylation of aryl iodides and bromides catalyzed by NiCl2(dppe) and NiCl2(dppp) is reported. Electron-rich and electron-deficient aryl neopentylglycolboronates were efficiently cross-coupled with aryl iodides, bromides, chlorides, mesylates, and tosylates by exploiting complementary Pd/Ni and Ni/Ni catalysis. The borylation route was further extended to a three-step, one-pot synthesis of biaryls via in situ Ni-catalyzed borylation and Pd-mediated cross-coupling.

Dynamic Loading and Unloading of Proteins in Polymeric Stomatocytes: Formation of an Enzyme-Loaded Supramolecular Nanomotor

Self-powered artificial nanomotors are currently attracting increased interest as mimics of biological motors but also as potential components of nanomachinery, robotics, and sensing devices. We have recently described the controlled shape transformation of polymersomes into bowl-shaped stomatocytes and the assembly of platinum-driven nanomotors. However, the platinum encapsulation inside the structures was low; only 50% of the structures contained the catalyst and required both high fuel concentrations for the propelling of the nanomotors and harsh conditions for the shape transformation. Application of the nanomotors in a biological setting requires the nanomotors to be efficiently propelled by a naturally available energy source and at biological relevant concentrations. Here we report a strategy for enzyme entrapment and nanomotor assembly via controlled and reversible folding of polymersomes into stomatocytes under mild conditions, allowing the encapsulation of the proteins inside the stomach with almost 100% efficiency and retention of activity. The resulting enzyme-driven nanomotors are capable of propelling these structures at low fuel concentrations (hydrogen peroxide or glucose) via a one-enzyme or two-enzyme system. The confinement of the enzymes inside the stomach does not hinder their activity and in fact facilitates the transfer of the substrates, while protecting them from the deactivating influences of the media. This is particularly important for future applications of nanomotors in biological settings especially for systems where fast autonomous movement occurs at physiological concentrations of fuel.