Yohei Kotsuchibashi

Bioinspired nanoarchitectonics as emerging drug delivery systems

We propose an important paradigm shift in the preparation of functional materials with well-designed nanostructures, from the nanotechnological to the nanoarchitectonic approach. Nanoarchitectonics is a methodology for arranging nanoscale structural units in the required configurations for new functional materials by the sophisticated combination and harmonization of several processes including atom/molecule manipulation, chemical nanomanipulation, field-induced materials control and controlled supramolecular self-assembly. In particular, nanoarchitectonics bears features of nanoscale phenomena including their flexibility and uncertainty of structure due to the unavoidable influence of thermal fluctuation. It shares characteristics with structural constructions in biological systems and could become a powerful bioinspired approach for materials science. Here, we focus on examples involving drug delivery functions due to these promising applications of bioinspired materials research. We commence with a discussion of recent developments involving assemblies of small amphiphilic molecules, polymer micelles and molecular conjugates and follow this with examples of challenging concepts including inorganic nanostructure design for drug delivery and mechanically controlled drug release. The new concept of bioinspired nanoarchitectonics could significantly expand the possibilities of systems design for drug delivery.

Fabrication of doubly responsive polymer functionalized silica nanoparticles via a simple thiol–ene click chemistry

Temperature and pH responsive silica nanoparticles were easily prepared by a simple thiol–ene click chemistry. Well-defined poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) and poly(N-isopropylacrylamide) (PNIPAAm) were first synthesized by a reversible addition–fragmentation chain transfer (RAFT) process. The polymers were then reduced to generate a thiol group at the chain end to react with vinyl groups on the surface of silica nanoparticles via a simple ‘click’ reaction. The ratio of the PDEAEMA and PNIPAAm segments on the silica nanoparticles surface was controlled by adjusting the feed weight ratios of the polymers in the reaction solution. The surface coated silica nanoparticles were characterized by a range of techniques such as thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The functionalized silica nanoparticles showed both pH and temperature responsive behavior and the solution properties were dependent on the ratio of the two polymers on the surface.

Temperature-Responsive Hyperbranched Amine-Based Polymers for Solid–Liquid Separation

Temperature-responsive hyperbranched polymers containing primary amines as pendent groups have been synthesized for solid-liquid separation of kaolinite clay suspension. The effects of temperature, polymer charge density, and polymer architecture on particle flocculation have been investigated. Suspensions treated with the temperature-responsive amine-based hyperbranched polymers showed remarkable separation of the fine particles at a low polymer dosage of 10 ppm and at testing temperatures of 40 °C. In comparison to other polymers studied (linear and hyperbranched homopolymers and copolymers), the temperature-responsive amine-based hyperbranched copolymers showed better particle flocculation at 40 °C, as evidenced by the formation of a thinner sediment bed without compromising the amount of clay particles being flocculated. This superior solid-liquid separation performance can be explained by the hydrophobic interaction of PNIPAM segments on particle surfaces or the capture of additional free particles or small floc due to the exposure of buried positive charges (because of the phase separation of the hydrophilic amines and hydrophobic PNIPAM part) at temperatures above the lower critical solution temperature (LCST).

Novel temperature-responsive polymer brushes with carbohydrate residues facilitate selective adhesion and collection of hepatocytes

Abstract Temperature-responsive glycopolymer brushes were designed to investigate the effects of grafting architectures of the copolymers on the selective adhesion and collection of hypatocytes. Homo, random and block sequences of N-isopropylacrylamide and 2-lactobionamidoethyl methacrylate were grafted on glass substrates via surface-initiated atom transfer radical polymerization. The galactose/lactose-specific lectin RCA120 and HepG2 cells were used to test for specific recognition of the polymer brushes containing galactose residues over the lower critical solution temperatures (LCSTs). RCA120 showed a specific binding to the brush surfaces at 37 °C. These brush surfaces also facilitated the adhesion of HepG2 cells at 37 °C under nonserum conditions, whereas no adhesion was observed for NIH-3T3 fibroblasts. When the temperature was decreased to 25 °C, almost all the HepG2 cells detached from the block copolymer brush, whereas the random copolymer brush did not release the cells. The difference in releasing kinetics of cells from the surfaces with different grafting architectures can be explained by the correlated effects of significant changes in LCST, mobility, hydrophilicity and mechanical properties of the grafted polymer chains. These findings are important for designing ‘on–off’ cell capture/release substrates for various biomedical applications such as selective cell separation.

Recent Advances in Dual Temperature Responsive Block Copolymers and Their Potential as Biomedical Applications

The development of stimuli responsive polymers has progressed significantly with novel preparation techniques, which has allowed access to new materials with unique properties. Dual thermoresponsive (double temperature responsive) block copolymers are particularly of interest as their properties can change depending on the lower critical solution temperature (LCST) or upper critical solution temperature (UCST) of each segment. For instance, these block copolymers can change from being hydrophilic, to amphiphilic or to hydrophobic simply by changing the solution temperature without any additional chemicals and the block copolymers can change from being fully solubilized to self-assembled structures to macroscopic aggregation/precipitation. Based on the unique solution properties, these dual thermo-responsive block copolymers are expected to be suitable for biomedical applications. This review is divided into three parts; LCST-LCST types of block copolymers, UCST-LCST types of block copolymers, and their potential as biomedical applications.

Construction of ‘smart’ surfaces with polymer functionalized silica nanoparticles

Silica nanoparticles (SiNPs) coated with the pH responsive poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) shells have been synthesized in different sizes using surface-initiated atom transfer radical polymerization (ATRP). A mixture of the PDEAEMA functionalized SiNPs (20 and 128 nm) was found to efficiently change the surface property of a substrate. The surface properties were investigated at different ratios of functionalized SiNPs. Moreover, fluorescent-doped SiNPs with PDEAEMA were also prepared to study the adsorption/desorption behavior of the SiNPs on the substrates at different pHs. A Surface Forces Apparatus (SFA) was used to measure the interactions between PDEAEMA surfaces in aqueous solutions of different pHs, and the force–distance profiles directly indicate that the intermolecular interactions of PDEAEMA are pH sensitive. At pH < pKa (∼7.3) steric repulsion dominates while at pH ≥ pKa the hydrophobic attraction between PDEAEMA molecules plays a critical role in their molecular behaviors in solutions and on surfaces. Our results provide a new insight into the fundamental understanding and development of environmentally responsive and multifunctional surfaces and nanomaterials.

A ‘smart’ approach towards the formation of multifunctional nano-assemblies by simple mixing of block copolymers having a common temperature sensitive segment

A smart approach has been developed to form nanoassemblies with tunable shells functions by simply mixing three different block copolymers with a common temperature-responsive segment at 25 °C. The formation of nanoassemblies and their thermodynamic stability are driven by the hydrophobic interaction of the common poly(N-isopropylacrylamide-co-N-(isobutoxymethyl)acrylamide) (P(NIPAAm-co-BMAAm)) segment which has a lower critical solution temperature (LCST) below 25 °C. Three series of copolymers with different polymer structures, acrylamide-type P(NIPAAm-co-N-(hydroxymethyl)acrylamide (HMAAm))-b-P(NIPAAm-co-BMAAm), poly(ethylene oxide) (PEO)-b-P(NIPAAm-co-BMAAm), and methacrylate-type poly(2-lactobionamidoethyl methacrylate) (PLAMA)-b-P(NIPAAm-co-HMAAm)-b-P(NIPAAm-co-BMAAm), were successfully polymerized by reversible addition–fragmentation chain transfer (RAFT) polymerization. Regardless of the block copolymer types the selected block copolymers successfully formed a stable core–shell assembly with the collapsed common segments forming the inner core by simple mixing in aqueous solutions. The size distributions were monodisperse and relatively narrow when all or two of these three block copolymers were mixed, while addition of free-copolymers without the common segment did not affect the assembly formation. The ratio of functional segments into shell could be easily tuned by changing the mixing ratio of three block copolymers. This system is highly expected to find use as smart nano-carriers for encapsulation, targeting, and triggered release of drug under control through a combination of temperature-responsive chains, accessible functionality, and choice of sugar moiety.

Spatiotemporal Control of Synergistic Gel Disintegration Consisting of Boroxole- and Glyco-Based Polymers via Photoinduced Proton Transfer

We demonstrate here a local- and remote-control of gel disintegration by using photoinduced proton transfer chemistry of photoacid generator (PAG). The gels were prepared by simply mixing two polymers, poly(N-isopropylacrylamide-co-5-methacrylamido-1,2-benzoxaborole) (P(NIPAAm-co-MAAmBO)) and poly(3-gluconamidopropyl methacrylamide) (PGAPMA) via the synergistic interaction of benzoxaborole and diol groups. The o-nitrobenzaldehyde (o-NBA) was then loaded into the gel as a PAG. The benzoxaborole-diol interaction was successfully disintegrated upon UV irradiation due to the local pH decrease inside the gel. When the gel was irradiated to a specific gel region, the synergistic interactions were disintegrated only at the exposed region. Of special interest is that the whole material eventually transitioned from gel to sol state, as the generated protons diffused gradually toward the nonilluminated region. The ability of the proposed gel-sol transition system via photoinduced proton diffusion may be beneficial for not only prompt pH changes within the gel but also the design of predictive and programmable devices for drug delivery.

Simple Coating with pH-Responsive Polymer-Functionalized Silica Nanoparticles of Mixed Sizes for Controlled Surface Properties

Different-sized silica nanoparticles (SiNPs) were functionalized by pH-responsive poly(2-(diisopropylamino)ethyl methacrylate) (PDP) via surface-initiated atom transfer radical polymerization (ATRP). The functionalized PDP-SiNPs were used to coat glass surfaces, polymeric nanofibers, and paper via simple coating methods such as dip, cast, and spray coating. A PDP-SiNPs mixture having different sizes was found to change the surface properties of the substrates remarkably, compared to one containing PDP-SiNPs with uniform sizes. High surface roughness was achieved with very little coating materials, which is beneficial from an economical point of view. Moreover, adsorption/desorption of PDP-SiNPs onto/from the substrates could be controlled by changing solution pH due to the protonation/deprotonation of the PDP. The surface properties of the coated substrates were analyzed by contact angle (CA) measurement, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). This inexpensive system provides a simple, quick, and effective approach to changing the surface properties of substrates that could be exploited for large-scale surface modification.

Study of Bacterial Adhesion on Biomimetic Temperature Responsive Glycopolymer Surfaces

Pseudomonas aeruginosa is an opportunistic pathogen responsible for diseases such as bacteremia, chronic lung infection, and acute ulcerative keratitis. P. aeruginosa induced diseases can be fatal as the exotoxins and endotoxins released by the bacterium continue to damage host tissues even after the administration of antibiotics. As bacterial adhesion on cell surfaces is the first step in bacterial based pathogen infections, the control of bacteria-cell interactions is a worthwhile research target. In this work, thermally responsive poly(N-isopropylacrylamide) [P(NIPAAm)] based biomimetic surfaces were developed to study the two major bacterial infection mechanisms, which is believed to be mediated by hydrophobic or lectin-carbohydrate interactions, using quartz crystal microbalance with dissipation. Although, a greater number of P. aeruginosa adhered to the NIPAAm homopolymer modified surfaces at temperatures higher than the lower critical solution temperature (LCST), the bacterium-substratum bond stiffness was stronger between P. aeruginosa and a galactose based P(NIPAAm) surface. The high bacterial adhesion bond stiffness observed on the galactose based thermally responsive surface at 37 °C might suggest that both hydrophobic and lectin-carbohydrate interactions contribute to bacterial adhesion on cell surfaces. Our investigation also suggests that the lectin-carbohydrate interaction play a significant role in bacterial infections.