Ying-Wei Yang

Enzyme-Responsive Snap-Top Covered Silica Nanocontainers

Mesoporous silica nanoparticles, capable of storing a payload of small molecules and releasing it following specific catalytic activation by an esterase, have been designed and fabricated. The storage and release of the payload is controlled by the presence of [2]rotaxanes, which consist of tri(ethylene glycol) chains threaded by α-cyclodextrin tori, located on the surfaces of the nanoparticles and terminated by a large stoppering group. These modified silica nanoparticles are capable of encapsulating guest molecules when the [2]rotaxanes are present. The bulky stoppers, which serve to hold the tori in place, are stable under physiological conditions but are cleaved by the catalytic action of an enzyme, causing dethreading of the tori and release of the guest molecules from the pores of the nanoparticles. These snap-top covered silica nanocontainers (SCSNs) are prepared by a modular synthetic method, in which the stoppering unit, incorporated in the final step of the synthesis, may be changed at will to target the response of the system to any of a number of hydrolytic enzymes. Here, the design, synthesis, and operation of model SCSNs that open in the presence of porcine liver esterase (PLE) are reported. The empty pores of the silica nanoparticles were loaded with luminescent dye molecules (rhodamine B), and stoppering units that incorporate adamantyl ester moieties were then attached in the presence of α-cyclodextrin using the copper-catalyzed azide−alkyne cycloaddition (CuAAC), closing the SCSNs. The release of rhodamine-B from the pores of the SCSN, following PLE-mediated hydrolysis of the stoppers, was monitored using fluorescence spectroscopy.

pH-responsive supramolecular nanovalves based on cucurbit[6]uril pseudorotaxanes

The ability to control the release of molecules from mesoporous silica nanoparticles promises to have far-reaching consequences for drug-delivery applications. Both molecular and supramolecular nanovalves, which regulate the release of guest molecules from nanopores of mesostructured silica nanoparticles, and operate under a range of stimuli including pH, competitive binding, light, and redox control, have been designed and their successful operation demonstrated in organic solvents. These systems are based upon the switching of components that have been tethered to the nanoparticle surfaces, such that access to the entrances of the nanopores can be opened and gated on demand. Since most of the traditional nanovalve designs have been based on [2]pseudorotaxanes and bistable [2]rotaxanes that rely upon donor–acceptor and hydrogen-bonding interactions between the ring and stalk components, they are limited largely to use in organic solvents. However, to realize the potential of nanovalves in therapeutic applications, it is imperative that they not only employ biocompatible components but that they also operate under physiological conditions. For nanovalves to be viable in biological environments, a recognition and binding motif which operates in aqueous media has to be identified, and then tried and tested. Herein, we describe a pH-responsive nanovalve that relies on the ion–dipole interaction between cucurbit[6]uril (CB[6]) and bisammonium stalks, and operates in water. CB[6], a pumpkin-shaped polymacrocycle with D6h symmetry consisting of six glycouril units strapped together by pairs of bridging methylene groups between nitrogen atoms, has received considerable attention because of its highly distinctive range of physical and chemical properties. Of particular interest in the field of supramolecular chemistry is the ability of CB[6] to form inclusion complexes with a variety of polymethylene derivatives, especially diaminoalkanes: the stabilities of these 1:1 complexes are highly pHdependent. The pH-dependent complexation/decomplexation behavior of CB[6] with diaminoalkanes has enabled the preparation of dynamic supramolecular entities which can be controlled by pH. Another important characteristic of CB[6] is its ability to catalyze 1,3-dipolar cycloadditions, such that the reaction between an azide-substituted ammonium ion and an alkyne-containing ammonium ion yields a disubstituted 1,2,3-triazole derivative encircled by a CB[6] ring. In view of these particular properties of CB[6], we set about to employ it as a catalyst for the formation of monolayers of [2]pseudorotaxanes on the surfaces of mesoporous silica nanoparticles so as to generate ultimately pHresponsive, biocompatible nanovalves capable of executing different missions. Mesoporous silica has proven to be an excellent support for the formation of dynamic nanosystems, including nanovalves, because it is chemically stable and optically transparent. In this current study, [2]pseudorotaxanes consisting of bisammonium stalks and CB[6] rings were constructed (Figure 1a,b) on the surface of mesoporous silica nanoparticles, and the pH-dependent binding of CB[6] with the bisammonium stalks is exploited to control the release of guest molecules from the pores of the silica nanoparticles. At neutral and acidic pH values, the CB[6] rings encircle the bisammonium stalks tightly, thereby blocking the nanopores efficiently when employing tethers of suitable lengths. Deprotonation of the stalks upon addition of base results in spontaneous dethreading (Figure 1b,c) of the CB[6] rings and unblocking of the silica nanopores. The silica supports employed were approximately 400nm-diameter spherical particles which contain ordered 2D hexagonal arrays of tubular pores (pore diameters of ca. 2 nm with a lattice spacing of ca. 4 nm) prepared by using a basecatalyzed sol–gel method. The nanopores were templated by cetyltrimethylammonium bromide (CTAB) surfactants, and tetraethylorthosilicate (TEOS) was used as the silica precursor. Empty nanopores were obtained by removal of the templating agents by solvent extraction. The ordered structure and particle morphology were confirmed (Figure 2) by X-ray diffraction (XRD) and scanning electron microscopy. This system was designed (Scheme 1a) such that the nanovalve components could be assembled in a stepwise, divergent manner from the nanoparticle surface outwards. Following solvent extraction, the nanoparticles were heated under reflux in an aminopropyltriethoxysilane (APTES) solution, which afforded the amino-modified nanoparticles 1. These nanoparticles were recovered by vacuum filtration [*] S. Angelos, Dr. Y.-W. Yang, K. Patel, Prof. J. F. Stoddart, Prof. J. I. Zink California NanoSystems Institute and Department of Chemistry and Biochemistry University of California, Los Angeles 405 Hilgard Avenue, Los Angeles, CA 90095-1569 (USA) Fax: (+1)310-206-1843 E-mail: stoddart@chem.ucla.edu zink@chem.ucla.edu Homepage: http://stoddart.chem.ucla.edu http://www.chem.ucla.edu/dept/Faculty/jzink/ [] These authors have contributed equally and both should be considered first author.

Viologen-Mediated Assembly of and Sensing with Carboxylatopillar[5]arene-Modified Gold Nanoparticles

Carboxylatopillar[5]arene (CP[5]A), a new water-soluble macrocyclic synthetic receptor, has been employed as a stabilizing ligand for in situ preparation of gold nanoparticles (AuNPs) to gain new insights into supramolecular host-AuNP interactions. CP[5]A-modified AuNPs with good dispersion and narrow size distributions (3.1 ± 0.5 nm) were successfully produced in aqueous solution, suggesting a green synthetic pathway for the application of AuNPs in biological systems. Supramolecular self-assembly of CP[5]A-modified AuNPs mediated by suitable guest molecules was also investigated, indicating that the new hybrid material is useful for sensing and detection of the herbicide paraquat.

pH Clock-Operated Mechanized Nanoparticles

Mechanized nanoparticles (MNPs) consisting of supramolecular machines attached to the surface of mesoporous silica nanoparticles are designed to release encapsulated guest molecules controllably under pH activation. The molecular machines are comprised of cucurbit[6]uril (CB[6]) rings that encircle tethered trisammonium stalks and can be tuned to respond under specific pH conditions through chemical modification of the stalks. Luminescence spectroscopy demonstrates that the MNPs are able to contain guest molecules within nanopores at neutral pH levels and then release them once the pH is lowered or raised.

Dual-Controlled Nanoparticles Exhibiting AND Logic

Dual-controlled nanoparticles (DCNPs) are synthesized by attaching two different types of molecular machines, light-responsive nanoimpellers and pH-responsive nanovalves, to different regions of mesoporous silica nanoparticles. Nanoimpellers are based on azobenzene derivatives that are tethered to the nanopore interiors, while nanovalves are based on [2]pseudorotaxanes that are tethered to the nanoparticle surfaces. The different molecular machines operate through separate mechanisms to control the release of guest molecules that are loaded into the nanopores. When used in conjunction with one another, a sophisticated controllable release system behaving as an AND logic gate is obtained.

A Mechanical Actuator Driven Electrochemically by Artificial Molecular Muscles

A microcantilever, coated with a monolayer of redox-controllable, bistable [3]rotaxane molecules (artificial molecular muscles), undergoes reversible deflections when subjected to alternating oxidizing and reducing electrochemical potentials. The microcantilever devices were prepared by precoating one surface with a gold film and allowing the palindromic [3]rotaxane molecules to adsorb selectively onto one side of the microcantilevers, utilizing thiol-gold chemistry. An electrochemical cell was employed in the experiments, and deflections were monitored both as a function of (i) the scan rate (< or =20 mV s(-1)) and (ii) the time for potential step experiments at oxidizing (>+0.4 V) and reducing (<+0.2 V) potentials. The different directions and magnitudes of the deflections for the microcantilevers, which were coated with artificial molecular muscles, were compared with (i) data from nominally bare microcantilevers precoated with gold and (ii) those coated with two types of control compounds, namely, dumbbell molecules to simulate the redox activity of the palindromic bistable [3]rotaxane molecules and inactive 1-dodecanethiol molecules. The comparisons demonstrate that the artificial molecular muscles are responsible for the deflections, which can be repeated over many cycles. The microcantilevers deflect in one direction following oxidation and in the opposite direction upon reduction. The approximately 550 nm deflections were calculated to be commensurate with forces per molecule of approximately 650 pN. The thermal relaxation that characterizes the devices deflection is consistent with the double bistability associated with the palindromic [3]rotaxane and reflects a metastable contracted state. The use of the cooperative forces generated by these self-assembled, nanometer-scale artificial molecular muscles that are electrically wired to an external power supply constitutes a seminal step toward molecular-machine-based nanoelectromechanical systems (NEMS).

Mechanized Silica Nanoparticles Based on Pillar[5]arenes for On-Command Cargo Release

Mechanized silica nanoparticles, equipped with pillar[5]arene-[2]pseudorotaxane nanovalves, operate in biological media to trap cargos within their nanopores, but release them when the pH is lowered or a competitive binding agent is added. Although cargo size plays an important role in cargo loading, cargo charge-type does not appear to have any significant influence on the amount of cargo loading or its release. These findings open up the possibility of using pillar[n]arene and its derivatives for the formation of robust and dynamic nanosystems that are capable of performing useful functions.

Metal–Organic Framework (MOF)-Based Drug/Cargo Delivery and Cancer Therapy

Metal-organic frameworks (MOFs)-an emerging class of hybrid porous materials built from metal ions or clusters bridged by organic linkers-have attracted increasing attention in recent years. The superior properties of MOFs, such as well-defined pore aperture, tailorable composition and structure, tunable size, versatile functionality, high agent loading, and improved biocompatibility, make them promising candidates as drug delivery hosts. Furthermore, scientists have made remarkable achievements in the field of nanomedical applications of MOFs, owing to their facile synthesis on the nanoscale and alternative functionalization via inclusion and surface chemistry. A brief introduction to the applications of MOFs in controlled drug/cargo delivery and cancer therapy that have been reported in recent years is provided here.

Acid−Base Actuation of [c2]Daisy Chains

A versatile synthetic strategy, which was conceived and employed to prepare doubly threaded, bistable [c2]daisy chain compounds, is described. Propargyl and 1-pentenyl groups have been grafted onto the stoppers of [c2]daisy chain molecules obtained using a template-directed synthetic protocol. Such [c2]daisy chain molecules undergo reversible extension and contraction upon treatment with acid and base, respectively. The dialkyne-functionalized [c2]daisy chain (AA) was subjected to an [AA+BB] type polymerization with an appropriate diazide (BB) to afford a linear, mechanically interlocked, main-chain polymer. The macromolecular properties of this polymer were characterized by chronocoulometry, size exclusion chromatography, and static light-scattering analysis. The acid-base switching properties of both the monomers and the polymer have been studied in solution, using (1)H NMR spectroscopy, UV/vis absorption spectroscopy, and cyclic voltammetry. The experimental results demonstrate that the functionalized [c2]daisy chains, along with their polymeric derivatives, undergo quantitative, efficient, and fully reversible switching processes in solution. Kinetics measurements demonstrate that the acid/base-promoted extension/contraction movements of the polymeric [c2]daisy chain are actually faster than those of its monomeric counterpart. These observations open the door to correlated molecular motions and to changes in material properties.

Towards biocompatible nanovalves based on mesoporous silica nanoparticles

Over the past two decades, cancer has ascended to become the number one or two cause of death in many nations worldwide. Encapsulation of anticancer drugs within nanocarriers that selectively target diseased cells promises to increase the effectiveness of conventional chemotherapy and decrease its side effects. Nanoparticles show great potential as superior intelligent drug delivery platforms. Among them, mesoporous silica nanoparticles (MSNs) are particularly interesting candidates for powerful drug carriers because of their unique characteristics and abilities to efficiently and specifically entrap cargo molecules. The biggest challenge in current development is the design and synthesis of controlled biocompatible nanovalves or cap systems on MSNs to realize “zero premature release” of drugs and targeted delivery of anticancer drugs in a controlled fashion for “smart” cancer therapies. This review article evaluates drug delivery systems which comprise MSNs functionalized with well-defined self-assembled layers of biocompatible molecular and supramolecular nanovalves based on (supra)molecular switches, polymers, and biomolecules. Recent research progress on MSN-based smart materials that can simultaneously address targeted delivery of anticancer drugs, ideally “zero premature release”, and controlled release by external physical, chemical and biological stimuli will be highlighted and discussed.