Pillararene-Based Supramolecular Vesicles for Stimuli-Responsive Drug Delivery.

Supramolecular vesicles (SMVs) self-assembled from the supra-amphiphiles, consisting of two scaffolds linked together through noncovalent interactions, can realize stimuli-responsive controlled release of encapsulated drugs for enhanced therapeutic efficacy and minimized side effect of drugs. Pillararenes (PAs), an emerging kind of macrocyclic hosts in 2008, are easy to modify with a variety of functionalities. SMVs from PAs and specific guests mainly based on the host-guest interactions have attracted increasing attention because of their drug delivery and controlled drug release. A great progress in the construction and stimuli-responsive drug delivery of the PA-based SMVs has been made since the first work was reported in 2012. This review summarizes the major achievements of the PA-based SMVs for stimuli-responsive drug delivery over the past 5 years, including the microstructures of SMVs, multiple stimuli-responsive SMVs, prodrug SMVs from prodrug PAs and guests, bola-type SMVs, multifunctional SMVs, glucose-responsive SMVs for insulin delivery, novel SMVs from responsive PAs, thermo-responsive SMVs, and ternary SMVs, for chemotherapy, photothermal therapy, photodynamic therapy, and other biological applications. The future challenges and research directions of PA-based SMVs are also outlined from the points of views of the fundamental research, biological applications, and clinical applications of PA-based SMVs.

Creation of glycoprotein imprinted self-assembled monolayers with dynamic boronate recognition sites and imprinted cavities for selective glycoprotein recognition.

Glycoproteins are involved in the pathogenesis and development of many diseases and are used as biomarkers for disease diagnosis. It is highly desirable to develop highly sensitive and selective methods for the detection of glycoproteins without the use of antibodies. Imprinting of proteins represents one of the most challenging tasks. Glycoprotein imprinted self-assembled monolayers (SAMs) were created, for the first time, from an oligo(ethylene glycol) (OEG) terminated 1,2-dithiolane derivative linked through an alkyl chain incorporated with two amide groups (DHAP) and combined functional thiols of p-mercaptophenylboronic acid (PMBA) and p-aminothiophenol (PATP) in aqueous media, without the use of polymerization initiators. Combined action of PMBA and PATP was essential for the development of boronate recognition sites for glycoproteins at the physiological pH, attributed to the water molecule-mediated Lewis acid-base interactions between the electron-deficient PMBA and the electron-rich PATP. DHAP played key roles not only in cementation of imprinted cavities by means of double hydrogen bond networks through the amide groups but also in resistance to nonspecific protein binding by terminal OEG moieties, as well as hydrogen bond binding sites from the amide groups exposed to imprinted cavities. The created glycoprotein imprinted SAMs showed excellent recognition selectivity of target glycoproteins. The strategy for tailor-made glycoprotein imprinted SAMs explores a new avenue to the creation of intelligent biomaterials and fabrication of chemosensors.

Supramolecular Vesicles Coassembled from Disulfide-Linked Benzimidazolium Amphiphiles and Carboxylate-Substituted Pillar[6]arenes that Are Responsive to Five Stimuli.

Novel supramolecular vesicles based on host-guest systems were coassembled from carboxylate-substituted pillar[6]arene (CPA[6]) and disulfide-linked benzimidazolium amphiphiles, and the microstructures of the CPA-based supramolecular vesicles were clearly elaborated. The supramolecular vesicles showed controlled drug release in response to five stimuli, with glutathione, pH, CO2 , Zn2+ ions, and hexanediamine, leading to cleavage of the disulfide bonds, protonation of the carboxylate groups, metal chelation, and competitive binding. This is the first case of a smart pillararene-based supramolecular vesicle being integrated with five stimuli-responsive functions to meet the diverse requirements of controlled drug release. Importantly, each of the five stimuli is closely related to microenvironments of tumors and diseases of the human body. The smart stimuli-responsive supramolecular vesicles have promising applications in drug therapy of tumors and relevant diseases.

Facile and sensitive glucose sandwich assay using in situ-generated Raman reporters.

A facile and sensitive glucose sandwich assay using surface-enhanced Raman scattering (SERS) has been developed through the use of the self-assembled p-mercaptophenylboronic acid (PMBA) monolayer on a smooth gold-coated slide and the SERS tags of Ag nanoparticles (AgNPs) modified with p-aminothiophenol (PATP) and PMBA. The photocoupling product 4,4'-dimercaptoazobenzene (DMAB), generated in situ from PATP on the AgNP surface during the SERS measurement, possessed considerably intense characteristic SERS peaks and acted as the actual Raman reporter, which improved the sensitivity of glucose detection devoid of interference of other biomolecules. The facile sandwich assay showed a high selectivity of glucose over fructose and galactose. This facile, sensitive, and selective SERS-based glucose sandwich assay can be developed into a diagnostic tool for determination of glucose levels.

Reduced steric hindrance and optimized spatial arrangement of carbohydrate ligands in imprinted monolayers for enhanced protein binding.

Imprinted monolayers provide several advantages over bulk imprinting methods. This is especially important for large templates such as proteins. Concanavalin A (Con A)-imprinted binary monolayers consisting of glycolipids with oligo(ethylene glycol) (OEG) spacers and zwitterionic phospholipids (DPPC) were constructed and investigated. The shorter phosphorylcholine (PC) headgroups with an almost flat-on orientation in the binary monolayers gave rise to reduced steric hindrance favorable to the accommodation of Con A with greater ease and facilitated the access of the OEG-linked mannose moieties for enhanced protein binding. Further enhanced binding resulted from optimized spatial rearrangement of the glycolipids at the air-water interface directed by Con A in the subphase to create bivalent binding sites and to minimize steric crowding of neighboring mannose ligands. The combination of the exposed carbohydrate ligands from biologically inert surfaces and the optimized ligand arrangement is the most reasonable solution to enhancement of protein affinity. The bivalent carbohydrate binding sites protruding from the imprinted monolayers were created to be complementary to the Con A binding pockets. This strategy generates tailor-made surfaces with enhanced protein binding and opens the possibility of controlled assembly of intellectual biomaterials and preparation of biosensors.

Multi-responsive and logic controlled release of DNA-gated mesoporous silica vehicles functionalized with intercalators for multiple delivery.

Novel DNA-gated mesoporous silica nanoparticle (MSN) vehicles functionalized with disulfide-linked acridinamine intercalators are constructed for multi-responsive controlled release. The DNA-gated MSN vehicles release cargo encapsulated in the MSN pores under different stimuli, including disulfide reducing agents, elevated temperature, and deoxyribonuclease I (DNase I), for codelivery of drugs and DNA/genes in different forms. Furthermore, the cascade release of encapsulated and intercalative drugs is controlled by AND logic gates in combination of dual stimuli. The ingeniously designed DNA-gated MSN vehicles integrates multiple responses and AND logic gate operations into a single smart nanodevice not only for codelivery of drugs and DNA/genes but also for cascade release of two drugs and has promising biological applications to meet diverse requirements of controlled release.

Smart controlled-release nanopesticides based on metal-organic frameworks.

The practical utilization rates of conventional pesticide formulations by target organisms are very low, which results in the pollution of ecological environments and the formation of pesticide residues in agricultural products. Water-based nanopesticide formulations could become alternative and effective formulations to eventually resolve the main issues of conventional pesticide formulations. In this feature article, we describe the design concept of smart (stimuli-responsive) controlled-release nanopesticides, which are created toward hierarchical targets (pests, pathogens, and foliage) in response to multidimensional stimuli from physiological and environmental factors (such as sunlight) of target organisms and plants, for achieving enhanced insecticidal and fungicidal efficacies. The pore sizes and functionalities of metal-organic frameworks (MOFs) can be fine-tuned through the choice of metal-containing units and organic ligands. Tailor-made MOF nanoparticles with large microporous or mesoporous sizes, as well as good biocompatibility and high thermal, mechanical, and chemical durabilities, are used to load pesticides within these pores followed by coating of plant polyphenols and natural polymers for stimuli-responsive controlled pesticide release. This feature article highlights our works on smart controlled-release MOF-based nanopesticides and also includes related works from other laboratories. The future challenges and promising prospects of smart controlled-release MOF-based nanopesticides are also discussed.

Creating protein-imprinted self-assembled monolayers with multiple binding sites and biocompatible imprinted cavities.

Imprinted monolayers have several advantages over bulk imprinted polymers such as excellent mass transfer of molecules into and out of imprinted sites and transduction of binding signals detected in real time. Protein-imprinted self-assembled monolayers (SAMs) were created with multiple binding sites and biocompatible imprinted cavities from functional thiols and novel disulfide compounds containing an oligoethylene glycol (OEG) terminal moiety and two amide groups incorporated in the chain (DHAP) in a biologically benign solution. DHAP played an important role in the formation of multiple binding sites and biocompatible cavities in addition to resisting nonspecific protein binding. The created protein-imprinted SAMs exhibited the excellent ability of specific binding of target proteins determined by multiple binding sites and imprinted cavities. The strategy generates tailor-made monolayer surfaces with specific protein binding and opens the possibility of controlled assembly of intellectual biomaterials and preparation of biosensors.

Tandem assays of protein and glucose with functionalized core/shell particles based on magnetic separation and surface-enhanced Raman scattering.

Tandem assays of protein and glucose in combination with mannose-functionalized Fe3 O4 @SiO2 and Ag@SiO2 tag particles have promising potential in effective magnetic separation and highly sensitive and selective SERS assays of biomaterials. It is for the first time that tandem assay of glucose is developed using SERS based on the Con A-sandwiched microstructures between the functionalized magnetic and tag particles.

Silane-Functionalized Metal-Organic Frameworks for Stimuli-Responsive Drug Delivery Systems: A New Universal Strategy.

A new universal strategy for silane functionalization of metal-organic frameworks (MOFs) was developed. It was demonstrated that silanes were coupled both with terminal hydroxyl (OH) groups and with bridging OH groups of metal-oxo clusters of MOFs through condensation reactions between the silanols of hydrolyzed silanes and the terminal/bridging OH groups to form metal-O-Si bonds. A wide variety of functionalization of MOFs with conventional silanes can be realized by combining synthesis reactions in the solution phase and chemical modifications on the surface. Multivalent supramolecular nanovalves based on the host-guest chemistry of cyclodextrin polymer (CDP) and benzimidazole stalks silanized on the nanoscale MOF (NMOF) surface were successfully constructed. The CDP-valved NMOFs showed the excellent performance of low pH- and α-amylase-responsive controlled drug release. In vitro and in vivo results demonstrated that the CDP-valved NMOFs had a significant inhibitory effect on tumor growth and almost no damage/toxicity to normal tissues. The silanization strategy is universal and opens up a new way for the functionalization of MOFs, which are endowed with a wide variety of applications spanning gas storage, chemical sensing, adsorption and separation, heterogeneous catalysis, and drug delivery.

Smart, degradable, and eco-friendly carboxymethyl cellulose-CaII hydrogel-like networks gated MIL-101(FeIII) nanoherbicides for paraquat delivery.

Nanopesticides have been selected as one of the top 10 chemical innovations for enhancing the efficacy and safety of agrochemicals. Herein, smart, degradable, and eco-friendly metal-organic framework MIL-101(FeIII) nanoherbicides coated with carboxymethyl cellulose-CaII (CMC-CaII) cross-linking hydrogel-like networks are synthesized via a simple strategy. The coating of the CMC-CaII hydrogel-like gatekeepers is oriented by the coordination unsaturated FeIII clusters on the surfaces of the MIL-101(FeIII) nanocarriers to form a dense film network to prevent paraquat (PQ) leakage. Based on the stimuli factors (acid/basic pH, GSH, phosphates, and EDTA) of physiological and natural environments of target plants, the nanoherbicides are combined with five stimuli-responsive properties to attain the various controlled release of packaged PQ by the disassembly of the gatekeepers and/or the degradation of the MOF skeleton structure. More importantly, based on the stimuli-responsive controlled release mechanisms, the eco-friendly nanocarriers are ultimately degraded against bioaccumulation in plants or soil. The coating of natural CMC could promote the spreading of PQ owing to improvement of wettability for aqueous droplets of nanoherbicides on hydrophobic foliage. The PQ trapped in nanocarriers can effectively prevent PQ degradation, which showed that cumulative degradation rate is ca. 2.6 times lower than that of technical PQ under UV irradiation. The prepared nanoherbicides loaded with PQ show good control efficacy against weeds by controlling the release of PQ; good safety on seed germination (germination rate 97.32-99.67 %), seedling emergence (emergence rate 95.53-99.67 %), and are beneficial for the growth of wheat seedling (increase rate of plant height 1.89-6.97 % and 0.54-5.67 % after 7 and 15 days of seedling emergence, respectively) in the greenhouse; good biosafety for honeybees (Apis mellifera L.), which shows that lethal rates were 2.04 and 2.55 times lower than technical PQ for incubation 24 and 48 h, respectively. The nanoherbicides have potential applications in the field for PQ green agriculture.

Multivalent protein binding in carbohydrate-functionalized monolayers through protein-directed rearrangement and reorientation of glycolipids at the air-water interface.

Multivalent protein binding plays an important role not only in biological recognition but also in biosensor preparation. Infrared reflection absorption spectroscopy and surface plasmon resonance techniques have been used to investigate concanavalin A (Con A) binding to binary monolayers composed of 1,2-di-O-hexadecyl-sn-glycerol and derived glycolipids with the mannose moieties. The glycolipids in the binary monolayers at the air-water interface underwent both lateral rearrangement and molecular reorientation directed by Con A in the subphase favorable to access of the carbohydrate ligands to protein binding pockets for the formation of multivalent binding sites and the minimization of steric crowding of neighboring ligands for enhanced binding. The amounts of specifically bound proteins in the binary monolayers at the air-water interface were accordingly increased in comparison with those in the initially immobilized monolayers at the air-water interface. The directed rearranged binary monolayers with multivalent protein binding were preserved for the preparation of biosensors.

Self-assembly and molecular recognition of adenine- and thymine-functionalized nucleolipids in the mixed monolayers and thymine-functionalized nucleolipids on aqueous melamine at the air-water interface.

Self-assembly and molecular recognition of the monolayers composed of an equimolar mixture of adenine- and thymine-functionalized nucleolipids at the air-water interface have been investigated in detail using surface pressure-molecular area isotherms and in situ infrared reflection absorption spectroscopy (IRRAS). Prior to molecular recognition, the adenine moieties in the monolayer were almost oriented on an end-on mode through π-stacking and hydrogen bonding interactions, and the C-C-C planes of the alkyl chains were preferentially oriented perpendicular to the water surface, while the thymine moieties in the monolayer were involved in hydrogen bonding almost with a flat-on orientation. On aqueous subphases containing complementary bases, no significant molecular recognition was observed for the monolayers of individual nucleolipids. In the monolayer of equimolar mixture, molecular recognition occurred between the adenine and thymine moieties through hydrogen bonding probably with the development of cyclic structures of adenine-thymine-adenine-thymine quartets. Although molecular recognition between the monolayer of thymine-functionalized nucleolipids and aqueous melamine took place through triple hydrogen bonds, no melamine binding to the monolayer of equimolar mixture was observed, which reflects the formation of the quartets in the mixed monolayers at the air-water interface. FTIR and small-angle X-ray diffraction (XRD) results of the corresponding Langmuir-Blodgett films support the hydrogen bonding recognition and molecular orientation.

Structure of the complex monolayer of gemini surfactant and DNA at the air/water interface.

The properties of the complex monolayers composed of cationic gemini surfactants, [C(18)H(37)(CH(3))(2)N(+)-(CH(2))(s)-N(+)(CH(3))(2)C(18)H(37)],2Br(-) (18-s-18 with s = 3, 4, 6, 8, 10 and 12), and ds-DNA or ss-DNA at the air/water interface were in situ studied by the surface pressure-area per molecule (π-A) isotherm measurement and the infrared reflection absorption spectroscopy (IRRAS). The corresponding Langmuir-Blodgett (LB) films were also investigated by the atomic force microscopy (AFM), the Fourier transform infrared spectroscopy (FT-IR), and the circular dichroism spectroscopy (CD). The π-A isotherms and AFM images reveal that the spacer of gemini surfactant has a significant effect on the surface properties of the complex monolayers. As s ≤ 6, the gemini/ds-DNA complex monolayers can both laterally and normally aggregate to form fibril structures with heights of 2.0-7.0 nm and widths of from several tens to ~300 nm. As s > 6, they can laterally condense to form the platform structure with about 1.4 nm height. Nevertheless, FT-IR, IRRAS, and CD spectra, as well as AFM images, suggest that DNA retains its double-stranded character when complexed. This is very important and meaningful for gene therapy because it is crucial to maintain the extracellular genes undamaged to obtain a high transfection efficiency. In addition, when s ≤ 6, the gemini/ds-DNA complex monolayers can experience a transition of DNA molecule from the double-stranded helical structure to a typical ψ-phase with a supramolecular chiral order.

Myoglobin-directed assemblies of binary monolayers functionalized with iminodiacetic acid ligands at the air-water interface through metal coordination for multivalent protein binding.

Myoglobin binding to the binary monolayers composed of sodium hexadecylimino diacetate and hexadecanol at the air-water interface by means of metal coordination has been investigated using infrared reflection absorption spectroscopy (IRRAS). In the absence of Cu(2+), no myoglobin binding to the binary monolayers was observed. In the presence of Cu(2+), remarkable myoglobin binding to the binary monolayers resulted from the formation of ternary complexes of iminodiacetate (IDA)-Cu(2+)-surface histidine. Myoglobin-directed assemblies of the binary monolayers facilitated multivalent protein binding through lateral rearrangements of the IDA ligands and reorientations of the alkyl chains for enhanced protein binding. Myoglobin binding to and desorption from the binary monolayers could be readily controlled through metal coordination.

Ultrathin Porous Nitrogen-Doped Carbon-Coated CuSe Heterostructures for Combination Cancer Therapy of Photothermal Therapy, Photocatalytic Therapy, and Logic-Gated Chemotherapy.

The construction of nanoplatforms for the multimodal cancer therapy still remains an enormous challenge. Ultrathin porous nitrogen-doped carbon coated stoichiometric copper selenide heterostructures (CuSe/NC) are prepared using a facile and green one-pot hydrothermal method. Interestingly, CuSe/NC itself can achieve both photothermal therapy (PTT) and photocatalytic therapy (PCT) under irradiation of a single near-infrared (NIR) light (808 nm), which is convenient and safe for clinical applications. Importantly, the triple-enhanced NIR light-activated PCT, including O2-independent free radicals, Fenton-like reaction, and glutathione (GSH) depletion, breaks through the limitations of hypoxia and overexpressed GSH in cancer cells. Furthermore, CuSe/NC is loaded with doxorubicin (DOX) via metal coordination and then decorates with DNA to construct the CuSe/NC-DOX-DNA nanoplatform. Surprisingly, the facile nanoplatform has an advanced biocomputing capability of an "AND" Boolean logic gate with the smart "AND" logic controlled release of DOX upon combined stimuli of pH and GSH for precise cancer chemotherapy. The synergistic mechanism of proton-mediated ligand exchange between DOX and GSH is proposed for the "AND" logic controlled drug release from CuSe/NC-DOX-DNA. In vitro and in vivo studies demonstrate that CuSe/NC-DOX-DNA has excellent anticancer efficacy and negligible toxicity. This innovative nanoplatform with multienhanced anticancer efficacy provides a paradigm for combination cancer therapy of PTT, PCT, and chemotherapy.

Enzyme-inspired controlled release of cucurbit[7]uril nanovalves by using magnetic mesoporous silica.

The controlled release of drugs by biostimuli is highly desirable under physiological conditions for their potential use in advanced applications. The enzyme-inspired controlled release of cucurbituril nanovalves by using magnetic mesoporous silica nanoparticles (MSNs) in near-neutral aqueous solutions is reported for the first time. The encirclement of cucurbit[7]uril (CB[7]) onto the protonated 1,4-butanediamine stalks tethered to the external surfaces of superparamagnetic Fe(3) O(4) -embedded mesoporous silica particles leads to tight blocking of the nanopores. The supramolecular nanovalves are activated by the enzymatic decarboxylation products of lysine, cadaverine (in the protonated form), which has a high affinity for CB[7], so that the encapsulated guest molecules, calcein, in the nanopores are released into the bulk solution. The release of calcein can be controlled in small portions on command by alternating changes in enzymatic decarboxylation products and CB[7]. The amino acid derived polyamines have long been associated with cell growth and cancers. The guest molecules released from the delivery system of magnetic MSNs can act not only on sensing probes for levels of decarboxylases and polyamines, but also on efficacious drugs to specific tissues and cells for regulation of polyamine synthesis.

Iminodiacetic acid-functionalized gold nanoparticles for optical sensing of myoglobin via Cu2+ coordination.

A novel gold nanoparticle (AuNP)-based optical sensing system has been developed for the detection of myoglobin (Mb), which is of significant importance for early disease diagnosis. Two thiol molecules containing an iminodiacetic acid moiety (IDA) were synthesized. This detection is based on the Mb-induced aggregation of IDA-functionalized AuNPs resulting from the structures of Mb sandwiched between the functionalized AuNPs via Cu(2+) bridges in the coordination interactions of IDA-Cu(2+)-histidine residues available on the Mb surface, which was confirmed by UV-vis spectroscopy, transmission electron microscopy, dynamic light scattering, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The induction aggregation resulted in a red shift in plasmon resonance band of the AuNPs concomitant with a change in solution color from red to purple. The qualitative and quantitative detections of Mb can be achieved by colorimetric observations and UV-vis spectral measurements, respectively. The selectivity of protein assay with the functionalized AuNPs was further investigated, and it is found that the optical sensing of histidine-rich proteins is closely related to number and distribution of surface histidine residues as well as size of proteins.

DNA-targeted formation and catalytic reactions of DNAzymes for label-free ratiometric electrochemiluminescence biosensing.

A label-free ratiometric electrochemiluminescence (ECL) sensing strategy for the sensitive detection of target DNA (T-DNA) was proposed on the basis of G-quadruplex/hemin-regulated ECL emissions of CdS quantum dots (QDs) and luminol with their common coreactant of H2O2. The ECL biosensor was constructed through stepwise assemblies of CdS QDs and hairpin DNA (H-DNA) on a glassy carbon electrode, and subsequent introduction of T-DNA resulted in the development of G-quadruplex/hemin DNAzymes via the specific recognition of T-DNA and H-DNA in the presence of hemin and K+ ions. The formed DNAzymes not only prompted the catalytic oxidation of hydroquinone followed by deposition of insoluble oxidation oligomers on the electrode surface to attenuate the cathodic ECL emission of CdS QDs but also triggered the catalytic oxidation of luminol to enhance the anodic ECL emission. The label-free ratiometric ECL biosensor for the detection of T-DNA showed a wide response range from 1 to 10,000 fM (10-15 M) with a low detection limit of 0.2 fM and exhibited excellent selectivity against mismatched base sequences. This work provides a reliable and sensitive sensing platform for the detection of targets in analytical community by means of rational design of DNA sequences.

Protein-Gated Upconversion Nanoparticle-Embedded Mesoporous Silica Nanovehicles via Diselenide Linkages for Drug Release Tracking in Real Time and Tumor Chemotherapy.

Two novel stimuli-responsive drug delivery systems (DDSs) were successfully created from bovine serum albumin- or myoglobin-gated upconversion nanoparticle-embedded mesoporous silica nanovehicles (UCNP@mSiO2) via diselenide (Se-Se)-containing linkages. More importantly, multiple roles of each scaffold of the nanovehicles were achieved. The controlled release of the encapsulated drug doxorubicin (DOX) within the mesopores was activated by triple stimuli (acidic pH, glutathione, or H2O2) of tumor microenvironments, owing to the conformation/surface charge changes in proteins or the reductive/oxidative cleavages of the Se-Se bonds. Upon release of DOX, the Förster resonance energy transfer between the UCNP cores and encapsulated DOX was eliminated, resulting in an increase in ratiometric upconversion luminescence for DOX release tracking in real time. The two protein-gated DDSs showed some differences in the drug release performances, relevant to structures and properties of the protein nanogates. The introduction of the Se-Se linkages not only increased the versatility of reductive/oxidative cleavages but also showed less cytotoxicity to all cell lines. The DOX-loaded protein-gated nanovehicles showed the inhibitory effect on tumor growth in tumor-bearing mice and negligible damage/toxicity to the normal tissues. The constructed nanovehicles in a spatiotemporally controlled manner have fascinating prospects in targeted drug delivery for cancer chemotherapy.