Theranostic Activity of Nitric Oxide-Releasing Carbon Quantum Dots.

The synthesis and anticancer cell activity of nitric oxide (NO)-releasing carbon quantum dots (CQDs) are described as potential theranostics. A series of secondary amine-modified CQDs were prepared using a hydrothermal method to modify ß-cyclodextrin with hydroxyl and primary amine terminal functional groups. Subsequent reaction of the CQDs with NO gas under alkaline conditions yielded N-diazeniumdiolate NO donor-modified CQDs with adjustable NO payloads (0.2-1.1 µmol/mg) and release kinetics (half-lives from 29 to 79 min) depending on the level of secondary amines and surface functional groups. The anticancer activity of the NO-releasing CQDs against Pa14c, A549, and SW480 cancer cell lines proved to be dependent on both NO payloads and surface functionalizations. Primary amine-modified CQDs with NO payloads ∼1.11 µmol/mg exhibited the greatest anticancer action. A fluorescence microscopy study demonstrated the utility of these NO-releasing CQDs as dual NO-releasing and bioimaging probes.

Bioinspired Peptoid Nanotubes for Targeted Tumor Cell Imaging and Chemo-Photodynamic Therapy.

Substantial progress has been made in applying nanotubes in biomedical applications such as bioimaging and drug delivery due to their unique architecture, characterized by very large internal surface areas and high aspect ratios. However, the biomedical applications of organic nanotubes, especially for those assembled from sequence-defined molecules, are very uncommon. In this paper, the synthesis of two new peptoid nanotubes (PepTs1 and PepTs2) is reported by using sequence-defined and ligand-tagged peptoids as building blocks. These nanotubes are highly robust due to sharing a similar structure to those of nontagged ones, and offer great potential to hold guest molecules for biomedical applications. The findings indicate that peptoid nanotubes loaded with doxorubicin drugs are promising candidates for targeted tumor cell imaging and chemo-photodynamic therapy.

Solid-phase synthesis of three-armed star-shaped peptoids and their hierarchical self-assembly.

Due to the branched structure feature and unique properties, a variety of star-shaped polymers have been designed and synthesized. Despite those advances, solid-phase synthesis of star-shaped sequence-defined synthetic polymers that exhibit hierarchical self-assembly remains a significant challenge. Hence, we present an effective strategy for the solid-phase synthesis of three-armed star-shaped peptoids, in which ethylenediamine was used as the centric star pivot. Based on the sequence of monomer addition, a series of AA'A''-type and ABB'-type peptoids were synthesized and characterized by UPLC-MS (ultrahigh performance liquid chromatography-mass spectrometry). By taking advantage of the easy-synthesis and large side-chain diversity, we synthesized star-shaped peptoids with tunable functions. We further demonstrated the aqueous self-assembly of some representative peptoids into biomimetic nanomaterials with well-defined hierarchical structures, such as nanofibers and nanotubes. These results indicate that star-shaped peptoids offer the potential in self-assembly of biomimetic nanomaterials with tunable chemistries and functions.

Hierarchical Assembly of Peptoid-Based Cylindrical Micelles Exhibiting Efficient Resonance Energy Transfer in Aqueous Solution.

Herein we show that by appending bulky ß-cyclodextrin (CD) groups onto sheet-forming peptoids, we obtain cylindrical micelles that further assembly into membranes and intertwined ribbons on substrates in aqueous solution, depending on the choice of solution and substrate conditions. In situ atomic force microscopy (AFM) shows that micelle assembly occurs in two steps, starting with "precursor" particles that transform into worm-like micelles, which extend and coalesce to form the higher order structures with a rate and a degree of cooperativity dependent on pH and Ca2+ concentration. After co-assembly with hydrophobic 4-(2-hydroxyethylamino)-7-nitro-2,1,3-benzoxadiazole (NBD) donors that occupy the hydrophobic core, followed by exposure to hydrophilic Rhodamine B as acceptors that insert into cyclodextrin, the micelles exhibit highly efficient Förster resonance energy transfer efficiency in aqueous solution, thereby mimicking natural light harvesting systems.

Nitric Oxide-Releasing Cyclodextrins.

A series of secondary amine-modified cyclodextrin (CD) derivatives was synthesized with diverse exterior terminal groups (i.e., hydroxyl, methyl, methoxyl, and primary amine). Subsequent reaction with nitric oxide (NO) gas under alkaline conditions yielded N-diazeniumdiolate-modified CD derivatives. Adjustable NO payloads (0.6-2.4 µmol/mg) and release half-lives (0.7-4.2 h) were achieved by regulating both the amount of secondary amine precursors and the functional groups around the NO donors. The bactericidal action of these NO-releasing cyclodextrin derivatives was evaluated against Pseudomonas aeruginosa, a Gram-negative pathogen, with antibacterial activity proving dependent on both the NO payload and exterior modification. Materials containing a high density of NO donors or primary amines exhibited the greatest ability to eradicate P. aeruginosa. Of the materials prepared, only the primary amine-terminated heptasubstituted CD derivatives exhibited toxicity against mammalian L929 mouse fibroblast cells. The NO donor-modified CD was also capable of delivering promethazine, a hydrophobic drug, thus demonstrating potential as a dual-drug-releasing therapeutic.

Efficient Cytosolic Delivery Using Crystalline Nanoflowers Assembled from Fluorinated Peptoids.

The design and synthesis of biocompatible nanomaterials as cargoes for the intracellular delivery of therapeutic proteins or genes have attracted intense attention because of their potential for use in therapeutics. Despite the advances in this area, very few nanomaterials can be efficiently delivered to the cytosol. To address these challenges, crystalline nanoflower-like particles are designed and synthesized from fluorinated sequence-defined peptoids; the crystallinity and fluorination of these particles enable highly efficient cytosolic delivery with minimal cytotoxicity. A cytosol delivery rate of 80% has been achieved for the fluorinated peptoid nanoflowers. Furthermore, these nanocrystals can carry therapeutic genes, such as mRNA and effectively deliver the payload into the cytosol, demonstrating the universal delivery capability of the nanocrystals. The results indicate that self-assembly of crystalline nanomaterials from fluorinated peptoids paves a new way toward development of nanocargoes with efficient cytosolic gene delivery capability.

Hierarchical C/SiO x /TiO2 ultrathin nanobelts as anode materials for advanced lithium ion batteries.

TiO2-based nanomaterials are demonstrated to be a promising candidate for next generation lithium ion batteries due to their stable performance and easy preparation. However, their inherent low capacity impedes their wide application compared to commercial carbon nanomaterials. Here we present a unique in situ grafting-graphitization method to achieve a ternary nanocomposite of C/SiO x /TiO2 ultrathin nanobelts with a core-shell heterostructure. The obtained ternary nanocomposite integrates the merits of high specific capacity of SiO x , the excellent mechanical stability of graphite-like carbon and the high reactivity of TiO2. Cyclic voltammetric curves and cycling performance manifest the optimal ternary nanocomposite and deliver a very high initial specific capacity of ∼1196 mA h g-1 with both good rate capability (∼200 mA h g-1 up to 10 C) and especially enhanced cycle stability. Our work demonstrates that building hierarchical core-shell heterostructures is an effective strategy to improve capacity and cycling performance in other composite anodes for electrochemical energy storage materials.

Designable Photo-Responsive Micron-Scale Ultrathin Peptoid Nanobelts for Enhanced Performance on Hydrogen Evolution Reaction.

The development of high-reactive single-atom catalysts (SACs) based on long-range-ordered ultrathin organic nanomaterials (UTONMs) (i.e., below 3 nm) provides a significant tactic for the advancement in hydrogen evolution reactions (HER) but remains challenging. Herein, photo-responsive ultrathin peptoid nanobelts (UTPNBs) with a thickness of ≈2.2 nm and micron-scaled length are generated using the self-assembly of azobenzene-containing amphiphilic ternary alternating peptoids. The pendants hydrophobic conjugate stacking mechanism reveals the formation of 1D ultralong UTPNBs, whose thickness is dictated by the length of side groups that are linked to peptoid backbones. The photo-responsive feature is demonstrated by a reversible morphological transformation from UTPNBs to nanospheres (21.5 nm) upon alternative irradiation with UV and visible lights. Furthermore, the electrocatalyst performance of these aggregates co-decorated with nitrogen-rich ligand of terpyridine (TE) and uniformly-distributed atomic platinum (Pt) is evaluated toward HER, with a photo-controllable electrocatalyst activity that highly depended on both the presence of Pt element and structural characteristic of substrates. The Pt-based SACs using TE-modified UTPNBs as support exhibit a favorable electrocatalytic capacity with an overpotential of ≈28 mV at a current density of 10 mA cm-2. This work presents a promising strategy to fabricate stimuli-responsive UTONMs-based catalysts with controllable HER catalytic performance.

A supramolecular Janus hyperbranched polymer and its photoresponsive self-assembly of vesicles with narrow size distribution.

Herein, we report a novel Janus particle and supramolecular block copolymer consisting of two chemically distinct hyperbranched polymers, which is coined as Janus hyperbranched polymer. It is constructed by the noncovalent coupling between a hydrophobic hyperbranched poly(3-ethyl-3-oxetanemethanol) with an apex of an azobenzene (AZO) group and a hydrophilic hyperbranched polyglycerol with an apex of a ß-cyclodextrin (CD) group through the specific AZO/CD host-guest interactions. Such an amphiphilic supramolecular polymer resembles a tree together with its root very well in the architecture and can further self-assemble into unilamellar bilayer vesicles with narrow size distribution, which disassembles reversibly under the irradiation of UV light due to the trans-to-cis isomerization of the AZO groups. In addition, the obtained vesicles could further aggregate into colloidal crystal-like close-packed arrays under freeze-drying conditions. The dynamics and mechanism for the self-assembly of vesicles as well as the bilayer structure have been disclosed by a dissipative particle dynamics simulation.

Biocompatible or biodegradable hyperbranched polymers: from self-assembly to cytomimetic applications.

Self-assembly of amphiphilic hyperbranched polymers (HBPs) is a newly emerging research area and has attracted increasing attention due to the great advantages in biomedical applications. This tutorial review focuses on the self-assembly of biocompatible or biodegradable amphiphilic HBPs and their cytomimetic applications, and specialities or advantages therein owing to the hyperbranched structure have also been summarized. As shown here, various supramolecular structures including micelles, vesicles, tubes, fibers and films have been prepared through the primary self-assembly processes. The primary self-assemblies can be further assembled into more complex structures through hierachical self-assembly processes. Besides, the hyperbranched polymer vesicles have demonstrated great potential to be used as model membranes to mimic cellular behaviors, such as fusion, fission and cell aggregation. Other biomedical applications of HBPs as well as their self-assemblies are also briefly summarized.

Sustainable sepiolite-based composites for fast clotting and wound healing.

Uncontrolled bleeding and bacterial coinfection are the major causes of death after an injury. Fast hemostatic capacity, good biocompatibility, and bacterial coinfection inhibition pose great challenges to hemostatic agent development. A prospective sepiolite/Ag nanoparticles (sepiolite@AgNPs) composite has been prepared by using natural clay sepiolite as template. A tail vein hemorrhage mouse model and a rabbit hemorrhage model were used to evaluate the hemostatic properties of the composite. The sepiolite@AgNPs composite can quickly absorb fluid to subsequently stop bleeding due to the natural fibrous crystal structure of sepiolite, and inhibit bacterial growth with the antibacterial ability of AgNPs. Compared with commercially-available zeolite material, the as-prepared composite exhibits competitive hemostatic properties without exothermic reaction in the rabbit model of femoral and carotid artery injury. The rapid hemostatic effect was due to the efficient absorption of erythrocyte and activation of the coagulation cascade factors and platelets. Besides, after heat-treatment, the composites can be recycled without significant reduction of hemostatic performance. Our results also prove that sepiolite@AgNPs nanocomposites can stimulate wound healing. The sustainability, lower-cost, higher bioavailability, and stronger hemostatic efficacy of sepiolite@AgNPs composite render these nanocomposites as more favorable hemostatic agents for hemostasis and wound healing.

Small-molecule nanoprodrug with high drug loading and EGFR, PI3K/AKT dual-inhibiting properties for bladder cancer treatment.

Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5-year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR-based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL-HSP EGFR-targeting prodrug (THE), which further self-assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR-targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR-targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR-targeted therapy.

Construction of macroscopic cytomimetic vesicle aggregates based on click chemistry: controllable vesicle fusion and phase separation.

Vesicle-vesicle aggregation to mimic cell-cell aggregation has attracted much attention. Here, hyperbranched polymer vesicles (branched-polymersomes, BPs) with a cell-like size were selected as model membranes, and the vesicle aggregation process, triggered by click chemistry of the copper-catalysed azide-alkyne cycloaddition reaction, was systematically studied. For this purpose, azide and alkynyl groups were loaded on the membranes of BPs through the co-assembly method to obtain N(3)-BPs and Alk-BPs, respectively. Subsequently, macroscopic vesicle aggregates were obtained when these two kinds of functional BPs were mixed together with the ratio of azide to alkynyl groups of about 1:1. Both the vesicle fusion events and lateral phase separation on the vesicle membrane occurred during such a vesicle aggregation process, and the fusion rate and phase-separation degree could be controlled by adjusting the clickable group content. The vesicle aggregation process with N(3) -micelles as desmosome mimics to connect with Alk-BPs through click-chemistry reaction was also studied, and large-scale vesicle aggregates without vesicle fusion were obtained in this process. The present work has extended the controllable cytomimetic vesicle aggregation process with the use of covalent bonds, instead of noncovalent bonds, as the driving force.

Cytomimetic large-scale vesicle aggregation and fusion based on host-guest interaction.

Herein, we have shown a large-scale cell-mimetic (cytomimetic) aggregation process by using cell-sized polymer vesicles as the building blocks and intervesicular host-guest molecular recognition interactions as the driving force. We first prepared the hyperbranched polymer vesicles named branched polymersomes (BPs) around 5-10 µm through the aqueous self-assembly of a hyperbranched multiarm copolymer of HBPO-star-PEO [HBPO = hyperbranched poly(3-ethyl-3-oxetanemethanol); PEO = poly(ethylene oxide)]. Subsequently, adamantane-functionalized BPs (Ada-BPs) or ß-cyclodextrin-functionalized BPs (CD-BPs) were prepared through the coassembly of HBPO-star-PEO and Ada-modified HBPO-star-PEO (HBPO-star-PEO-Ada), or of HBPO-star-PEO and CD-modified HBPO-star-PEO (HBPO-star-PEO-CD), respectively. Macroscopic vesicle aggregates were obtained by mixing CD-BPs and Ada-BPs. The intervesicular host-guest recognition interactions between ß-CD units in CD-BPs and Ada units in Ada-BPs, which were proved by (1)H nuclear Overhauser effect spectroscopy (NOESY) spectrum and the fluorescence probe method, are responsible for the vesicle aggregation. Additionally, the vesicle fusion events happened frequently in the process of vesicle aggregation, which were certified by double-labeling fluorescent assay, real-time observation, content mixing assay, and component mixing assay.

A facile method for fabricating TiO2@mesoporous carbon and three-layered nanocomposites.

Herein, we report a new and facile method for fabricating TiO(2)@mesoporous carbon hybrid materials. Uniform polydopamine (PDA) layers were coated onto the surface of titanate nanotubes (TNTs) and TiO(2) nanorods (TNDs) through the spontaneous adhesion and self-polymerization of dopamine during the dipping process. Core-shell mesoporous carbon nanotubes with TiO(2) nanorods or nanoparticles encapsulated inside (TiO(2)@MC) were then obtained by transforming PDA layers into carbonaceous ones through calcination in nitrogen at 800 °C. The thickness of the mesoporous carbon layers is tens of nanometers and can be controlled by adjusting the coated PDA layers through the self-polymerization reaction time. In addition, three-layered nanocomposites of TiO(2)@MC@MO (MO, metal oxide) can be readily prepared by utilizing PDA layers in TNTs@PDA or TNDs@PDA to adsorb the metal ions, followed by the calcination process.

A POSS-based supramolecular amphiphile and its hierarchical self-assembly behaviors.

A polyhedral oligomeric silsesquioxane (POSS)-based supramolecular amphiphile is prepared from the host-guest inclusion complexation between a mono adamantane-functionalized POSS (AD-POSS) and a ß-cyclodextrin oligomer (P(ß-CD)). Assisted by the interface of H(2)O/toluene, the obtained supramolecular hybrids self-assemble into stable hollow nanospheres with thick walls. These hollow nanospheres aggregate together into a sphere layer through a spin coating technique, which then further transforms into a thin porous film containing nanometer-scale holes. The hollow nanospheres have a low cytotoxicity. The in vitro cell culture indicates the nanoporous films promote adhesion and proliferation of cells. The self-assembly morphologies and structures have been carefully characterized by SEM, TEM, AFM, DLS, XPS and water-contact angle measurements, and the self-assembly mechanism has also been discussed.

Light-Induced Reversible Hierarchical Self-Assembly of Amphiphilic Diblock Copolymers into Microscopic Vesicles with Tunable Optical and Nanocarrier Properties.

In contrast to the conventional hierarchical self-assembly process, effective methods to enable reversible hierarchical self-assembly of block copolymers are comparatively few and limited in scope. Herein, we report, for the first time, a simple yet robust strategy for light-induced reversible hierarchical self-assembly of an amphiphilic diblock copolymer, poly(4-vinylpyridine)-block-poly[6-[4-(4-butyloxyphenylazo)phenoxy]hexyl methacrylate] (denoted P4VP-b-PAzoMA). The hierarchical structures are constructed via a two-step self-assembly process (first-level reverse micelles, second-level compound micelles, and rearrangement into micrometer-sized vesicles) driven by use of solvent. Intriguingly, because of reversible photoinduced trans-to-cis isomerization of azobenzene moieties in PAzoMA, the vesicles could disassemble into subunits upon UV light and then recover the nearly identical vesicular morphology upon visible light. Such a reversible hierarchical self-assembly process is accompanied by reversible fluorescence, encapsulation, and controlled release of dyes and can be used as a template for the synthesis of nanoparticles. Clearly, the ability to render the light-enabled reversible hierarchical self-assembly provides a unique platform for smart delivery vehicles and templates for nanomaterials.

Polymerization-like multilevel hierarchical self-assembly of polymer vesicles into macroscopic superstructures with controlled complexity.

We demonstrate a high-leveled hierarchical self-assembly process into fractal structures. Two hyperbranched multiarm copolymers are first coassembled into binary isotropic vesicles in the primary self-assembly. Then, these primary vesicles are in situ endowed with anisotropic hydrophobic "binding sites" through a pH-induced lateral microphase separation, undergoing an isotropic-anisotropic transition. Subsequently, the anisotropic vesicles further assemble together through the specific self-recognition between the binding sites into linear, branched, cyclization, and network-like vesicle chains. Furthermore, the obtained vesicle chains can transform into linear, branched, ring-like, and network tubes through successive vesicle fusion. Such a hierarchical process is pH-triggered and well-controlled by adjusting the vesicle compositions and is coined as "polymerization-like" self-assembly due to the striking analogy between the vesicle association model and polymerization process.

Nitric oxide diffusion through cystic fibrosis-relevant media and lung tissue.

A simplified diffusion cell methodology was employed to measure the diffusion coefficient of nitric oxide (NO) through phosphate buffered saline (PBS) and artificial sputum medium (ASM)-an in vitro analog for airway mucus. Diffusion through the proteinaceous ASM yielded a significantly lower diffusion coefficient compared to PBS, which is attributed to both the physical obstruction by the mucin mesh and reactive nature of NO radicals towards the biological compounds in ASM. To further confirm that ASM was restricting NO from diffusing freely, a macromolecular propylamine-modified cyclodextrin donor (CD-PA) was employed to release the NO more slowly. The NO diffusion characteristics in ASM via the NO donor were also slower relative to PBS. As NO is likely to interact with lung cells after passing through the mucus barrier, the diffusion of both NO and the CD-PA macromolecular NO donor through differentiated lung tissue was investigated with and without an ASM layer. Comparison of NO diffusion through the three diffusion barriers indicated that the lung tissue significantly impeded NO penetration over the course of the experiment compared to PBS and ASM. In fact, the diffusion of CD-PA through the lung tissue was hindered until after the release of its NO payload, potentially due to the increased net charge of the NO donor structure. Of importance, the viability of the tissue was not influenced by the NO-releasing CD-PA at bactericidal concentrations.

Crystalline Facet-Directed Generation Engineering of Ultrathin Platinum Nanodendrites.

In this work, we successfully prepare two-dimensional ultrathin single-crystalline platinum nanodendrites (PtNDs) with precisely controlled generation (size) through a surfactant-directed solution-phase synthesis. The amphiphilic surfactant of C22H45-N+(CH3)2CH2COOH (Br-) acts as the structure-directing template and facet-capping agent simultaneously to kinetically engineer in-the-plane epitaxial growth of Pt nanocrystals along selectively exposed {111} facets into ultrathin PtNDs. A novel formation mechanism defined as crystalline facet-directed step-by-step in-the-plane epitaxial growth, similar to the synthesis of organic dendrimers, is proposed on the basis of the nanostructure and crystalline evolution of PtNDs. The generation growth process is readily extended to precisely engineer the generation of PtNDs (from 0 to 25) and can also be utilized to grow other noble metal NDs (e.g., PdNDs and AuNDs) and core-shell Pt-Pd NDs. Because of the structural advantages, ultrathin PtNDs exhibit enhanced electrocatalytic performance toward hydrogen evolution reaction.