Reduction Triggered In Situ Polymerization in Living Mice.

"Smart" biomaterials that are responsive to physiological or biochemical stimuli have found many biomedical applications for tissue engineering, therapeutics, and molecular imaging. In this work, we describe in situ polymerization of activatable biorthogonal small molecules in response to a reducing environment change in vivo. We designed a carbohydrate linker- and cyanobenzothiazole-cysteine condensation reaction-based small molecule scaffold that can undergo rapid condensation reaction upon physiochemical changes (such as a reducing environment) to form polymers (pseudopolysaccharide). The fluorescent and photoacoustic properties of a fluorophore-tagged condensation scaffold before and after the transformation have been examined with a dual-modality optical imaging method. These results confirmed the in situ polymerization of this probe after both local and systemic administration in living mice.

Efficient charge generation by relaxed charge-transfer states at organic interfaces.

Interfaces between organic electron-donating (D) and electron-accepting (A) materials have the ability to generate charge carriers on illumination. Efficient organic solar cells require a high yield for this process, combined with a minimum of energy losses. Here, we investigate the role of the lowest energy emissive interfacial charge-transfer state (CT1) in the charge generation process. We measure the quantum yield and the electric field dependence of charge generation on excitation of the charge-transfer (CT) state manifold via weakly allowed, low-energy optical transitions. For a wide range of photovoltaic devices based on polymer:fullerene, small-molecule:C60 and polymer:polymer blends, our study reveals that the internal quantum efficiency (IQE) is essentially independent of whether or not D, A or CT states with an energy higher than that of CT1 are excited. The best materials systems show an IQE higher than 90% without the need for excess electronic or vibrational energy.

Linear side chains in benzo[1,2-b:4,5-b']dithiophene-thieno[3,4-c]pyrrole-4,6-dione polymers direct self-assembly and solar cell performance.

While varying the size and branching of solubilizing side chains in π-conjugated polymers impacts their self-assembling properties in thin-film devices, these structural changes remain difficult to anticipate. This report emphasizes the determining role that linear side-chain substituents play in poly(benzo[1,2-b:4,5-b']dithiophene-thieno[3,4-c]pyrrole-4,6-dione) (PBDTTPD) polymers for bulk heterojunction (BHJ) solar cell applications. We show that replacing branched side chains by linear ones in the BDT motifs induces a critical change in polymer self-assembly and backbone orientation in thin films that correlates with a dramatic drop in solar cell efficiency. In contrast, we show that for polymers with branched alkyl-substituted BDT motifs, controlling the number of aliphatic carbons in the linear N-alkyl-substituted TPD motifs is a major contributor to improved material performance. With this approach, PBDTTPD polymers were found to reach power conversion efficiencies of 8.5% and open-circuit voltages of 0.97 V in BHJ devices with PC71BM, making PBDTTPD one of the best polymer donors for use in the high-band-gap cell of tandem solar cells.

Enhanced solid-state order and field-effect hole mobility through control of nanoscale polymer aggregation.

Efficient charge carrier transport in organic field-effect transistors (OFETs) often requires thin films that display long-range order and close π-π packing that is oriented in-plane with the substrate. Although some polymers have achieved high field-effect mobility with such solid-state properties, there are currently few general strategies for controlling the orientation of π-stacking within polymer films. In order to probe structural effects on polymer-packing alignment, furan-containing diketopyrrolopyrrole (DPP) polymers with similar optoelectronic properties were synthesized with either linear hexadecyl or branched 2-butyloctyl side chains. Differences in polymer solubility were observed and attributed to variation in side-chain shape and polymer backbone curvature. Averaged field-effect hole mobilities of the polymers range from 0.19 to 1.82 cm(2)/V·s, where PDPP3F-C16 is the least soluble polymer and provides the highest maximum mobility of 2.25 cm(2)/V·s. Analysis of the films by AFM and GIXD reveal that less soluble polymers with linear side chains exhibit larger crystalline domains, pack considerably more closely, and align with a greater preference for in-plane π-π packing. Characterization of the polymer solutions prior to spin-coating shows a correlation between early onset nanoscale aggregation and the formation of films with highly oriented in-plane π-stacking. This effect is further observed when nonsolvent is added to PDPP3F-BO solutions to induce aggregation, which results in films with increased nanostructural order, in-plane π-π orientation, and field-effect hole mobilities. Since nearly all π-conjugated materials may be coaxed to aggregate, this strategy for enhancing solid-state properties and OFET performance has applicability to a wide variety of organic electronic materials.

Sensitivity to molecular order of the electrical conductivity in oligothiophene monolayer films.

Using conducting probe atomic force microscopy (CAFM), we show that electrical conductivity in oligothiophene molecular films deposited on SiO(2)/Si wafers is extremely sensitive to degree of crystalline order in the film. By locally distorting the molecular order in the films through the controlled application of pressure with the AFM tip, the lateral charge transport was reduced by factors varying from 2 to 10, even when no changes in the height of the film could be observed.

Polyphosphonium polymers for siRNA delivery: an efficient and nontoxic alternative to polyammonium carriers.

A water-soluble polyphosphonium polymer was synthesized and directly compared with its ammonium analog in terms of siRNA delivery. The triethylphosphonium polymer shows transfection efficiency up to 65% with 100% cell viability, whereas the best result obtained for the ammonium analog reaches only 25% transfection with 85% cell viability. Moreover, the nature of the alkyl substituents on the phosphonium cations is shown to have an important influence on the transfection efficiency and toxicity of the polyplexes. The present results show that the use of positively charged phosphonium groups is a worthy choice to achieve a good balance between toxicity and transfection efficiency in gene delivery systems.

Side-chain tunability of furan-containing low-band-gap polymers provides control of structural order in efficient solar cells.

The solution-processability of conjugated polymers in organic solvents has classically been achieved by modulating the size and branching of alkyl substituents appended to the backbone. However, these substituents impact structural order and charge transport properties in thin-film devices. As a result, a trade-off must be found between material solubility and insulating alkyl content. It was recently shown that the substitution of furan for thiophene in the backbone of the polymer PDPP2FT significantly improves polymer solubility, allowing for the use of shorter branched side chains while maintaining high device efficiency. In this report, we use PDPP2FT to demonstrate that linear alkyl side chains can be used to promote thin-film nanostructural order. In particular, linear side chains are shown to shorten π-π stacking distances between backbones and increase the correlation lengths of both π-π stacking and lamellar spacing, leading to a substantial increase in the efficiency of bulk heterojunction solar cells.

Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA.

New conjugation chemistry for polysaccharides, exemplified by dextran, was developed to enable the attachment of therapeutic or other functional moieties to the polysaccharide through cleavable acetal linkages. The acid-lability of the acetal groups allows the release of therapeutics under acidic conditions, such as that of the endocytic compartments of cells, regenerating the original free polysaccharide in the end. The physical and chemical behavior of these acetal groups can be adjusted by modifying their stereoelectronic and steric properties, thereby providing materials with tunable degradation and release rates. We have applied this conjugation chemistry in the development of water-soluble siRNA carriers, namely acetal-linked amino-dextrans, with various amine structures attached through either slow- or fast-degrading acetal linker. The carriers with the best combination of amine moieties and structural composition of acetals showed high in vitro transfection efficiency and low cytotoxicity in the delivery of siRNA.

A monolithic lipase reactor for biodiesel production by transesterification of triacylglycerides into fatty acid methyl esters.

An enzymatic reactor with lipase immobilized on a monolithic polymer support has been prepared and used to catalyze the transesterification of triacylglycerides into the fatty acid methyl esters commonly used for biodiesel. A design of experiments procedure was used to optimize the monolithic reactor with variables including control of the surface polarity of the monolith via variations in the length of the hydrocarbon chain in alkyl methacrylate monomer, time of grafting of 1-vinyl-4,4-dimethylazlactone used to activate the monolith, and time used for the immobilization of porcine lipase. Optimal conditions involved the use of a poly(stearyl methacrylate-co-ethylene dimethacrylate) monolith, grafted first with vinylazlactone, then treated with lipase for 2 h to carry out the immobilization of the enzyme. Best conditions for the transesterification of glyceryl tributyrate included a temperature of 37°C and a 10 min residence time of the substrate in the bioreactor. The reactor did not lose its activity even after pumping through it a solution of substrate equaling 1,000 reactor volumes. This enzymatic reactor was also used for the transesterification of triacylglycerides from soybean oil to fatty acid methyl esters thus demonstrating the ability of the reactor to produce biodiesel.

Aerosolized antimicrobial agents based on degradable dextran nanoparticles loaded with silver carbene complexes.

Degradable acetalated dextran (Ac-DEX) nanoparticles were prepared and loaded with a hydrophobic silver carbene complex (SCC) by a single-emulsion process. The resulting particles were characterized for morphology and size distribution using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The average particle size and particle size distribution were found to be a function of the ratio of the organic phase to the surfactant containing aqueous phase with a 1:5 volume ratio of Ac-DEX CH(2)Cl(2) (organic):PBS (aqueous) being optimal for the formulation of nanoparticles with an average size of 100 ± 40 nm and a low polydispersity. The SCC loading was found to increase with an increase in the SCC quantity in the initial feed used during particle formulation up to 30% (w/w); however, the encapsulation efficiency was observed to be the best at a feed ratio of 20% (w/w). In vitro efficacy testing of the SCC loaded Ac-DEX nanoparticles demonstrated their activity against both Gram-negative and Gram-positive bacteria; the nanoparticles inhibited the growth of every bacterial species tested. As expected, a higher concentration of drug was required to inhibit bacterial growth when the drug was encapsulated within the nanoparticle formulations compared with the free drug illustrating the desired depot release. Compared with free drug, the Ac-DEX nanoparticles were much more readily suspended in an aqueous phase and subsequently aerosolized, thus providing an effective method of pulmonary drug delivery.

Branched polymeric media: perchlorate-selective resins from hyperbranched polyethyleneimine.

Perchlorate (ClO(4)(-)) is a persistent contaminant found in drinking groundwater sources in the United States. Ion exchange (IX) with selective and disposable resins based on cross-linked styrene divinylbenzene (STY-DVB) beads is currently the most commonly utilized process for removing low concentrations of ClO(4)(-) (10-100 ppb) from contaminated drinking water sources. However, due to the low exchange capacity of perchlorate-selective STY-DVB resins (∼0.5-0.8 eq/L), the overall cost becomes prohibitive when treating groundwater with higher concentration of ClO(4)(-) (e.g., 100-1000 ppb). In this article, we describe a new perchlorate-selective resin with high exchange capacity. This new resin was prepared by alkylation of branched polyethyleneimine (PEI) beads obtained from an inverse suspension polymerization process. Batch and column studies show that our new PEI resin with mixed hexyl/ethyl quaternary ammonium chloride exchange sites can selectively extract trace amounts of ClO(4)(-) from a makeup groundwater (to below detection limit) in the presence of competing ions. In addition, this resin has a strong-base exchange capacity of 1.4 eq/L, which is 1.75-2.33 times larger than those of commercial perchlorate-selective STY-DVB resins. The overall results of our studies suggest that branched PEI beads provide versatile and promising building blocks for the preparation of perchlorate-selective resins with high exchange capacity.

Conjugation to Biocompatible Dendrimers Increases Lanthanide T2 Relaxivity of Hydroxypyridinone (HOPO) Complexes for Magnetic Resonance Imaging (MRI).

Magnetic resonance imaging (MRI) contrast agents represent a worldwide billion-dollar market annually. While T1 relaxivity enhancement contrast agents receive greater attention and a significantly larger market share, the commercial potential for T2 relaxivity enhancing contrast agents remains a viable diagnostic option due to their increased relaxivity at high field strengths. Improving the contrast and biocompatibility of T2 MRI probes may enable new diagnostic prospects for MRI. Paramagnetic lanthanides have the potential to decrease T1 and T2 proton relaxation times, but are not commercially used in MRI diagnostics as T2 agents. In this article, oxygen donor chelates (hydroxypyridinone, HOPO, and terephthalamide, TAM) of various lanthanides are demonstrated as biocompatible macromolecular dendrimer conjugates for the development of T2 MRI probes. These conjugates have relaxivities up to 374 mm-1s-1 per dendrimer, high bioavailability, and low in vitro toxicity.

Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy.

Materials that combine facile synthesis, simple tuning of degradation rate, processability, and biocompatibility are in high demand for use in biomedical applications. We report on acetalated dextran, a biocompatible material that can be formed into microparticles with degradation rates that are tunable over 2 orders of magnitude depending on the degree and type of acetal modification. Varying the degradation rate produces particles that perform better than poly(lactic-co-glycolic acid) and iron oxide, two commonly studied materials used for particulate immunotherapy, in major histocompatibility complex class I (MHC I) and MHC II presentation assays. Modulating the material properties leads to antigen presentation on MHC I via pathways that are dependent or independent of the transporter associated with antigen processing. To the best of our knowledge, this is the only example of a material that can be tuned to operate on different immunological pathways while maximizing immunological presentation.

Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis.

A biodegradable positron-emitting dendritic nanoprobe targeted at alpha(v)beta(3) integrin, a biological marker known to modulate angiogenesis, was developed for the noninvasive imaging of angiogenesis. The nanoprobe has a modular multivalent core-shell architecture consisting of a biodegradable heterobifunctional dendritic core chemoselectively functionalized with heterobifunctional polyethylene oxide (PEO) chains that form a protective shell, which imparts biological stealth and dictates the pharmacokinetics. Each of the 8 branches of the dendritic core was functionalized for labeling with radiohalogens. Placement of radioactive moieties at the core was designed to prevent in vivo dehalogenation, a potential problem for radiohalogens in imaging and therapy. Targeting peptides of cyclic arginine-glycine-aspartic acid (RGD) motifs were installed at the terminal ends of the PEO chains to enhance their accessibility to alpha(v)beta(3) integrin receptors. This nanoscale design enabled a 50-fold enhancement of the binding affinity to alpha(v)beta(3) integrin receptors with respect to the monovalent RGD peptide alone, from 10.40 nM to 0.18 nM IC(50). Cell-based assays of the (125)I-labeled dendritic nanoprobes using alpha(v)beta(3)-positive cells showed a 6-fold increase in alpha(v)beta(3) receptor-mediated endocytosis of the targeted nanoprobe compared with the nontargeted nanoprobe, whereas alpha(v)beta(3)-negative cells showed no enhancement of cell uptake over time. In vivo biodistribution studies of (76)Br-labeled dendritic nanoprobes showed excellent bioavailability for the targeted and nontargeted nanoprobes. In vivo studies in a murine hindlimb ischemia model for angiogenesis revealed high specific accumulation of (76)Br-labeled dendritic nanoprobes targeted at alpha(v)beta(3) integrins in angiogenic muscles, allowing highly selective imaging of this critically important process.

Electrical transport properties of oligothiophene-based molecular films studied by current sensing atomic force microscopy.

Using conducting probe atomic force microscopy (CAFM) we have investigated the electrical conduction properties of monolayer films of a pentathiophene derivative on a SiO(2)/Si-p+ substrate. By a combination of current-voltage spectroscopy and current imaging we show that lateral charge transport takes place in the plane of the monolayer via hole injection into the highest occupied molecular orbitals of the pentathiophene unit. Our CAFM data suggest that the conductivity is anisotropic relative to the crystalline directions of the molecular lattice.

Molecular design and ordering effects in π-functional materials for transistor and solar cell applications.

Organic electronics are broadly anticipated to impact the development of flexible thin-film device technologies. Among these, solution-processable π-conjugated polymers and small molecules are proving particularly promising in field-effect transistors and bulk heterojunction solar cells. This Perspective analyzes some of the most exciting strategies recently suggested in the design and structural organization of π-functional materials for transistor and solar cell applications. Emphasis is placed on the interplay between molecular structure, self-assembling properties, nanoscale and mesoscale ordering, and device efficiency parameters. A critical look at the various approaches used to optimize both materials and device performance is provided to assist in the identification of new directions and further advances.

A biocompatible oxidation-triggered carrier polymer with potential in therapeutics.

Dextran, a water-soluble, biocompatible polymer of glucose, was modified at its hydroxyls with arylboronic esters to make it soluble in common organic solvents, allowing for the facile preparation of oxidation-sensitive dextran (Oxi-DEX) carrier microparticles. These particles were found to release their payload with a half-life of 36 min at 1 mM H2O2, which can be compared with a half-life of greater than 1 week in the absence of H2O2. When used in a model vaccine application, Oxi-DEX particles loaded with ovalbumin (OVA) increased the presentation to CD8+ T-cells 27-fold relative to OVA encapsulated in a classical vehicle not sensitive to oxidation. No presentation was observed from cells incubated with unencapsulated OVA. Additionally, Oxi-DEX was found to be nontoxic in preliminary in vitro cytotoxicity assays. Because it is easy to prepare, sensitive to biological oxidation, and biocompatible, this material may represent an attractive new platform for selective delivery applications.

Steric control of the donor/acceptor interface: implications in organic photovoltaic charge generation.

The performance of organic photovoltaic (OPV) devices is currently limited by modest short-circuit current densities. Approaches toward improving this output parameter may provide new avenues to advance OPV technologies and the basic science of charge transfer in organic semiconductors. This work highlights how steric control of the charge separation interface can be effectively tuned in OPV devices. By introducing an octylphenyl substituent onto the investigated polymer backbones, the thermally relaxed charge-transfer state, and potentially excited charge-transfer states, can be raised in energy. This decreases the barrier to charge separation and results in increased photocurrent generation. This finding is of particular significance for nonfullerene OPVs, which have many potential advantages such as tunable energy levels and spectral breadth, but are prone to poor exciton separation efficiencies. Computational, spectroscopic, and synthetic methods were combined to develop a structure-property relationship that correlates polymer substituents with charge-transfer state energies and, ultimately, device efficiencies.

Conjugation effects of various linkers on Gd(III) MRI contrast agents with dendrimers: optimizing the hydroxypyridinonate (HOPO) ligands with nontoxic, degradable esteramide (EA) dendrimers for high relaxivity.

One essential requirement for more sensitive gadolinium-based MRI contrast agents is to slow the molecular tumbling of the gadolinium(III) ion, which increases the gadolinium's relaxivity (i.e., its ability to speed up the NMR relaxation of nearby water molecules). One route to this is through conjugation to high-molecular-weight polymers such as dendrimers. In this work, amine-functionalized TREN-bis(1,2-HOPO)-TAM-ethylamine and TREN-bis(1-Me-3,2-HOPO)-TAM-ethylamine ligands have been synthesized and attached to biocompatible 40 kDa esteramide (EA)- and poly-l-lysine (PLL)-based dendrimers capable of binding up to eight gadolinium complexes. These conjugates have T(1) relaxivities of up to 38.14 ± 0.02 mM(-1) s(-1) per gadolinium at 37 °C, corresponding to relaxivities of up to 228 mM(-1) s(-1) per dendrimer molecule. This relaxivity expressed on a "per Gd" basis is several times that of the small-molecule complexes and an order of magnitude higher than that of current commercial agents. Because of their high performance and low toxicity, these macromolecules may constitute an attractive complement to currently available gadolinium(III)-based contrast agents.

Porous polymer monoliths functionalized through copolymerization of a C60 fullerene-containing methacrylate monomer for highly efficient separations of small molecules.

Monolithic poly(glycidyl methacrylate-co-ethylene dimethacrylate) and poly(butyl methacrylate-co-ethylene dimethacrylate) capillary columns, which incorporate the new monomer [6,6]-phenyl-C(61)-butyric acid 2-hydroxyethyl methacrylate ester, have been prepared and their chromatographic performance have been tested for the separation of small molecules in the reversed phase. While addition of the C60-fullerene monomer to the glycidyl methacrylate-based monolith enhanced column efficiency 18-fold, to 85,000 plates/m at a linear velocity of 0.46 mm/s and a retention factor of 2.6, when compared to the parent monolith, the use of butyl methacrylate together with the carbon nanostructured monomer afforded monolithic columns with an efficiency for benzene exceeding 110,000 plates/m at a linear velocity of 0.32 mm/s and a retention factor of 4.2. This high efficiency is unprecedented for separations using porous polymer monoliths operating in an isocratic mode. Optimization of the chromatographic parameters affords near baseline separation of 6 alkylbenzenes in 3 min with an efficiency of 64,000 plates/m. The presence of 1 wt % or more of water in the polymerization mixture has a large effect on both the formation and reproducibility of the monoliths. Other factors such as nitrogen exposure, polymerization conditions, capillary filling method, and sonication parameters were all found to be important in producing highly efficient and reproducible monoliths.