Showing papers by "Bing Xu published in 2013"

d-Amino Acids Boost the Selectivity and Confer Supramolecular Hydrogels of a Nonsteroidal Anti-Inflammatory Drug (NSAID)

Abstract: As systemically used therapeutics for treating acute or chronic pains or inflammations, nonsteroidal anti-inflammatory drugs (NSAIDs) also associate with the adverse gastrointestinal and renal effects and cardiovascular risks. Thus, it is beneficial to develop topical gels that selectively inhibit cyclooxygenase-2 (COX-2) for the management of local inflammation. In this work, we demonstrate that the covalent conjugation of d-amino acids to naproxen (i.e., a NSAID) not only affords supramolecular hydrogelators for the topical gels but also unexpectedly and significantly elevates the selectivity toward COX-2 about 20× at little expense of the activity of naproxen. This work illustrates a previously unexplored approach that employs d-amino acids for the development of functional molecules that have dual or multiple roles and exceptional biostability, which offers a new class of molecular hydrogels of therapeutic agents.

Dephosphorylation of d-Peptide Derivatives to Form Biofunctional, Supramolecular Nanofibers/Hydrogels and Their Potential Applications for Intracellular Imaging and Intratumoral Chemotherapy

Abstract: d-Peptides, as the enantiomers of the naturally occurring l-peptides, usually resist endogenous proteases and are presumably insensitive to most enzymes. But, it is unclear whether or how a phosphatase catalyzes the dephosphorylation from d-peptides. In this work, we examine the formation of the nanofibers of d-peptides via enzymatic dephosphorylation. By comparing the enzymatic hydrogelation of l-peptide and d-peptide based hydrogelators, we find that the chirality of the precursors of the hydrogelators affects little on the enzymatic hydrogelation resulted from the removal of the phosphate group from a tyrosine phosphate residue. The attachment of a therapeutic agent (e.g., taxol) or a fluorophore (e.g., 4-nitro-2,1,3-benzoxadiazole) to the d-peptide based hydrogelators affords a new type of biostable or biocompatible hydrogelators, which may find applications in intratumoral chemotherapy or intracellular imaging, respectively. This work, as the first comprehensive and systematic study of the unexpected...

A Redox Responsive, Fluorescent Supramolecular Metallohydrogel Consists of Nanofibers with Single-Molecule Width

Abstract: The integration of a tripeptide derivative, which is a versatile self-assembly motif, with a ruthenium(II)tris(bipyridine) complex affords the first supramolecular metallo-hydrogelator that not only self assembles in water to form a hydrogel but also exhibits gel-sol transition upon oxidation of the metal center. Surprisingly, the incorporation of the metal complex in the hydrogelator results in the nanofibers, formed by the self-assembly of the hydrogelator in water, to have the width of a single molecule of the hydrogelator. These results illustrate that metal complexes, besides being able to impart rich optical, electronic, redox, or magnetic properties to supramolecular hydrogels, also offer a unique geometrical control to prearrange the self-assembly motif prior to self-assembling. The use of metal complexes to modulate the dimensionality of intermolecular interactions may also help elucidate the interactions of the molecular nanofibers with other molecules, thus facilitating the development of supramolecular hydrogel materials for a wide range of applications.

Disruption of the Dynamics of Microtubules and Selective Inhibition of Glioblastoma Cells by Nanofibers of Small Hydrophobic Molecules

Abstract: Self-organization of molecules via non-covalent interactions is able to generate complex matters and structures[1] that function at both supramolecular and cellular levels. For example, proteins self-assemble into a variety of nanofibers (or filaments), which are critical components for many essential cellular activities. Inside cells, actins, lamins and tubulins self-assemble to afford microfilaments, intermediate filaments, and microtubules, respectively;[2] outside cells, the self-assembly of collagen and elastin provides nanofibers that serve as the extracellular matrix to support and regulate differentiation, proliferation, and interaction of cells.[2] While the nanofibers of normal proteins are essential for normal cellular functions, the aggregation of aberrant proteins also results in aggregates (e.g., β-amyloid oligomers)[3] that are toxic to cells. Like proteins, certain small organic molecules also self-assemble in water to afford supramolecular nanofibers in which aromatic-aromatic interactions and hydrophobicity play critical roles for guiding hydrogen bonding, promoting the self-assembly, and stabilizing the resulted nanofibers.[4] While the successful formation of supramolecular nanofibers of small molecules has resulted in hydrogels[5] as a new class of biomaterials for tissue engineering,[6] drug delivery,[7] protein arrays,[8] electrophoresis,[9] bacteria typing,[10] and protocells,[11] there is little exploration on the protein targets[12] and cytotoxicity of the supramolecular nanofibers of small molecules,[10, 13] especially at the concentration below the critical gelation concentration (cgc).

Probing nanoscale self-assembly of nonfluorescent small molecules inside live mammalian cells.

Abstract: Like cellular proteins that form fibrillar nanostructures, small hydrogelator molecules self-assemble in water to generate molecular nanofibers. In contrast to the well-defined (dys)functions of endogenous protein filaments, the fate of intracellular assembly of small molecules remains largely unknown. Here we demonstrate the imaging of enzyme-triggered self-assembly of nonfluorescent small molecules by doping the molecular assemblies with a fluorescent hydrogelator. The cell fractionation experiments, fluorescent imaging, and electron microscopy indicate that the hydrogelators self-assemble and localize to the endoplasmic reticulum (ER) and are likely processed via the cellular secretory pathway (i.e., ER–Golgi–lysosomes/secretion). This work, as the first example of the use of correlative light and electron microscopy for probing the self-assembly of nonfluorescent small molecules inside live mammalian cells, not only establishes a general strategy to provide the spatiotemporal profile of the assemblies...

The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels

Abstract: Here we report supramolecular hydrogelators made of nonsteroidal anti-inflammatory drugs (NSAID) and small peptides. The covalent linkage of Phe–Phe and NSAIDs results in conjugates that self-assemble in water to form molecular nanofibers as the matrices of hydrogels. When the NSAID is naproxen (1), the resultant hydrogelator 1a forms a hydrogel at a critical concentration (cgc) of 0.2 wt % at pH 7.0. Hydrogelator 1a, also acting as a general motif, enables enzymatic hydrogelation in which the precursor turns into a hydrogelator upon hydrolysis catalyzed by a phosphatase at physiological conditions. The conjugates of Phe–Phe with other NSAIDs, such as (R)-flurbiprofen (2), racemic flurbiprofen (3), and racemic ibuprofen (4), are able to form molecular hydrogels, except in the case of aspirin (5). After the conjugation with the small peptides, NSAIDs exhibit improved selectivity to their targets. In addition, the peptides made of D-amino acids help preserve the activities of NSAIDs. Besides demonstrating that common NSAIDs are excellent candidates to promote aromatic–aromatic interaction in water to form hydrogels, this work contributes to the development of functional molecules that have dual or multiple roles and ultimately may lead to new molecular hydrogels of therapeutic agents for topical use.

Self-delivery multifunctional anti-HIV hydrogels for sustained release.

Abstract: None of the clinical trials of anti-HIV gels based on conventional polymers or lipid emulsions has been successful, suggesting the need of new molecular design of the anti-HIV gels. This paper reports the conversion of anti-HIV prodrugs into self-delivery supramolecular hydrogels. By covalently conjugating reverse transcriptase inhibitors to a versatile self-assembly motif, the hydrogelators that self-assemble to form supramolecular nanofibers as the matrices of hydrogels in a weak acidic condition are obtained. Upon the treatment of prostate acid phosphatase (PAP), the hydrogels exhibit drastically enhanced elasticity. The hydrogelators are biocompatible and able to release the inhibitors under physiological condition. The use of the self-assembly motif as a self-delivery agent containing non-steroid anti-inflammatory drug (NSAID) renders this hydrogel to be both anti-inflammatory and anti-HIV. This work illustrates an unprecedented approach for designing multifunctional supramolecular hydrogels that may serve as potential anti-HIV hydrogels for sustained drug release.

Active cross-linkers that lead to active gels.

Abstract: Chemomechanical reaction: The first octahedral ruthenium bipyridine complex that bears six polymerizable vinyl groups is used as an active cross-linker. It is a key building block for cross-linked polymeric networks (right) thus allowing the construction of molecular architectures in chemomechanical soft materials.

Imaging self-assembly dependent spatial distribution of small molecules in a cellular environment.

Abstract: Self-assembly of small molecules, as a more common phenomenon than one previously thought, can be either beneficial or detrimental to cells. Despite its profound biological implications, how the self-assembly of small molecules behave in a cellular environment is largely unknown and barely explored. This work studies four fluorescent molecules that consist of the same peptidic backbone (e.g., Phe–Phe–Lys) and enzyme trigger (e.g., a phosphotyrosine residue), but bear different fluorophores on the side chain of the lysine residue of the peptidic motif. These molecules, however, exhibit a different ability of self-assembly before and after enzymatic transformation (e.g., dephosphorylation). Fluorescent imaging reveals that self-assembly directly affects the distribution of these small molecules in a cellular environment. Moreover, cell viability tests suggest that the states and the locations of the molecular assemblies in the cellular environment control the phenotypes of the cells. For example, the molecu...

Interactions between cellular proteins and morphologically different nanoscale aggregates of small molecules

Abstract: Depending on the methods of preparation, amphiphilic small molecules aggregate to form nanostructures with different morphologies that interact with cytosol proteins in a drastically different manner, thus illustrating the first example of morphologically dependent protein binding of nanoscale molecular aggregates.

Post-Self-Assembly Cross-Linking to Integrate Molecular Nanofibers with Copolymers in Oscillatory Hydrogels

Abstract: We study the use of post-self-assembly cross-linking to combine molecular nanofibers of hydrogelators with copolymers to generate oscillatory materials using the Belousov–Zhabotinsky reaction. The formation of nanofibers from designed hydrogelators provides multiple polymerizable sites for copolymerizing with N-isopropylacrylamide and for attaching a catalytic ruthenium bipyridine complex on the copolymer. The combination of supramolecular self-assembly with copolymerization offers a versatile and facile approach for generating soft materials that have large pores in the gel network and robust mechanical integrity. These larger pores facilitate the diffusion of the reactants and accelerate the chemical oscillation by about a factor of 4 relative to a poly(NIPAAm-Ru) gel that contains no molecular nanofibers.

Length-dependent proteolytic cleavage of short oligopeptides catalyzed by matrix metalloprotease-9.

Abstract: Matrix metalloproteinases (MMPs), as the enzymes to degrade extracellular matrix proteins, play a major role on cell behaviors. Among them, MMP-9 usually catalyzes the degradation of proteins with the dominant cleavage at G/L site. Recent high-throughput screening suggests that S/L is a new major site for the cleavage when the substrates of MMP-9 are oligopeptides. Here we examine the cleavage sites of the N-terminal substituted short oligopeptides as the substrates of MMP-9. As the first example of such study of N-substituted small peptides, our results suggest that the substitute group at the N-terminal and the length of peptides significantly affect the position of the cleavage site on the oligopeptides, which provides a useful insight for the design of small peptide derivatives as the substrates of MMP-9.

Supramolecular nanofibers and hydrogels based on nucleic acids functionalized with nucleobases

Abstract: Disclosed are nucleopeptide compounds that include a nucleobase, and an amino acid. Certain compounds further comprise a glycoside. The compounds may self-assemble to form supramolecular hydrogels. Also, the compounds may be used as a platform to examine specific biological functions (e.g., binding to DNA and RNA) of a dynamic supramolecular system that is able to interact with both proteins and nucleic acids. Other uses include: methods of growing cells and methods of delivering a substance to a cell.

Hydrogelators comprising d-amino acids

Abstract: Described herein are compounds comprising an oligopeptide and a non-steroidal antiinflammatory agent. The compounds self-assemble into supramolecular hydrogels and can be used as topical treatments for inflammatory conditions, such as osteoarthritis. Also described herein are oligopeptides compounds made from D-amino acid residues that form supramolecular hydrogels. The compounds may be functionalized with active agents, such as anticancer therapeutic agents, antiinflammatory agents, or imaging agents, therefore providing new mechanisms for delivery of active agents.