Volume 76, Issue 7-8

In recent years, supramolecular micellar assemblies formed from amphiphilic block copolymers have been receiving attention as potential drug carriers. The size of the carriers is ideal for avoiding rapid renal exclusion and reticuloendothelial uptake, and enables them to be targeted to certain tissues such as tumors. One important issue determining the effectiveness of a micellar drug carrier is the ability to control the time over which drug release takes place, or to possibly trigger drug release at a specific location or time. The mildly acidic pH encountered in tumor and inflammatory tissues as well as in the endosomal and lysosomal compartments of cells has inspired the development of micellar carriers capable of releasing their drug load in response to small changes in pH. One approach to the development of these systems has been to incorporate “titratable” groups such as amines and carboxylic acids into the copolymer backbone, thus altering the solubility of the polymer upon protonation and disrupting micelle formation. Another approach has been to incorporate acid-degradable linkages into the copolymer, either for direct attachment of the drug, or to cause a structural change of such magnitude that micellar integrity is lost and the drug is released.

Amphiphilic block copolymers have the ability to assemble into multiple morphologies in solution. Depending on the length of the hydrophilic block, the morphology can vary from spherical micelles, rods, and vesicles to large compound micelles (LCMs). Vesicle formation is favored upon an increase in total molecular weight of the block copolymer, that is, an increasing bending modulus ( K ). Owing to the polymeric character of this type of vesicle (also called polymersomes), they possess remarkable properties. The diffusion of (polymeric) amphiphiles in these vesicles is very low compared to liposomes and for high-molecular-weight chain entanglements even lead to reptation-type motions, which make it possible to trap near-equilibrium and metastable morphologies. Additionally, in contrast to liposomes, membrane thicknesses can exceed 200 nm. As a consequence, this increased membrane thickness, in combination with the conformational freedom of the polymer chains, leads to a much lower permeability for water of block copolymer vesicles compared to liposomes. The enhanced toughness and reduced permeability of polymersomes makes them, therefore, very suitable as stable nanocontainers, which can be used, for example, as reactors or drug delivery vehicles.

The oral delivery of drugs is regarded as the optimal means for achieving therapeutic effects owing to increased patient compliance. Unfortunately, the oral delivery route is beset with problems such as gastrointestinal (GI) destruction of labile molecules, low levels of macromolecular absorption, etc. To reduce the impact of digestive enzymes and to ensure the absorption of bioactive agents in an unaltered form, molecules may be incorporated into microparticulate carriers. Many approaches to achieve the oral absorption of a wide variety of drugs are currently under investigation. Among the different polymer-based drug delivery systems, polymeric micelles represent a promising delivery vehicle especially intended for poorly water-soluble pharmaceutical active ingredients in order to improve their oral bioavailability. Recent findings of a dextran-based polymeric micelle study for solubilization of a highly lipophilic drug, cyclosporin A (CsA), will be discussed.

Hydrogen-bonded side-chain liquid-crystalline block copolymers (SCLCBCPs) containing block segments with proton donors were combined with functionalized mesogenic pendent groups. Studies of a wide range of mesogen and polymer combinations were carried out to study the relationship between morphology and mesophase behavior. The thermal behaviors of the resulting self-assembled microstructures were also examined. A model of the assembly process leading to mesogenic group organization corresponding to different compositions was proposed.

Studies of how hydrogen bonding can be used to control molecular association continue to yield exciting discoveries in supramolecular chemistry. A simple way to make molecules that associate predictably is to link carefully selected cores to functional groups that form multiple hydrogen bonds according to reliable patterns. Bifunctional molecules constructed according to this strategy can associate to form linear aggregates robust enough to warrant the name supramolecular polymers, even though the bifunctional monomers are joined only by hydrogen bonds. More complex molecules with multiple hydrogen-bonding sites can be devised so that neighbors are held in predetermined positions, giving crystalline solids with predictable architectures and properties not previously seen in other materials. Initial studies of the ability of such compounds to associate in solution and in the molten state suggest that hydrogen-bonded networks can be purposefully designed to create novel par- tially ordered liquid materials, including liquid crystals, gels, and fluids with unusual rheological properties.

The morphology of blends of two types of hydrogen-bonding systems was studied with a view to understanding the effect of blending on the extent of hydrogen bonding and changes in the morphology.One of them is the long-chain carbamate with a C 18 alkyl side chain, and the other is stearic acid, which also has a C 17 alkyl chain. At low concentrations, the C 18 carbamate reduces the size of the crystals of stearic acid. However, the stearic acid has no effect on the morphology of the carbamate. The morphological changes are due to the disruptive packing of the alkyl chains, rather than a change in the extent of hydrogen bonding. The blends of homologous carbamates studied before [Moniruzzaman, Goodbrand, Sundararajan, J. Phys. Chem. Part B 107 , 8416 (2003)] are more effective in mutually controlling the spherulite size and imparting transparency than the carbamate/stearic acid blend. The presence of the carbamate as the minor component changes the ratio of the intensities of the X-ray reflections at 2 (theta)=21.6 and 2.21°. It is found that in the blends with the carbamates quenched from the melt, the stearic acid exhibits a polymorphic transition from the E to the C form in the differential scanning calorimetry (DSC) analysis.

Poly(divinylbenzene-55)[poly(DVB-55] microspheres were used as building blocks to form polymer capsule walls consisting of interconnected microspheres. The microspheres had to be surface-functionalized with maleic acid to facilitate their interfacial assembly. In addition, porous and functionalized poly(DVB-55) microspheres were embedded across interfacial polyurea capsule membranes to form composite tectocapsules where release of core materials is designed to occur through the microsphere pores, rather than by conventional wall diffusion. Electron microscopy and X-ray spectromicroscopy were used to characterize the wall compositions, and release data are presented to illustrate the role of microspheres acting as release portals.

Research on dendrimers continues to expand as further advances in synthetic methodology and characterization techniques translate to additional applications. Recently, dendritic polymers composed of the natural metabolites glycerol and succinic acid were synthesized, functionalized, and evaluated as new medical materials. The design and synthesis of poly(glycerol-succinic acid) dendritic polymers are discussed, including comparing and contrasting the convergent versus the divergent methodologies for preparing such macromolecules. Finally, a photocrosslinkable dendritic macromolecule was prepared and successfully used to close linear corneal lacerations as well as to secure LASIK flaps.

Multilayer thin films prepared from weak polyelectrolytes can exhibit a rich suite of anomalous physicochemical properties. One of the major factors that influence the properties of such films is the acid/base chemistry of the weak functional groups of the poly- electrolytes. In fact, the apparent dissociation constants of weak polyelectrolytes can shift by as much as 1–4 pH units upon incorporation into multilayer films from that in dilute solution. Here, we discuss this variability in the dissociation behavior of polyelectrolytes in multilayer films, and how it relates to understanding the diversity in the physicochemical properties observed for films assembled from the same polyelectrolytes, but under different pH conditions. In turn, we review some of the recent research that attempts to take advantage of the pH-tunable properties of multilayer films for a variety of applications.

Dendritic polyphenylazomethines (DPAs) were synthesized as novel topological polymer ligands with pi-conjugated structures by the convergent method via dehydration of aromatic ketones with aromatic amines in the presence of TiCl 4 . DPA G4 molecules are revealed to have a sphere-like structure with a 2.3-nm diameter and are regularly assembled without deformation of the molecule on a plate as observed by means of gel permeation chromatography (GPC), molecular modeling, transmission electron microscopy (TEM), atomic force microscopy (AFM), and pi-A measurements. The stepwise radial complexation in DPAs with SnCl 2 was observed as a stepwise shift in the isosbestic point in the UV-vis spectra. The number of added equivalents of SnCl 2 required to induce a shift was in agreement with the number of imine groups present in the different shells of the DPAs. These spectral changes suggest that the complexation is proceeding in a stepwise fashion from the core imines to the terminal imines of the DPAs, which was further supported by shell-selective reduction (SSR) of the imines.

Novel series of monodisperse, end-functionalized oligophenylenevinylenes (OPVs) containing up to eight phenyl rings have been designed and synthesized by a convergent approach using the stereoselective Wadsworth–Emmons reactions for an investigation of technologically useful functional properties. According to PM3 semiempirical quantum mechanical calculations, the frontier molecular orbitals and the energy gap of an OPV could be shifted or tuned by the functional substituent(s) that are incorporated as end-caps. Our theoretical and experimental evidences have shown that the end-substituents of an oligomer do not affect coplanarity of the pi-conjugated system. It has also been found that the newly synthesized OPVs can exhibit various useful functional properties such as light-emitting properties, photovoltaic effects, third-order nonlinear optical responses, and chemical sensing properties depending on the nature of the end-substituents. In this contribution, the structural factor(s) that can enhance a specific functional property of a molecule or material will be discussed.

The macroscopic electrooptic activity of organic materials depends upon the molecular hyperpolarizability, beta, of individual organic chromophores and upon the product of number density, N , and noncentrosymmetric order, <cos 3 theta>, of the chromophores in a hardened polymer lattice. Quantum and statistical mechanical calculations provide the basis for rational improvement of these parameters leading to electro-optic coefficients (at telecommunication wavelengths) of greater than 100 pm/V (a factor of 3 larger than values for the best inorganic material, lithium niobate). Such calculations also provide insight into what further improvements can be expected. Owing to low and relatively dispersionless dielectric constants and refractive indicies, organic materials facilitate the fabrication of devices with 3 dB operational bandwidths of greater than 100 GHz. Moreover, robust and low optical loss materials can be fabricated by design. An under-appreciated advantage of organic electro-optic materials is their processability, and a variety of stripline, cascaded prism and super-prism, and ring microresonator devices are readily fabricated. Conformal, flexible, and three-dimensional devices are also readily produced. With ring microresonator devices, active wavelength division multiplexing, optical network reconfiguration, and laser frequency tuning are straightforwardly accomplished.

Organic solids and polymers that absorb in the near-infrared (NIR) region (1000–2000 nm) represent a class of emerging materials and show a great potential for use in photonics and telecommunications. The radical anions of stacked aromatic imides, fused phorphyrin arrays, polythiophenes, sandwich-type lanthanide bisphthalocyanines, semiquinones, and mixed-valence dinuclear metal complexes are a few known examples of NIR-absorbing organic materials. Most of these NIR-absorbing materials are also electro- chemically active or electrochromic (EC). This brief review covers several types of NIR-absorbing organic materials and discusses their potential for applications in EC variable optical attenuators (VOAs).

Azobenzene chromophores can be switched between two geometric isomers using visible light. This photoisomerization is rapid, reversible, and of high quantum yield, and the wavelengths effecting the transformation can be tuned synthetically with substituent groups to the chromphores. Upon isomerization, there can be significant changes to the optical, geometric, mechanical, and chemical properties of azobenzene molecules, and these photo-switchable properties can often be transferred to large host systems into which azobenzene is incorporated. This review describes polymers and surfaces that have been prepared recently that incorporate azobenzene groups, and some of the interesting physical and chemical properties that can be switched reversibly as a result.

Liquid-crystalline gels and elastomers were prepared by polymerization of mixtures containing azobenzene monomers and cross linkers with azobenzene moieties. Oriented liquid-crystalline gels and elastomer films were found to undergo anisotropic bending and unbending behavior only along the rubbing direction, when exposed to alternate irradiation of unpolarized UV and visible light. In the case of polydomain liquid-crystalline elastomer films, the bending and unbending were induced exactly along the polarization direction of incident linearly polarized light. By altering the polarization direction of light, a single film could be bent repeatedly and precisely along any chosen direction.

The following article is a tribute to the late Almeria Natansohn and is based on a brief summary of her research in azopolymers. She showed that reversible trans–cis–trans photoisomerization of aromatic azo groups covalently bonded within polymers could trigger a variety of motions in the polymer materials at molecular, nanometer, and micrometer levels. The photoinduced motions could be limited only to the azo rigid chromophore or could involve many polymer chains and ordered domains. Some of the effects of these motions such as reversible photo-orientation of chromophores, amplification effects, photorefractive effects, formation of surface relief gratings (SRGs), and photoinduced chirality and switching in amorphous and liquid-crystalline (LC) polymer films are discussed in relation to the polymer structure and physical parameters. Possible photonic applications originating from these phenomena are also mentioned.

The reversible trans–cis photoisomerization of azobenzene and azopyridine chromophore was used to design and exploit novel photoactive materials based on polymers and liquid crystals. This paper reviews our recent studies on several systems. These include azobenzene-containing thermoplastic elastomers that can be used to prepare mechanically tunable diffraction gratings, side-chain azopyridine polymers for combined self-assembly and photoactivity, azobenzene polymer-stabilized ferroelectric liquid crystals whose bulk alignment can be achieved by light with no need for surface orientation layers, and, finally, self-assembled photoactive liquid-crystal gels that can display light-induced reorganization leading to the formation of electrically switchable diffraction gratings.

Pai and coworkers have reported that the charge carrier mobility of the hole transport molecule N,N' -diphenyl- N,N' -bis(3-methylphenyl)-[1,1'-biphenyl]-4,4'-diamine (TPD) is higher with polystyrene (PS) as the host polymer, in comparison to bisphenol A polycarbonate (PC) as the binder. It was proposed that the enhanced interaction of TPD with PC and the effect of the carbonyl dipole are responsible for such a phenomenon.We present a morphological study that lends support to the above proposal. The morphology and thermal behavior of TPD/polystyrene (TPD/PS) composites have been investigated as a binary solid solution and compared with that of the TPD/polycarbonate (TPD/PC) pair. The depression of the glass-transition temperature (T g ) with the concentration of TPD is more pronounced with PC than with PS. On the other hand, the recovery of the T g upon annealing is significantly higher in the case of PS. Fourier transform infrared (FTIR) study shows that the molecular- level interaction between TPD and PS is not as significant as in the case PC. Molecular modeling based on the MM+ molecular mechanics calculations also shows an electrostatic component to the total interaction energy in the case of PC. In addition, small crystals are present in the as-prepared films of TPD/PS that, upon chaining, could enhance the charge carrier mobility. Thus, it is suggested that the enhanced interaction between TPD and PC as well as the small crystals of TPD in PS are responsible for the higher mobility in the latter. PS serves as an inert host, while there are specific interactions between TPD and PC.

Fifty years have passed since Watson and Crick proposed the molecular basis for the replication of nucleic acid and hence the transfer of genetic information. During this time, a model for the expression of this genetic information has been proposed and refined considerably. Coincident with these advances, the chemical synthesis of oligonucleotides combined with the power of molecular biology has facilitated dramatic advances in our understanding of the fundamental workings of the living cell.

This review summarizes the history and most recent advances in aptamers and ribozymes that bind and use redox (reduction–oxidation) cofactors. Redox reactions, catalyzed by protein enzymes in an extant world, play a central role in the metabolism of numerous biological molecules in the living organisms. The burden of catalyzing these reactions in a pre-protein-based world (i.e., the hypothesized RNA World) could have been borne by RNA molecules. To this end, we raise a fundamental question: can RNA accelerate the redox chemical transformation? We hope that this article will be able to shed light on this intriguing question.

PS2.M, an 18-nucleotide DNA molecule, has been shown to be a dual enzyme for porphyrin metallation and, when complexed with hemin, for peroxidation. To date, detailed information has not been available on either the actively folded structure of PS2.M or on the contribution of specific nucleotides within it toward the peroxidase activity. Here, we report a variety of experiments that probe the structure and function of PS2.M as well as of a number of point mutants of PS2.M. Based on these experiments, a structural model for the folding of PS2.M and the location of a functionally relevant hemin-binding site are proposed. A key finding is that PS2.M, originally obtained by in vitro selection from a random-sequence DNA library, is uniquely suited for its catalysis of peroxidation; all point mutants examined showed significantly poorer catalytic activity than PS2.M itself.

Single-stranded DNA molecules with ligand-binding ability and catalytic function, referred to as DNA aptamers and DNA enzymes, respectively, are special DNA sequences isolated from random-sequence DNA libraries by “in vitro selection”. These two new classes of artificial DNA molecules have the potential of being used as molecular tools in a variety of innovative applications ranging from biosensing to gene regulation. Our laboratory is interested in engineering fluorescence-signaling DNA aptamers and DNA enzymes that can be widely exploited for detection-directed applications. In this article, we will first discuss our recent efforts on the rational design of a new class of signaling aptamers denoted “structure- switching signaling aptamers”, which report target binding by switching structures from DNA/DNA duplex to DNA/target complex. We will then describe the in vitro selection of fluorescence-signaling DNA enzymes that exhibit a synchronized catalysis-signaling capability by cleaving a chimeric RNA/DNA substrate at the lone RNA linkage surrounded by closely spaced fluorophore-quencher pair. Potential utilities of these signaling DNA molecules will also be discussed.

DNA-methyltransferases catalyze the sequence-specific transfer of the methyl group of S -adenosylmethionine to target bases in genomic DNA. For gaining access to their target embedded within a double-helical structure, DNA-methyltransferases (DNA-MTases) rotate the target base out of the DNA helix. This base-flipping leads to the formation of an apparent abasic site. MTases such as cytosine-specific M Hha I and M Hae III and also the repair enzyme uracil DNA glycosylase (UDG) insert amino acid side chains into the opened space and/or rearrange base-pairing. The adenine-specific DNA MTase M Taq I binds without amino acid insertion. This binding mode allows for a substitution of the orphaned thymine with larger DNA base surrogates without steric interference by inserted amino acid side chains. DNA containing pyrenyl, naphthyl, acenaphthyl, and biphenyl residues was tested in M Taq I binding studies. The synthesis of DNA building blocks required the formation of a C -glycosidic bond, which was established by using protected 1-chloro-2-deoxy- ribose as glycosyl donor and organocuprates as glycosyl acceptors. It is shown that all of the base surrogates enhanced the binding affinity to M Taq I. Incorporation of pyrene increased the binding affinity by a factor of 400. Interestingly, there is a correlation between the observed order of dissociation constants and the ability of a base surrogate to stabilize abasic sites in model duplexes.

We have been interested in merging synthetic nucleotide chemistry with combinatorial selection of DNAzymes to deliver a more complete (and complex) chemical complement to the catalytic repertoire of nucleic acids. Thus we ask, what do modified dNTPs really bring to nucleic acids in terms of an increased repertoire? In asking this question, we have looked first at conditions, and more recently for reaction classes where nucleic acids are found to be catalytically inefficient, deficient, or at least to date, seemingly incapable of certain functions. A case of this is M 2+ -independent ribophosphodiester hydrolysis at physiological pH and low ionic strength where nucleic acids exhibit especially low rate constants for self-cleavage and seem to be incapable of turnover.

We hypothesize that we can exploit what Nature has already evolved by manipulating the alpha-helix molecular recognition scaffold. Therefore, minimalist proteins capable of sequence-specific, high-affinity binding of DNA were generated to probe how proteins are used and can be used to recognize DNA. The already minimal basic region/leucine zipper motif (bZIP) of GCN4 was reduced to an even more simplified structure by substitution with alanine residues —hence, a generic, Ala-based, helical scaffold. The proteins generated, wt bZIP , 4A , 11A , and 18A , contain 0, 4, 11, and 18 alanine mutations in their DNA-binding basic regions, respectively. All alanine mutants still retain alpha-helical structure and DNA-bind- ing function, despite loss of virtually all Coulombic protein-DNA interactions. Mass spectrometry allowed characterization of proteins and post-translational modifications. Fluorescence anisotropy and DNase I footprinting were used to measure in situ binding of these mutant proteins to DNA duplexes containing target sites AP-1 (5'-TGACTCA-3'), ATF/CREB (5'-TGACGTCA-3'),or nonspecific DNA. The roles of van der Waals and Coulombic interactions toward binding specificity and affinity are being investigated. Thus, both DNA-binding specificity and affinity are maintained in all our bZIP derivatives. This Ala-rich scaffold may be useful in design and synthesis of small, alpha-helical proteins with desired DNA-recognition properties.

Peptide nucleic acid (PNA) presents a versatile scaffold for chemical modifications that may benefit its solubility and hybridization properties, conjugation chemistry, cell membrane permeability, and so forth. We have employed straightforward chemical methods for the synthesis of PNA monomers containing C5-or C6-modified pyrimidines.The C5-modified pyrimidines are based on 5-hydroxymethyl-uracil or cytosine, or are achieved by cross-coupling from the 5-iodonucleobase derivatives, while C6 modifications are accessed from 6-carboxyuracil (orotic acid). We have also developed an on-resin activation/conversion of uracil-containing PNA oligomers to N 4 -cytosine-containing derivatives.

The remarkable medicinal importance of the achiral, acyclic, and uncharged aminoethylglycyl peptide nucleic acids ( aeg PNAs) as DNA/RNA mimics has challenged chemists to circumvent the limitations of their in vivo efficacy. In this context, we have designed conformationally restricted five- and six-membered cyclic PNA analogs by introduction of chemical bridges in aeg PNAs leading to a large variety of structures with defined configurations and conformational preferences, effecting concomitant installation of a positive charge in the backbone. The synthesis and biophysical properties of these cationic aminoethylprolyl PNAs, pyrrolidine PNAs, and piperidine PNAs endowed with increased water solubility and affinity toward target nucleic acids is presented. These nucleic acid analogs as lead structures are a part of a chemical evolution process that might give rise to a synthetic nucleic acid analog having optimum properties for medicinal applications.