Crosslinked poly(ethylene oxide) for drug release systems

Three types of poly(ethylene oxide) (PEO)- based hydrogels have been synthesized and studied for drug release applications: γ-irradiated high molecular weight PEO, biodegradable polyether-polyester networks with malic acid as crosslinker of poly(ethylene glycol)s and amphiphilic PEO-based polyureas crosslinked with multifunctional isocyanates. Varying the length of the PEO chain and the type of the crosslinker, hydrogels with different swelling properties, loading capacities and release characteristics were obtained. A large number of pharmaceuticals (acebutolol. HCl, diclofenac. Na, procaine. HCl, phenobarbital.a, propranolol, etc.) were tested for a sustained release in different media (pH=1.2, 6.5, 7.4). Most of them # gave reasonable retarded release profiles for 8 hours when incorporated before the γ-irradiation crosslinking of PEO. While amphiphilic hydrogels were found to be suitable for hydrophobic solutes, the biodegradable PEO-based polyester ones affected predominantly the release of water-soluble drugs. No pH effect was found for the γ-irradiated PEO as a carrier in contrast to the strong pH dependence for the degradable polyester networks.     

Let There Be Light: Targeted Photodynamic Therapy Using High Aspect Ratio Plant Viral Nanoparticles

The development of plant viral nanoparticles (VNP) loaded with different molecular versions of a photodynamic drug is described. Specifically, tobacco mosaic virus (TMV) and tobacco mild green mosaic virus (TMGMV) are developed as drug carriers that encapsulate the monocationic, dicationic, tricationic, and tetracationic versions of a porphyrin‐based photosensitizer drug (Zn‐Por). While TMV has been extensively explored for various nanotechnology applications, this is the first study investigating TMGMV for medical applications. Light‐activated cancer cell killing of Zn‐Por‐loaded VNPs is studied in vitro using melanoma and cervical cancer models. Native and nucleolin‐targeted VNP drug carriers are developed and their efficacy assessed. A fivefold increase in cancer cell killing is observed using nucleolin‐targeted TMV loaded with tricationic Zn‐Por and displaying the nucleolin‐specific F3 peptide.     

Anionic ring opening polymerization of cyclotetrasiloxanes with large substituents

Cyclotetrasiloxanes with large substituents were synthesized by hydrosilylation of 1,3,5,7-tetramethylcyclotetrasiloxane with CH₂=CHCH₂X, X being (CH₂)₂CH₃, O(CH₂CH₂O)₃CH₃, OCH₂epoxy and OCH₂- benzo-18-crown-6. The tetrasubstituted cycles were homo-polymerized or copolymerized with octamethylcyclotetrasiloxane in the presence of potassium silanolate to yield polysiloxanes with side chains containing oxirane rings, crown ethers or oxyethylene ligands. In addition to a complex mixture of cycles, about 50 to 80% polymer can be recovered. The copolymer generally contains less of the substituted monomer than the starting monomer feed, but the bulky substituents do not appear to prevent formation of homo- or copolymer.     

In vivo incorporation of unnatural amino acids to probe structure, dynamics, and ligand binding in a large protein by nuclear magnetic resonance spectroscopy

In vivo incorporation of isotopically labeled unnatural amino acids into large proteins drastically reduces the complexity of nuclear magnetic resonance (NMR) spectra. Incorporation is accomplished by coexpressing an orthogonal tRNA/aminoacyl-tRNA synthetase pair specific for the unnatural amino acid added to the media and the protein of interest with a TAG amber codon at the desired incorporation site. To demonstrate the utility of this approach for NMR studies, 2-amino-3-(4-(trifluoromethoxy)phenyl)propanoic acid (OCF 3Phe), (13)C/(15)N-labeled p-methoxyphenylalanine (OMePhe), and (15)N-labeled o-nitrobenzyl-tyrosine (oNBTyr) were incorporated individually into 11 positions around the active site of the 33 kDa thioesterase domain of human fatty acid synthase (FAS-TE). In the process, a novel tRNA synthetase was evolved for OCF 3Phe. Incorporation efficiencies and FAS-TE yields were improved by including an inducible copy of the respective aminoacyl-tRNA synthetase gene on each incorporation plasmid. Using only between 8 and 25 mg of unnatural amino acid, typically 2 mg of FAS-TE, sufficient for one 0.1 mM NMR sample, were produced from 50 mL of Escherichia coli culture grown in rich media. Singly labeled protein samples were then used to study the binding of a tool compound. Chemical shift changes in (1)H-(15)N HSQC, (1)H-(13)C HSQC, and (19)F NMR spectra of the different single site mutants consistently identified the binding site and the effect of ligand binding on conformational exchange of some of the residues. OMePhe or OCF 3Phe mutants of an active site tyrosine inhibited binding; incorporating (15)N-Tyr at this site through UV-cleavage of the nitrobenzyl-photocage from oNBTyr re-established binding. These data suggest not only robust methods for using unnatural amino acids to study large proteins by NMR but also establish a new avenue for the site-specific labeling of proteins at individual residues without altering the protein sequence, a feat that can currently not be accomplished with any other method.     

Über die Einführung der idealen Elemente in die ebene Geometrie mit Hilfe des Satzes vom vollständigen Vierseit

Ohne Zusammenfassung     

Space-efficient geometric divide-and-conquer algorithms

We develop a number of space-efficient tools including an approach to simulate divide-and-conquer space-efficiently, stably selecting and unselecting a subset from a sorted set, and computing the kth smallest element in one dimension from a multi-dimensional set that is sorted in another dimension. We then apply these tools to solve several geometric problems that have solutions using some form of divide-and-conquer. Specifically, we present a deterministic algorithm running in time using extra memory given inputs of size n for the closest pair problem and a randomized solution running in expected time and using extra space for the bichromatic closest pair problem. For the orthogonal line segment intersection problem, we solve the problem in time using extra space where n is the number of horizontal and vertical line segments and k is the number of intersections.     

New practical synthesis of indazoles via condensation of o-fluorobenzaldehydes and their O-methyloximes with hydrazine

The reaction of o-fluorobenzaldehydes and their O-methyloximes with hydrazine has been developed as a new practical synthesis of indazoles. Utilization of the methyloxime derivatives of benzaldehydes (in the form of the major E-isomers) in this condensation effectively eliminated a competitive Wolf-Kishner reduction to fluorotoluenes, which was observed in the direct preparations of indazoles from aldehydes. Reaction of Z-isomers of methyloximes with hydrazine resulted in the formation of 3-aminoindazoles via a benzonitrile intermediate.