The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale ...delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.
Numerous oral and parenteral anticoagulant drugs are now available for clinical use. Understanding the precise pharmacologic properties of each anticoagulant is imperative for those practitioners who ...prescribe these drugs, including knowing the current recommendations for reversing the anticoagulant effect of each anticoagulant. This review provides a brief description of the various anticoagulants used today and also discusses the pharmacologic properties of those drugs used to reverse the anticoagulant action of specific anticoagulants.
Reaction of (IPr)Ni(μ-Cl)2 (1-Cl; IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) with ClMg{CH(SiMe3)2}·Et2O affords (IPr)Ni{CH(SiMe3)2} (2), a two-coordinate Ni(I) alkyl complex. An ...analogous two-coordinate aryl derivative, (IPr)Ni(dmp) (dmp = 2,6-dimesitylphenyl), can be similarly prepared from Li(dmp) and 1-Cl. Reaction of 2 with alkyl bromides gives the three-coordinate Ni(II) alkyl halide complex (IPr)Ni{CH(SiMe3)2}Br. Evidence for a radical mechanism is presented to explain the reaction of 2 with alkyl halides.
The alkylaluminum-complexed zirconocene trihydride cation (SBI)Zr(μ-H)3(Al i Bu2)2+, which is obtained by reaction of (SBI)ZrCl2 with Ph3CB(C6F5)4 and excess HAl i Bu2 in toluene solution, catalyzes ...the formation of isotactic polypropene when exposed to propene at −30 °C. This cation remains the sole observable species in catalyst systems free of AlMe compounds. In the presence of AlMe3, however, exposure to propene causes the trihydride cation to be completely converted, under concurrent consumption of all hydride species by propene hydroalumination, to the doubly Me-bridged cation (SBI)Zr(μ-Me)2AlMe2+. The latter then becomes the resting state for further propene polymerization, which produces, by chain transfer to Al, mainly AlMe2-capped isotactic polypropene.
The ansa-zirconocene complex rac-Me2Si(1-indenyl)2ZrCl2 ((SBI)ZrCl2) reacts with diisobutylaluminum hydride and trityl tetrakis(perfluorophenyl)borate in hydrocarbon solutions to give the cation ...(SBI)Zr(μ-H)3(Al i Bu2)2+, the identity of which is derived from NMR data and supported by a crystallographic structure determination. Analogous reactions proceed with many other zirconocene dichloride complexes. (SBI)Zr(μ-H)3(Al i Bu2)2+ reacts reversibly with ClAl i Bu2 to give the dichloro-bridged cation (SBI)Zr(μ-Cl)2Al i Bu2+. Reaction with AlMe3 first leads to mixed-alkyl species (SBI)Zr(μ-H)3(AlMe x i Bu2−x )2+ by exchange of alkyl groups between aluminum centers. At higher AlMe3/Zr ratios, (SBI)Zr(μ-Me)2AlMe2+, a constituent of methylalumoxane-activated catalyst systems, is formed in an equilibrium, in which the hydride cation (SBI)Zr(μ-H)3(AlR2)2+ strongly predominates at comparable HAl i Bu2 and AlMe3 concentrations, thus implicating the presence of this hydride cation in olefin polymerization catalyst systems.
PDF
