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1.
Proc Natl Acad Sci U S A ; 102(37): 13019-22, 2005 Sep 13.
Article in English | MEDLINE | ID: mdl-16135564

ABSTRACT

Although it is widely accepted that the local structure of liquid water has tetrahedral arrangements of molecules ordered by hydrogen bonds, the mechanism by which water molecules switch hydrogen-bonded partners remains unclear. In this mechanism, the role of nonhydrogen-bonded configurations (NHBs) between adjacent molecules is of particular importance. A molecule may switch hydrogen-bonding partners either (i) through thermally activated breaking of a hydrogen bond that creates a dangling hydrogen bond before finding a new partner or (ii) by infrequent but rapid switching events in which the NHB is a transition state. Here, we report a combination of femtosecond 2D IR spectroscopy and molecular dynamics simulations to investigate the stability of NHB species in an isotopically dilute mixture of HOD in D2O. Measured 2D IR spectra reveal that hydrogen-bonded configurations and NHBs undergo qualitatively different relaxation dynamics, with NHBs returning to hydrogen-bonded frequencies on the time scale of water's fastest intermolecular motions. Simulations of an atomistic model for the OH vibrational spectroscopy of water yield qualitatively similar 2D IR spectra to those measured experimentally. Analysis of NHBs in simulations by quenching demonstrates that the vast majority of NHBs are in fact part of a hydrogen-bonded well of attraction and that virtually all molecules return to a hydrogen-bonding partner within 200 fs. The results from experiment and simulation demonstrate that NHBs are intrinsically unstable and that dangling hydrogen bonds are an insignificant species in liquid water.


Subject(s)
Hydrogen Bonding , Water/chemistry , Deuterium , Kinetics , Spectrophotometry, Infrared
2.
Science ; 301(5640): 1698-702, 2003 Sep 19.
Article in English | MEDLINE | ID: mdl-14500975

ABSTRACT

We investigated rearrangements of the hydrogen-bond network in water by measuring fluctuations in the OH-stretching frequency of HOD in liquid D2O with femtosecond infrared spectroscopy. Using simulations of an atomistic model of water, we relate these frequency fluctuations to intermolecular dynamics. The model reveals that OH frequency shifts arise from changes in the molecular electric field that acts on the proton. At short times, vibrational dephasing reflects an underdamped oscillation of the hydrogen bond with a period of 170 femtoseconds. At longer times, vibrational correlations decay on a 1.2-picosecond time scale because of collective structural reorganizations.

3.
Int J Pharm ; 200(1): 27-39, 2000 Apr 25.
Article in English | MEDLINE | ID: mdl-10845683

ABSTRACT

The development of stable spherical lipid-coated drug particles that are termed 'lipocores' is reported here. Unlike conventional lipid-based particles (i.e. liposomes, emulsions, micelles), these particles are comprised solely of a core of a poorly water soluble drug surrounded by polyethyleneglycol conjugated lipid (PEG-lipid) and are formed via a 'kinetic' trapping process. These lipocore particles were made with the acyl chain of 16 carbon length (C16) acyl-chain derivatives of paclitaxel or vinblastine and with the polyene antifungal hamycin. Formation of the particles occurred regardless of the type of PEG-phospholipid used (i.e. acyl chain length, chain saturation, and polymer length) and could also be formed with the negatively charged lipid N-glutaryl-dioleoyl-phosphatidylethanolamine (DOPE-GA). Images from both freeze-fracture electron microscopy and electron cryo-microscopy revealed solid spherical structures with no internal lamellae for the PEG-lipid particles made with the C16 derivatives of paclitaxel (BrC16-T) or vinblastine (C16-Vin). From a solute distribution study of lipocores made with BrC16-T and distearoyl-phosphatidylethanolamine-PEG2000 (DSPE-PEG2000), the particles were found to have no measurable aqueous captured volume. Fluorescence anisotropy and order parameter measurements revealed the core material of these particles to be highly immobilized. The mole ratio of BrC16-T:lipid in the lipocores was typically > 90: < 10 and as high as 98:2, and the refrigerated lipocores were stable for several months. BrC16-T/DSPE-PEG2000 lipocores of 50-100 nm particle size were far less toxic than paclitaxel (Taxol) after intraperitoneally (i.p.) or intravenously (i.v.) administration in mice and were active against i.p. and subcutaneously (s.c.) planted human (OvCar3) ovarian carcinoma grown in SCID mice. It is believed the high drug:lipid ratio, the stability, and therapeutic efficacy of these novel particles make them a paradigm for delivery of poorly water soluble drugs and/or their hydrophobic derivatives.


Subject(s)
Drug Carriers/chemistry , Liposomes/chemistry , Pharmaceutical Preparations/chemistry , Animals , Anisotropy , Antineoplastic Agents, Phytogenic/pharmacokinetics , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/toxicity , Centrifugation, Density Gradient , Chemical Phenomena , Chemistry, Physical , Electron Spin Resonance Spectroscopy , Emulsions , Female , Mice , Mice, SCID , Micelles , Ovarian Neoplasms/drug therapy , Paclitaxel/pharmacokinetics , Paclitaxel/pharmacology , Paclitaxel/toxicity , Particle Size , Pharmaceutical Preparations/administration & dosage , Polyethylene Glycols , Prodrugs , Solubility , Sucrose , Vinblastine/pharmacokinetics , Vinblastine/pharmacology , Vinblastine/toxicity
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