פרסומים

Collagen matrices can be used as non-viral biocompatible gene carriers for localized implantable gene therapy. Collagen matrices embedding pDNA with enhanced binding through condensing agent linkage to the matrix or to the pDNA have been formulated, and characterized in various systems. pDNA and condensed pDNA were released intact from the matrices within 1-2 days. In vitro transfection with collagen matrices containing pDNA (luciferase encoding), pDNA in liposome (LIP), and pDNA with polyethylenimine (PEI) resulted in significantly higher expression levels in comparison to naked pDNA. pDNA-LIP matrices exhibited a dose response transfection of NIH 3T3, 293, MDA-MB-231 and smooth muscle cells (SMCs) in cell cultures. Subdermal implantations of collagen-polylysine-pDNA matrices in rats resulted in significantly higher gene expression levels in comparison to non-condensed pDNA matrices. Perivascular treatment with pDNA matrix and of naked pDNA solution in balloon-injured rat carotid arteries resulted in significant expression. In conclusion, a facile method for embedding cationic formulations of pDNA in collagen matrices was developed. These bioactive matrices seem to be suitable for tissue engineering and local gene therapy strategies.

PURPOSE: To assess the corneal iontophoretic delivery of gentamicin by drug-loaded hydrogel probe, and to determine the resultant ocular disposition and elimination of the drug from the cornea and anterior chamber. METHODS: Corneal iontophoresis of gentamicin sulfate was studied in healthy white rabbits by using drug-loaded disposable hydroxyethyl methacrylate (HEMA) hydrogel disk probes and a portable mini-ion device designed in the authors' laboratory. The iontophoretic treatment was performed with a current intensity of 1 mA for 60 seconds only. Three control groups were used: mock iontophoresis (no current) for 60 seconds, topical eye drops of fortified gentamicin (1.4%) every 5 minutes for 1 hour, and subconjunctival injection of 0.25 mL of 40 mg/mL gentamicin solution. The animals in the iontophoretic experimental groups were killed at predetermined time points. The gentamicin concentrations in the cornea and aqueous humor were assayed with a fluorescence polarization immunoassay. Analysis of the gentamicin eye pharmacokinetics was performed with a modeling approach. RESULTS: Peak gentamicin concentrations in the cornea (363.1 +/- 127.3 microg/g) and in the aqueous humor (29.4 +/- 17.4 microg/mL) were reached at 0 and 2 hours after the iontophoretic treatment, respectively. The peak gentamicin concentrations after a single iontophoresis treatment were 12 to 15 times higher than those obtained after gentamicin injection or after topical eye drop instillation, and much higher than in mock iontophoresis. The concentration versus time profile of gentamicin in the cornea and the anterior chamber after iontophoresis was appropriately described by applying a two-compartment pharmacokinetic model. CONCLUSIONS: A short iontophoretic treatment using gentamicin-loaded hydrogels has potential clinical value in increasing drug penetration to the anterior segments of the eye and maintaining therapeutic drug levels in the cornea for more than 8 hours.

N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymers have been shown to be efficient carriers for anticancer drugs because of their versatile chemistry and good biocompatibility. As demonstrated with hepatocytes, targeting efficacy of anticancer drugs could be further improved when the drug (doxorubicin) was conjugated to HPMA copolymers with biorecognisable groups, such as simple carbohydrates. The present study was devised to learn whether the cluster (multivalent) construction of carbohydrate residues could improve the targeting capability of HPMA copolymer-doxorubicin (DOX) conjugates towards human colon adenocarcinoma cells. DOX was linked via a lysosomally degradable tetrapeptide sequence to HPMA copolymers bearing galactosamine (GalN), lactose (Lac), or multivalent galactose residues (TriGal) to produce targetable polymeric drug carriers. The effect of the type of sugar moiety and its three-dimensional cluster arrangement on biorecognition by three human colon-adenocarcinoma cell lines was studied. The role of galectin-3 in the biorecognition of HPMA copolymer conjugates was explored. Biorecognition of the targetable (glycoside-bearing) conjugates decreased their IC(50) doses in comparison to the non-targetable (non-glycosylated) conjugates. The biorecognition of the TriGal-containing HPMA copolymer-doxorubicin conjugate by the cells was superior with concomitant decrease of its IC(50) doses. It is suggested that the increased cytotoxicity of the glycosylated HPMA-copolymer-DOX conjugates toward human colon-adenocarcinoma cells was caused by their biorecognition and effective internalisation via receptor-mediated endocytosis. All three human colon adenocarcinoma cell lines tested, Colo-205, SW-480 and SW-620, expressed the galectin-3 protein and the galectin-3-specific RNA. However, contrary to expectation, Colo-205 cells did not express a detectable amount of galectin-3 on the cell surface. This suggests that the binding of the glycoside-bearing HPMA copolymer-DOX conjugates to the cells was mediated not only by galectin-3. We conclude that targeting of the anticancer agent, doxorubicin, using HPMA copolymer conjugates bearing multivalent galactoside residues can improve their cytotoxicity.

The dynamics of friction have been studied for hundreds of years, yet many aspects of these everyday processes are not understood. One such aspect is the onset of frictional motion (slip). First described more than 200 years ago as the transition from static to dynamic friction, the onset of slip is central to fields as diverse as physics, tribology, mechanics of earthquakes and fracture. Here we show that the onset of frictional slip is governed by three different types of coherent crack-like fronts: these are observed by real-time visualization of the net contact area that forms the interface separating two blocks of like material. Two of these fronts, which propagate at subsonic and intersonic velocities, have been the subject of intensive recent interest. We show that a third type of front, which propagates an order of magnitude more slowly, is the dominant mechanism for the rupture of the interface. No overall motion (sliding) of the blocks occurs until either of the slower two fronts traverses the entire interface.

Optical traps are routinely used for the manipulation of neutral particles. However, optical trap design is limited by the lack of an accurate theory. The generalized Lorenz-Mie theory (GLMT) solves the scattering problem for arbitrary particle size and predicts radial forces accurately. Here we show that the GLMT predicts the observed radial and axial forces in a variety of optical manipulators. We also present a dimensionless parameter β for the prediction of axial forces. Coupled with our correlation for radial escape forces, we now have a set of two simple correlations for the practical design of radiationforce-based systems. © 2004 Optical Society of America.