Target-Selective Drug Delivery through Liposomes Labeled with Oligobranched Neurotensin Peptides.

The structure and the in vitro behavior of liposomes filled with the cytotoxic drug doxorubicin (Doxo) and functionalized on the external surface with a branched moiety containing four copies of the 8-13 neurotensin (NT) peptide is reported. The new functionalized liposomes, DOPC-NT(4) Lys(C(18) )(2) , are obtained by co-aggregation of the DOPC phospholipid with a new synthetic amphiphilic molecule, NT(4) Lys(C(18) )(2) , which contains a lysine scaffold derivatized with a lipophilic moiety and a tetrabranched hydrophilic peptide, NT8-13, a neurotensin peptide fragment well known for its ability to mimic the neurotensin peptide in receptor binding ability. Dynamic light scattering measurements indicate a value for the hydrodynamic radius (RH) of 88.3±4.4 nm. The selective internalization and cytotoxicity of DOPC-NT(4) Lys(C(18) )(2) liposomes containing Doxo, as compared to pure DOPC liposomes, were tested in HT29 human colon adenocarcinoma and TE671 human rhabdomyosarcoma cells, both of which express neurotensin receptors. Peptide-functionalized liposomes show a clear advantage in comparison to pure DOPC liposomes with regard to drug internalization in both HT29 and TE671 tumor cells: FACS analysis indicates an increase in fluorescence signal of the NT(4) -liposomes, compared to the DOPC pure analogues, in both cell lines; cytotoxicity of DOPC-NT(4) Lys(C(18) )(2) -Doxo liposomes is increased four-fold with respect to DOPC-Doxo liposomes in both HT29 and TE671 cell lines. These effects could to be ascribed to the higher rate of internalization for DOPC-NT(4) Lys(C(18) )(2) -Doxo liposomes, due to stronger binding driven by a lower dissociation constant of the NT(4) -liposomes that bind the membrane onto a specific protein, in contrast to DOPC liposomes, which approach the plasma membrane unselectively

A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism

The different steps of the human Top1 (topoisomerase I) catalytic cycle have been analysed in the presence of a pentacyclic-diquinoid synthetic compound. The experiments indicate that it efficiently inhibits the cleavage step of the enzyme reaction, fitting well into the catalytic site. Surprisingly the compound, when incubated with the binary topoisomerase–DNA cleaved complex, helps the enzyme to remove itself from the cleaved DNA and close the DNA gap, increasing the religation rate. The compound also induces the religation of the stalled enzyme–CPT (camptothecin)– DNA ternary complex. Analysis of the molecule docked over the binary complex, together with its chemical properties, suggests that the religation enhancement is due to the presence on the compound of two oxygen atoms that act as hydrogen acceptors. This property facilitates the deprotonation of the 5 DNA end, suggesting that this is the limiting step in the topoisomerase religation mechanism

Penta-Hepta Defect Motion in Hexagonal Patterns

Structure and dynamics of penta-hepta defects in hexagonal patterns is studied in the framework of coupled amplitude equations for underlying plane waves. Analytical solution for phase field of moving PHD is found in the far field, which generalizes the static solution due to Pismen and Nepomnyashchy (1993). The mobility tensor of PHD is calculated using combined analytical and numerical approach. The results for the velocity of PHD climbing in slightly non-optimal hexagonal patterns are compared with numerical simulations of amplitude equations. Interaction of penta-hepta defects in optimal hexagonal patterns is also considered.Comment: 4 pages, Postscript (submitted to PRL

Defect Dynamics for Spiral Chaos in Rayleigh-Benard Convection

A theory of the novel spiral chaos state recently observed in Rayleigh-Benard convection is proposed in terms of the importance of invasive defects i.e defects that through their intrinsic dynamics expand to take over the system. The motion of the spiral defects is shown to be dominated by wave vector frustration, rather than a rotational motion driven by a vertical vorticity field. This leads to a continuum of spiral frequencies, and a spiral may rotate in either sense depending on the wave vector of its local environment. Results of extensive numerical work on equations modelling the convection system provide some confirmation of these ideas.Comment: Revtex (15 pages) with 4 encoded Postscript figures appende

Grain boundary motion in layered phases

We study the motion of a grain boundary that separates two sets of mutually perpendicular rolls in Rayleigh-B\'enard convection above onset. The problem is treated either analytically from the corresponding amplitude equations, or numerically by solving the Swift-Hohenberg equation. We find that if the rolls are curved by a slow transversal modulation, a net translation of the boundary follows. We show analytically that although this motion is a nonlinear effect, it occurs in a time scale much shorter than that of the linear relaxation of the curved rolls. The total distance traveled by the boundary scales as $\epsilon^{-1/2}$, where $\epsilon$ is the reduced Rayleigh number. We obtain analytical expressions for the relaxation rate of the modulation and for the time dependent traveling velocity of the boundary, and especially their dependence on wavenumber. The results agree well with direct numerical solutions of the Swift-Hohenberg equation. We finally discuss the implications of our results on the coarsening rate of an ensemble of differently oriented domains in which grain boundary motion through curved rolls is the dominant coarsening mechanism.Comment: 16 pages, 5 figure

Dynamics and Selection of Giant Spirals in Rayleigh-Benard Convection

For Rayleigh-Benard convection of a fluid with Prandtl number \sigma \approx 1, we report experimental and theoretical results on a pattern selection mechanism for cell-filling, giant, rotating spirals. We show that the pattern selection in a certain limit can be explained quantitatively by a phase-diffusion mechanism. This mechanism for pattern selection is very different from that for spirals in excitable media

New frontiers in bariatric surgery laparoscopic adjustable silicone gastric banding (LASGB)

LASGB is a minimally invasive procedure indicated for the treatment of morbid obesity. Since January 1996, six patients have successfully undergone the laparoscopic procedure. Preoperative BMI was 42 ± 3.1; range 39-46. Mean operative time was 260 ± 110, range was 160-360. Mean hospital stay was 3 ± 1 days

Bombesin peptide antagonist for target-selective delivery of liposomal doxorubicin on cancer cells

Purpose: This study addresses novel peptide modified liposomal doxorubicin to specifically target tissues overexpressing bombesin (BN) receptors. Methods: DOTA-(AEEA)2-peptides containing the [7–14]bombesin and the new BN-AA1 sequence have been synthesized to compare their binding properties and in serum stabilities. The amphiphilic peptide derivative (MonYBN- AA1) containing BN-AA1, a hydrophobic moiety, polyethylenglycole (PEG), and diethylenetriaminepentaacetate (DTPA), has been synthesized. Liposomes have been obtained by mixing of MonY-BN-AA1 with 1,2-distearoylsn-glycero-3-phosphocholine (DSPC). Results: Both 111In labeled peptide derivatives present nanomolar Kd to PC-3 cells. 177Lu labeled peptide DOTA- (AEEA)2-BN-AA1 is very stable (half-life 414.1 h), while DOTA-(AEEA)2-BN, shows a half-life of 15.5 h. In vivo studies on the therapeutic efficacy of DSPC/MonY-BN-AA1/Dox in comparison to DSPC/MonY-BN/Dox, were performed in PC-3 xenograft bearing mice. Both formulations showed similar tumor growth inhibition (TGI) compared to control animals treated with non-targeted DSPC/Dox liposomes or saline solution. For DSPC/MonY-BN-AA1/Dox the maximum effect was observed 19 days after treatment. Conclusions: DSPC/MonY-BN-AA1/Dox nanovectors confirm the ability to selectively target and provide therapeutic efficacy in mice. The lack of receptor activation and possible acute biological side effects provided by using the AA1 antagonist bombesin sequence should provide safe working conditions for further development of this class of drug delivery vehicles

Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of acute myocardial infarction

Background: This study was designed to investigate the association of the 894G>T polymorphism in the eNOS gene with risk of acute myocardial infarction (AMI), extent of coronary artery disease (CAD) on coronary angiography, and in-hospital mortality after AMI. Methods: We studied 1602 consecutive patients who were enrolled in the GEMIG study. The control group was comprised by 727 individuals, who were randomly selected from the general adult population. Results: The prevalence of the Asp298 variant of eNOS was not found to be significantly and independently associated with risk of AMI (RR = 1.08, 95%CI = 0.77–1.51, P = 0.663), extent of CAD on angiography (OR = 1.18, 95%CI = 0.63–2.23, P = 0.605) and in-hospital mortality (RR = 1.08, 95%CI = 0.29–4.04, P = 0.908). Conclusion: In contrast to previous reports, homozygosity for the Asp298 variant of the 894G>T polymorphism in the eNOS gene was not found to be associated with risk of AMI, extent of CAD and in-hospital mortality after AM