Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

Two small‐molecule–drug conjugates (SMDCs, 6 and 7 ) featuring lysosomally cleavable linkers (namely the Val–Ala and Phe–Lys peptide sequences) were synthesized by conjugation of the α_vβ₃‐integrin ligand cyclo[DKP–RGD]‐CH₂NH₂ ( 2 ) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP–RGD]–PTX conjugate with a nonpeptide “uncleavable” linker ( 8 ) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified α_Vβ₃‐integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8 , which possesses a nonpeptide “uncleavable” linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF‐CEM (α_Vβ₃?) and its subclone CCRF‐CEM α_Vβ₃ (α_Vβ₃+). Fairly effective integrin targeting was displayed by the cyclo[DKP–RGD]–Val–Ala–PTX conjugate ( 6 ), which was found to differentially inhibit proliferation in antigen‐positive CCRF‐CEM α_Vβ₃ versus antigen‐negative isogenic CCRF‐CEM cells. The total lack of activity displayed by the “uncleavable” cyclo[DKP–RGD]–PTX conjugate ( 8 ) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.     

A generalized Dedekind-Mertens lemma and its converse

We study content ideals of polynomials and their behavior under multiplication. We give a generalization of the Lemma of Dedekind-Mertens and prove the converse under suitable dimensionality restrictions.

     

Spin-flop ordering from frustrated ferro- and antiferromagnetic interactions: a combined theoretical and experimental study of a Mn/Fe(100) monolayer

The occurrence of a noncollinear magnetic structure at a Mn monolayer grown epitaxially on Fe(100) is predicted theoretically, using spinor density-functional theory, and observed experimentally, using x-ray magnetic circular dichroism (XMCD) and linear dichroism (XMLD) spectroscopies. The combined use of XMCD and XMLD at the Mn-absorption edge allows us to assess the existence of ferromagnetic and antiferromagnetic order at the interface, and also to determine the moment orientations with element specificity. The experimental results thus obtained are in excellent agreement with the magnetic structure determined theoretically.     

Core of projective dimension one modules

The core of a projective dimension one module is computed explicitly in terms of Fitting ideals. In particular, our formula recovers previous work by R. Mohan on integrally closed torsionfree modules over a two-dimensional regular local ring. The first author was partially supported by a Faculty Research Fellowship from the University of Kentucky. The second and third authors gratefully acknowledge partial support from the NSF.Mathematics Subject Classification (2000):Primary 13A30, 13B21; Secondary 13C99     

Comparison of Krylov subspace methods on the PageRank problem

PageRank algorithm plays a very important role in search engine technology and consists in the computation of the eigenvector corresponding to the eigenvalue one of a matrix whose size is now in the billions. The problem incorporates a parameter that determines the difficulty of the problem. In this paper, the effectiveness of stationary and nonstationary methods are compared on some portion of real web matrices for different choices of . We see that stationary methods are very reliable and more competitive when the problem is well conditioned, that is for small values of . However, for large values of the parameter the problem becomes more difficult and methods such as preconditioned BiCGStab or restarted preconditioned GMRES become competitive with stationary methods in terms of Mflops count as well as in number of iterations necessary to reach convergence.     

Synthesis,Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting αvβ3 Integrin and VEGF Receptors

A dual-action ligand targeting both integrin α_Vβ₃ and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic α_Vβ₃ Arg-Gly-Asp (RGD) ligand with a decapentapeptide. The latter was obtained from a known VEGFR antagonist by acetylation at the Lys13 side chain. Functionalization of the precursor ligands was carried out in solution and in the solid phase, affording two fragments: an alkyne VEGFR ligand and the azide integrin α_Vβ₃ ligand, which were conjugated by click chemistry. Circular dichroism studies confirmed that both the RGD and VEGFR ligand portions of the dual-action compound substantially adopt the biologically active conformation. In vitro binding assays on isolated integrin α_Vβ₃ and VEGFR-1 showed that the dual-action conjugate retains a good level of affinity for both its target receptors, although with one order of magnitude (10/20 times) decrease in potency. The dual-action ligand strongly inhibited the VEGF-induced morphogenesis in Human Umbilical Vein Endothelial Cells (HUVECs). Remarkably, its efficiency in preventing the formation of new blood vessels was similar to that of the original individual ligands, despite the worse affinity towards integrin α_Vβ₃ and VEGFR-1.     

Folding characterization in conservative chaotic fluid flows

We study transport of passive scalar fields in a bidimensional incompressible chaotic fluid flow. For a spatially smooth velocity field with impulsive perturbations, the model is described by a randomized standard mapping. We numerically investigate passive scalar field transport for given initial concentration distributions and their dependence on the nonlinearity and noise amplitude. We show that space and time concentration histograms are determined by the underlying mechanism of stretching and folding. Moreover, to characterize this process we introduce a parameter, the average derivative of a tracer line length, which shows interesting scale properties.