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.     

Hexametaphosphate‐Capped Silica Mesoporous Nanoparticles Containing CuII Complexes for the Selective and Sensitive Optical Detection of Hydrogen Sulfide in Water

Cu^II‐macrocycle functionalized hexametaphosphate‐capped silica mesoporous nanoparticles have been prepared and used for the selective and sensitive detection of hydrogen sulfide in aqueous environments. The possibility of using different metal complexes combined with different capping anions and choice of different dyes or other sensing molecules as indicators makes this new protocol highly appealing for the preparation of new sensing systems for sulfide detection in different environments.     

Quantum line defects and refined BPS spectra

Letters in Mathematical Physics - In this note, we study refined BPS invariants associated with certain quantum line defects in quantum field theories of class $${{\mathcal {S}}}$$. Such defects...     

Human mobility and COVID-19 initial dynamics

Nonlinear Dynamics - Countries in Europe took different mobility containment measures to curb the spread of COVID-19. The European Commission asked mobile network operators to share on a...     

Noise Reduction in Spur Gear Systems

This article lists some tips for reducing gear case noise. With this aim, a static analysis was carried out in order to describe how stresses resulting from meshing gears affect the acoustic emissions. Different parameters were taken into account, such as the friction, material, and lubrication, in order to validate ideas from the literature and to make several comparisons. Furthermore, a coupled Eulerian–Lagrangian (CEL) analysis was performed, which was an innovative way of evaluating the sound pressure level of the aforementioned gears. Different parameters were considered again, such as the friction, lubrication, material, and rotational speed, in order to make different research comparisons. The analytical results agreed with those in the literature, both for the static analysis and CEL analysis—for example, it was shown that changing the material from steel to ductile iron improved the gear noise, while increasing the rotational speed or the friction increased the acoustic emissions. Regarding the CEL analysis, air was considered a perfect gas, but its viscosity or another state equation could have also been taken into account. Therefore, the above allowed us to state that research into these scientific fields will bring about reliable results.