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...     

Solid-State Dynamics and High-Pressure Studies of a Supramolecular Spiral Gear

The structures and solid-state dynamics of the supramolecular salts of the general formula [(12-crown-4)₂ ⋅ DABCOH₂](X)₂ (where DABCO=1,4-diazabicyclo[2.2.2]octane, X=BF₄, ClO₄) have been investigated as a function of temperature (from 100 to 360 K) and pressure (up to 3.4 GPa), through the combination of variable-temperature and variable-pressure XRD techniques and variable-temperature solid-state NMR spectroscopy. The two salts are isomorphous and crystallize in the enantiomeric space groups P3₂2₁ and P3₁2₁. All building blocks composing the supramolecular complex display dynamic processes at ambient temperature and pressure. It has been demonstrated that the motion of the crown ethers is maintained on lowering the temperature (down to 100 K) or on increasing the pressure (up to 1.5 GPa) thanks to the correlation between neighboring molecules, which mesh and rotate in a concerted manner similar to spiral gears. Above 1.55 GPa, a collapse-type transition to a lower-symmetry ordered structure, not attainable at a temperature of 100 K, takes place, proving, thus, that the pressure acts as the means to couple and decouple the gears. The relationship between temperature and pressure effects on molecular motion in the solid state has also been discussed.