Inflammation-responsive nanoparticles suppress lymphatic clearance for prolonged arthritis therapy.

The clearance of nanomedicine in inflamed joints has been accelerated due to the increased lymph angiogenesis and lymph flow in arthritic sites. To maximize the therapeutic efficacy for rheumatoid arthritis (RA), it is necessary to facilitate targeted delivery and extended drug retention in inflamed synovium simultaneously. In general, nanosized particles are more likely to achieve prolonged circulation and targeted delivery. While drug carriers with larger dimension might be more beneficial for extending drug retention. To balance the conflicting requirements, an inflammation-responsive shape transformable nanoparticle, comprised of amyloid ß-derived KLVFF peptide and polysialic acid (PSA), coupled with therapeutic agent dexamethasone (Dex) via an acid-sensitive linker, was fabricated and termed as Dex-KLVFF-PSA (DKPNPs). Under physiological condition, DKPNPs can keep stable nanosized morphology, and PSA shell could endow DKPNPs with long circulation and active targeting to arthritic sites. While in inflamed joints, acidic pH-triggered Dex dissociation or macrophages-induced specific binding with PSA would induce the re-assembly of DKPNPs from nanoparticles to nanofibers. Our results reveal that intravenously injected DKPNPs display prolonged in vivo circulation and preferential distribution in inflamed joints, where DKPNPs undergo shape transition to fibrous structures, leading to declined lymphatic clearance and prolonged efficacy. Overall, our dual-stimulus responsive transformable nanoparticle offers an intelligent solution to achieve enhanced therapeutic efficacy in RA.

Divergent S- and C-Difluoromethylation of 2-Substituted Benzothiazoles.

Two unprecedented and complementary synthetic strategies for S- and C-difluoromethylation of 2-substituted benzothiazoles have been developed by taking advantage of the remarkably different reactivity of CF2H- and 2-PySO2CF2- nucleophiles. A variety of structurally diverse difluoromethyl 2-isocyanophenyl sulfides and 2-difluoromethylated benzothiazoles were synthesized with these two new synthetic protocols.

Stereoselective [3+2] cycloaddition of N-tert-butanesulfinyl imines to arynes facilitated by a removable PhSO2CF2 group: synthesis and transformation of cyclic sulfoximines.

An unprecedented [3+2] cycloaddition between N-tert-butanesulfinyl imines and arynes provides a stereoselective method for the synthesis of cyclic sulfoximines. Not only does the difluoro(phenylsulfonyl)methyl group play an important role in facilitating the cycloaddition reaction, it can also be removed or substituted through the transformation of the difluorinated cyclic sulfoximines to cyclic sulfinamides.

Palladium-catalyzed amidation-hydrolysis reaction of gem-dihaloolefins: efficient synthesis of homologated carboxamides from ketones.

A simple and efficient palladium-catalyzed amidation-hydrolysis reaction has been developed to afford N-aryl monosubstituted carboxamides in good to excellent yields from easily accessible ketone-derived gem-dihaloolefins and aryl amines.