Isopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis. The development of this organocatalytic transisopropenylation approach enables access to modular preparation of various acid-sensitive ketal-linked prodrugs and functionalized ketalated biomaterials. We expect our syntheses and transformations of isopropenyl ethers will find utility in several diverse fields, including medicinal chemistry, drug delivery, and biomaterials.
A combinatorial design, physical adsorption of water-soluble chitosan (WSC) to particle surface and covalent conjugation of wheat germ agglutinin (WGA) to WSC, was applied to surface modification of poly(lactic acid) nanoparticles (NPs) for targeted delivery of β-galactosidase to the intestinal mucosa. All the surface-engineered NPs in the size range of 500-600 nm were prepared by a w/o/w solvent diffusion/evaporation technique. β-Galactosidase encapsulated in these NPs was well protected from external proteolysis and exerted high hydrolytic activity on the permeable lactose. The presence of WSC coating, whether alone or with WGA, highly improved the suspension stability of NPs and tailored the particle surface positively charged. In comparison to NPs modified with WGA or WSC alone, the synergistic action of WGA and WSC greatly enhanced the NP-mucin interactions in vitro. The highest amount of NPs was found in the small intestine at 24 h after oral administration in rats. Notably, calculated half-life of WGA-WSC-NPs in the small intestine was 6.72 h, resulting in 2.1- and 4.3-fold increase when compared to WGA-polyvinylalcohol (PVA)-NPs and WSC-NPs, much longer than that of control PVA-NPs (6.9-fold). These results suggest that NPs with the combined WGA and WSC coating represent promising candidates for efficient mucosal drug delivery as well as biomimetic treatment of lactose intolerance.
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