pH-Responsive polymers have great potential in biomedical applications, including the selective delivery of preloaded drugs to tissues with low pH values. These polymers usually contain acid-labile linkages such as esters and acetals/ketals. However, these linkages are only mildly pH-responsive with relatively long half-lives (t1/2 ). Orthoester linkages are more acid-labile, but current methods suffer from synthetic challenges and are limited to the availability of monomers. To address these limitations, a sugar poly(orthoester) was synthesized as a highly pH-responsive polymer. The synthesis was achieved by using 2,3,4-tri-O-acetyl-α-D-glucopyranosyl bromide as a difunctional AB monomer and tetra-n-butylammonium iodide (TBAI) as an effective promoter. Under optimal conditions, polymers with molecular weights of 6.9 kDa were synthesized in a polycondensation manner. The synthesized glucose poly(orthoester), wherein all sugar units were connected through orthoester linkages, was highly pH-responsive with a half-life of 0.9, 0.6, and 0.2 hours at pH 6, 5, and 4, respectively.

High molecular weight sugar poly(orthoesters) were synthesized through reverse anomeric effect (RAE). We demonstrated that when RAE-enabled promoters, such as 4-(dimethylamino)pyridine (DMAP), triphenylphosphine (TPP) or imidazole, were employed, efficient polymerizations were achieved, giving sugar poly(orthoesters) with molecular weights up to 18 kDa.

AbstractpH‐Responsive polymers have great potential in biomedical applications, including the selective delivery of preloaded drugs to tissues with low pH values. These polymers usually contain acid‐labile linkages such as esters and acetals/ketals. However, these linkages are only mildly pH‐responsive with relatively long half‐lives (t1/2). Orthoester linkages are more acid‐labile, but current methods suffer from synthetic challenges and are limited to the availability of monomers. To address these limitations, a sugar poly(orthoester) was synthesized as a highly pH‐responsive polymer. The synthesis was achieved by using 2,3,4‐tri‐O‐acetyl‐α‐D‐glucopyranosyl bromide as a difunctional AB monomer and tetra‐n‐butylammonium iodide (TBAI) as an effective promoter. Under optimal conditions, polymers with molecular weights of 6.9 kDa were synthesized in a polycondensation manner. The synthesized glucose poly(orthoester), wherein all sugar units were connected through orthoester linkages, was highly pH‐responsive with a half‐life of 0.9, 0.6, and 0.2 hours at pH 6, 5, and 4, respectively.

The synthesis of clickable polysaccharides was achieved by using alkynylated 1,6-anhydro glucopyranose as a monomer and BF3·OEt2 as an effective catalyst. Subsequent click conjugation with polyethylene glycol (PEG) afforded PEG-grafted polysaccharides in nearly quantitative efficiency.