Catalyst Improved Stereoselectivity and Regioselectivity Control to Access Completely Alternating Poly(lactic‐co‐glycolic acid) with Enhanced Properties

Abstract The poly(lactic‐co‐glycolic acid) (PLGA) with completely alternating sequence has attracted growing attention as an ideal candidate in controlled drug delivery. However, the approach to completely alternating PLGA remains a challenge. Herein, we report the successful synthesis of completely alternating PLGA via highly regioselective and stereoselective ring‐opening polymerization. The chiral (BisSalen)Al catalyst promoted a robust polymerization of enantiopure 3‐methyl glycolide (MeG) with highly glycolyl site selectivity, affording alternating PLGA with regioselectivity up to more than 99 %. Impressively, the completely alternating PLGA exhibited a well‐defined melting temperature T m of 143.1 °C. Moreover, a stereocomplex between PLLGA and PDLGA was also formed with the improved T m of 211.8 °C. The In vitro degradation and drug release experiments revealed the linear degradation and controlled drug release behavior of completely alternating PLGA, which can be used as an ideal carrier for mild long‐acting drug delivery. Meanwhile, the reason of the high regioselectivity was investigated through the control experiments and DFT calculation. This highly regioselective (BisSalen)Al catalyst opens a door to providing completely alternating polymers.