Biodegradable Multiblock Polymers Based on N‐(2‐Hydroxypropyl)methacrylamide Designed as Drug Carriers for Tumor‐Targeted Delivery

Abstract

Biodegradable multiblock (co)polymers based on N‐(2‐hydroxypropyl)methacrylamide (HPMA) for drug delivery applications are prepared by azide–alkyne polycycloaddition of end‐functionalized precursors synthesized by reversible addition–fragmentation chain transfer polymerization. Copper‐catalyzed polyaddition of the heterotelechelic polymer precursors containing azide and alkyne groups provides (A)x‐type multiblock (co)polymers. For the first time, thermally degradable multiblock polymers of (AB)x‐type are prepared via polyaddition of homotelechelic polymer diazides with azo‐compounds containing two alkyne groups. A novel type of HPMA‐based multiblock (co)polymers undergoing the pH‐dependent hydrolysis is reported. The (co)polymers containing the Asp‐Pro‐Lys sequence are relatively stable in an aqueous buffer at physiological pH 7.4; however, they undergo rapid hydrolysis at pH 5.0 corresponding to the pH in lysosomes. The multiblock polymer containing the Gly‐Phe‐Leu‐Lys linkage is degraded in the presence of the lysosomal protease cathepsin B. Thermal degradation of the (AB)x‐type multiblock polymers proceeds even at 37 °C, yielding a mixture of polymer degradation products with molecular weights below the renal threshold. image