pH-Sensitive Drug-Conjugates on Water-Soluble Polymer Frameworks

A potent synthetic methodology is introduced to generate a useful intermediate for the preparation of smart' polymeric pro-drugs. Herein, living anionic block polymerization of ethylene oxide (EO) and N-phenylmaleimide (N-PMI), as well as the Gabriel process, are introduced. Hydrazinolysis of the resulting poly(ethylene oxide)-block-poly(N-PMI) (PEO-b-PN-PMI) using hydrazine under acidic conditions leads to the production of PEO-based frameworks with hydrazide (HZ) groups. The HZ groups are found to effect the formation of an acid-sensitive bond in reactions with medicines or drugs under neutral conditions (pH 7.2). The PEO-HZ intermediate, which shows a strong triplet splitting patterned chemical shift in the range = 6.5-8.5 ppm, represents the most powerful material employed for mass production of smart polymeric pro-drugs while controlling the drug-loading yield. Water-soluble smart polymeric pro-drugs, such as poly(ethylene oxide)-doxorubicin (PEO-HZ-Dox), poly(ethylene oxide)-methotrexate (PEO-HZ-MTX), and poly(ethylene oxide)-folate (PEO-HZ-FA) conjugates, show excellent acid-sensitive release profiles in water or alcohol at pH 4.5.