Alpha-helical, Hydrolysis-mediated Polymer-drug Conjugates derived from Poly(propargyl-L-glutamate)


Brian Zhong


Brian Zhong Wade Wang Paula T. Hammond

Author Affiliation: 

B. Zhong: MIT Department of Chemical Engineering W. Wang: MIT Department of Chemistry P. T. Hammond: MIT Department of Chemical Engineering


Cancer drugs are often small molecules that are effective at inhibiting cell growth, but suffer from low circulation time in the body due to rapid clearance by the kidneys. Polymer-drug conjugates mitigate this drawback by covalently binding the drug to polymers to reduce clearance. We have synthesized polymer-drug conjugates derived from an alpha-helical, poly(propargyl-L-glutamate) (PPLG) backbone using doxorubicin (Dox) as a model cancer drug. PPLG was synthesized via N-carboxyanhydride ring-opening polymerization of propargyl-L-glutamate. Dox was covalently bound to an azide-functionalized linker through an acid-labile hydrazone bond. Azide-functionalized Dox was attached to PPLG using copper-mediated azide-alkyne cycloaddition, and poly(ethylene glycol) (PEG) and dextran were attached as solubilizing fillers to yield polymer-drug conjugates with drug content of up to 34 wt%. Release profiles of the conjugates were obtained in PBS and cytotoxicity of the conjugates was evaluated in vitro. The conjugates released up to 65% of the drug content over 120 hours in PBS at pH 4 compared to 22% at pH 7.4. The IC50 values for the conjugates were found to be 10-100 times higher than those of free Dox. These results suggest that PPLG polymer-drug conjugates are viable drug-delivery vehicles for small molecule cancer drugs.