(378) Development of Targeted Polymer-Drug Conjugates for Ovarian Cancer Chemotherapy

Trainee Category: Graduate Student

Objective : To synthesize and characterize targeted, linear, and hydrophilic polymer-drug conjugates for ovarian cancer treatment using doxorubicin as the model drug.

Methods: An α-, ω-bis-azide- terminated, linear hydrophilic ethylenediaminetetraacetic acid derivative (azidePEG-EDTA) was coupled to glycylphenylalanylleucylglycine (GFLG) tetrapeptide via 9-fluorenyl-methoxycarbonyl solid phase peptide chemistry to obtain an intermediate for the polymer backbone. GFLG is a specific substrate for cathepsin-B, which is overexpressed in ovarian cancer and is widely reported for selective drug release in the tumor microenvironment. A bis-azide-terminated doxorubicin-coupled intermediate was synthesized by reacting doxorubicin hydrochloride with the synthesized polymer building block using 2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline as the coupling agent. Polymer synthesis using strain-promoted alkyne-azide cycloaddition-mediated polymerization is currently ongoing.

Results: A novel polymer backbone intermediate, azidePEG-EDTA coupled to GFLG, was successfully synthesized and characterized. Mass spectrometry of the intermediate showed m/z: 1616.9800 (m/z calculated: 1616.8410); and Fourier-transform infrared spectroscopy showed the expected azide stretch (2106cm-1). Additionally, the doxorubicin-coupled intermediate was confirmed by mass spectrometry [m/z observed: 2670.6306 [M+2H]+ (m/z calculated: 2668.842)] and proton nuclear magnetic resonance spectroscopy.

Conclusions: A linear hydrophilic doxorubicin-coupled intermediate was synthesized for the development of polymer-drug conjugates designed to target and treat ovarian cancer. This intermediate can undergo strain-promoted alkyne-azide cycloaddition click chemistry for the synthesis of the polymer-drug conjugates in drug delivery to ovarian cancer by the enhanced permeability and retention effect. Specific cathepsin B cleavage of the polymer-drug conjugates will allow selective drug release in the tumor microenvironment, thereby minimizing adverse side effects and off-target toxicity to healthy cells.