Hydrolytic stabilization of irinotecan active metabolite (SN38) against physiologic pH through self-assembly of conjugated poly (2-oxazoline) - poly (L-amino acid) block copolymer: A-synthesis and physicochemical characterization

SN-38 is the active metabolite of irinotecan, an FDA-approved chemotherapeutic agent indicated in colorectal carcinoma; however, its clinical applications are still challenging due to low solubility and instability in physiologic condition. Self-assembling block copolymers have attracted great attention to resolve these issues. Therefore, we attempted to synthesize the poly (2-ethyl 2-oxazoline) macro-initiated poly (L-glutamic acid) block copolymers and subsequently to chemically conjugate SN38. The products were characterized by FTIR, H-1 NMR and DSC, confirming successful SN38 conjugation via phenyl ester linkage. Pyrene fluorescence assay, DLS and TEM implied formation of self-assembled nanoparticles with sizes about 91 nm at concentrations above 20 mu g/ml. Interestingly, the SN38 solubility was enhanced more than 10(4) folds. Hydrolytic degradation of the SN38 lactone ring was also investigated using a stability-indicating HPLC-UV method, indicating sustained release of the conjugated SN38 attenuated the first-order degradation kinetic compared with free drug. Furthermore, the SN38 conjugated copolymer caused apoptotic death of CT26 cells remarkably more than free drug. Conclusively, the conjugated SN38 is suggested for enhancing the SN38 solubility and stability in physiologic pH.