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In this work, carboxyl-terminated PAMAM G-3.5 was covalently attached to SN38 via glycine and β-alanine spacers. The conjugates were stable at pH 7.4 and moderately hydrolyzed in cell culture media and rat plasma. Similarly to SN38 but to a lesser extent, both conjugates inhibited proliferation of human colorectal cancer HCT-116 cells, arrested the cell cycle in the G(2)/M phase, and led to nuclear fragmentation. However, activity of the conjugate with glycine spacer (IC(50) = 129 nM) was higher compared to that of the β-alanine linked conjugate (IC(50) = 387 nM). These PAMAM-SN38 conjugates have the potential for targeted therapy of colorectal carcinoma.

Carboxyl-Terminated PAMAM-SN38 Conjugates: Synthesis, Characterization, and in Vitro Evaluation