An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate containing 9-aminocamptothecin (9-AC) boundvia a spacer containing an aromatic azo bond and leucylalanine (P-Azo-Leu-Ala-9-AC) was synthesized. The in vivo pharmacokinetic profile after oral administration was examined in rats and comparedto free 9-AC. The aromatic azo bond of P-Azo-Leu-Ala-9-AC was stable in stomach and small intestine; the delivery of a large amount of intact conjugate to the colon was achieved. In the colon, the azoreductase activity first cleaved the azo bond followed by peptidase catalyzed cleavage of the leucylalanyl drug derivative resulting in the release of free 9-AC. However, the release rate from the conjugate was not fast enough to achieve high colon concentrations of free 9-AC. The results of the study suggest design features for the second generation of conjugates, including the use of a side-chain with a higher cleavage rate in the colon, combined with the incorporation of bioadhesion technology, to increase colon transit time.
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