Effect of Prodrug Activation Rate on In Vivo Drug Release and Antitumor Efficacy of SN38-Prodrug-Entrapped Liposomes

The aim of this study is to investigate the effects of prodrug activation rates on the in vivo drug release and antitumor activity of prodrug-entrapped liposomes. We performed such an investigation using two liposomes encapsulating hydrophilic SN38-glutathione (GSH) prodrugs (linked at 10- and 20-hydroxy of SN38) with different activation rates. The results showed that SN38-GSH was first released from liposomes and, consequently, activated into SN38. The SN38-GSH release rate from liposomes was similar, but the 10SN38-GSH activated much faster than 20SN38-GSH (t_1/2, < 1 min versus ∼60 min) in plasma. Such different activation rates did not influence the prodrug’s pharmacokinetics and biodistribution, but the fast prodrug activation rate resulted in 4–6-fold higher SN38 concentration in various organs and led to more potent antitumor efficacy. By contrast, the slowly activated SN38-GSH liposomes failed to exhibit potent antitumor activity, even at the maximum tolerance dose. Our data illustrated how the prodrug activation rate influences in vivo drug release and antitumor activity of prodrug-loaded liposomes, suggesting that sufficient prodrug activation is a prerequisite for potent prodrug-loaded liposomes.