SN38-SPL9111

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.

For most cancers, the combination of chemotherapy drugs is a promising approach. The combination of DNA damage agent Exatecan and proteolysis targeting chimera (PROTAC) agent ARV-825, which is a selective bromodomain-containing protein 4 degrader, can further improve efficacy through the DNA damage-repair mechanism. The Cathepsin B-sensitive prodrug with high albumin affinity of Exatecan (C14-VC-PAB-Exa) was introduced and co-encapsulated with ARV-825 into the nano-drug delivery system for improving the physicochemical properties of the two drugs. To promote the translation of Exatecan and the PROTAC into the clinics, it is important to develop a reliable and high-throughput bioanalytical method for the simultaneous determination of Exatecan, C14-VC-PAB-Exa, and ARV-825 that can evaluate the pharmacokinetic behaviors of the analytes. In this study, an HPLC-MS/MS method after preparation by one-step protein precipitation was developed and fully validated. The analytes were eluted completely on a ZORBAX SB-C18 column by gradient elution. Multiple reaction monitoring mode with positive electrospray ionization was applied to quantify the analytes. The validated method on selectivity, linearity (r ≥ 0.995), precision and accuracy (< 15 %), extraction recovery (> 88.0 %), matrix effect (< 9.1 %), carry-over, and stability were within the predefined acceptance criteria. The method was successfully applied to the pharmacokinetic study of Exatecan, C14-VC-PAB-Exa, and ARV-825 in rats for the first time. The proposed robust and economical method will be an alternative bioanalytical procedure for Exatecan and ARV-825 in the future. What is more, the present work could provide a reference for the clinical combination of the two drugs.