Redox-sensitive irinotecan liposomes with active ultra-high loading and enhanced intracellular drug release.

In this report, a novel irinotecan (IR) encapsulated redox-responsive liposome was developed. The redox-responsive liposomes were prepared based on disulfide phosphatidylcholine (SS-PC), DSPC, DSPE-PEG2000 and cholesterol by ethanol injection method. IR was actively loaded by triethylammonium sucrose octasulfate (TEA8-SOS) gradient method to generate IR/SS-PC liposomes (IR/SS-LP). The particle size of IR/SS-PC was characterized by using dynamic light scattering (DLS) and transmission electron microscopy (TEM). It was found that IR/SS-LP with 30 % content of SS-PC (IR/SS30-LP) had an average size of 125.5 ± 5.8 nm with a negative zeta potential of -19.5 ± 0.1. The encapsulation efficiency (EE) was further determined to be 98.1 ± 0.8 % and drug loading (DL) was 31.8 ± 0.1 %. The redox-responsiveness of IR/SS-LP was investigated by observing the change of particle size and morphology as well as the release behavior of IR triggered by glutathione (GSH). The data indicated GSH breaks the disulfide bonds in SS-PC and leads to the controlled release of IR. At 1 mM GSH, 60.2 % irinotecan was released from IR/SS30-LP within 24 h. Finally, the effects of IR/SS-LP in cell and animal experiments were evaluated in detail. The results showed that IR/SS30-LP had superior pharmacokinetic and antitumor efficacy compared to free irinotecan and traditional irinotecan liposome (ONIVYDE®-like). Taken together, IR/SS30-LP displayed redox-responsive release of IR, ultra-high loading and enhanced anti-tumor activity, which has great potential for clinical application as a new generation of IR liposomal formulation.