A disulfiram/copper gluconate co-loaded bi-layered long-term drug delivery system for intraperitoneal treatment of peritoneal carcinomatosis

To develop a long-term drug delivery system for the treatment of primary and metastatic peritoneal carcinoma (PC) by intraperitoneal (IP) injection, a disulfiram (DSF)/copper gluconate (Cu-Glu)-co-loaded bi-layered poly (lactic acid-coglycolic acid) (PLGA) microspheres (Ms) - thermosensitive hydrogel system (DSF-Ms-Cu-Glu-Gel) was established. Rate and mechanisms of drug release from DSF-Ms-Cu-Glu-Gel were explored. The anti-tumor effects of DSF-Ms-Cu-Glu-Gel by IP injection were evaluated using H22 xenograft tumor model mice. The accumulative release of DSF from Ms on the 10th day was 83.79% without burst release. When Ms were dispersed into B-Gel, burst release at 24 h decreased to 14.63%. The results showed that bis (diethyldithiocarbamate)-copper (Cu(DDC)2) was formed in DSF-Ms-Cu-Glu-Gel and slowly released from B-Gel. In a pharmacodynamic study, the mount of tumor nodes and ascitic fluid decreased in the DSF-Ms-Cu-Glu-Gel group. This was because: (1) DSF-Ms-Cu-Glu-Gel system co-loaded DSF and Cu-Glu, and physically isolated DSF and Cu-Glu before injection to protect DSF; (2) space and water were provided for the formation of Cu(DDC)2; (3) could provide an effective drug concentration in the abdominal cavity for a long time; (4) both DSF and Cu(DDC)2 were effective anti-tumor drugs, and the formation of Cu(DDC)2 occurred in the abdominal cavity, which further enhanced the anti-tumor activity. Thus, the DSF-Ms-Cu-Glu-Gel system can be potentially used for the IP treatment of PC in the future.