Sequential Sustained Release of Two Complementary Effect Biotoxins for Inhibiting Growth of Multidrug-Resistant Human Ovarian Cancer Xenograft

Abstract

To investigate the effect of sequential sustained-release biotoxins on inhibiting growth of multidrug-resistant human ovarian cancer xenograft. Cobra venom cytotoxin (CVC) was loaded in poly(lactide-co-glycolide) (PLGA) microspheres, then encapsulated in thermosensitive PLGA-PEG-PLGA hydrogel with ricin to prepare the sequential sustained-release biotoxins (SSRB). The SSRB were intratumorally injected once for mice bearing multidrug-resistant human ovarian cancer. The tumor growth inhibition rate was calculated and the survival time of tumor-bearing nude mice was recorded after the administration. The two biotoxins encapsulated in the SSRB preparation have different drug release rate and antitumor mechanisms, which can be complementary to each other. Ricin has a faster release rate than the CVC. It can combine with the tumor cell membrane and enter the cell, inhibiting protein synthesis within 18 days, whereas, the CVC releases slowly in 5 weeks directly dissolving the tumor cell membrane and killing the cells which are less-sensitive to ricin. The in vivo experiments showed that the average survival time of the tumor-bearing mice intratumorally injected with a blank carrier was 67.6±7.8 days. In contrast, when the mice were treated with SSRB, tumors in 5 out of 10 of the nude mice regressed and were cured on the 100th day. Local delivery of SSRB to treat ovarian cancer could maintain a high drug concentration on the target tumor achieving a thorough kill of tumor cells.