Development of a formulation that enhances gene expression and efficacy following intraperitoneal administration in rabbits and mice

Abstract

We conducted a series of experiments to determine if intraperitoneal (IP) delivery of recombinant adenovirus (rAd)-based therapies is improved through carrier vehicle selection, and compared an icodextrin solution (a high molecular weight dextrin with a prolonged peritoneal cavity residence time) with a standardized phosphate buffered saline (PBS) delivery solution. In vitro, comparative adenovirus particle concentration determination (27h) and bioactivity assay (24h) indicated equivalent compatibility with icodextrin or PBS. In vivo, rabbits treated IP (100 ml) with rAd-βgal 1 × 109 P/ml in icodextrin showed improved transgene expression throughout the peritoneal wall compared to rAd-βgal in PBS. In PC-3 tumor-bearing mice treated IP with 5 × 109 P/0.5ml or 1 × 1010 P/0.5 ml rAd-βgal, transgene expression was significantly enhanced (p < 0.01) with icodextrin compared to PBS in both tumor specimens and peritoneal wall. In subsequent studies we compared prolongation of survival in intraperitoneal PC-3 and MDAH-2774 human xenograft tumor models in nude mice using rAd-p53 in icodextrin or PBS in multi-dose ranging (1 × 108 to 1 × 1010 P) experiments. The icodextrin formulation alone significantly increased rAd-p53 mediated survival (p < 0.05). In animals, these results show that IP rAd gene therapy can be improved with the use of icodextrin, and suggest that prolonged retention and distribution in the peritoneal cavity is an important factor.