Development of a formulation that enhances gene expression and efficacy following intraperitoneal administration in rabbits and mice.
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 (27 h) and bioactivity assay (24h) indicated equivalent compatibility with icodextrin or PBS. In vivo, rabbits treated IP (100 ml) with rAd-betagal 1 x 10(9) P/ml in icodextrin showed improved transgene expression throughout the peritoneal wall compared to rAd-betagal in PBS. In PC-3 tumor-bearing mice treated IP with 5 x 10(9) P/0.5 ml or 1 x 10(10) P/0.5 ml rAd-betagal, 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 x 10(8) to 1 x 10(10) 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.
Engler
Heidrun
H
Canji, Inc., 3525 John Hopkins Court, San Diego, CA 92121, USA. heidrun.engler@canji.com
Machemer
Todd R
TR
Schluep
Thomas
T
Wen
Shu-Fen
SF
Quijano
Erlinda
E
Wills
Ken N
KN
Harper
Alexis E
AE
Maneval
Daniel C
DC
Conroy
Susan E
SE
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005936:Glucans / Q000008:administration & dosage* / Q000627:therapeutic use; D005947:Glucose / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D000077607:Icodextrin; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000628:therapy*; D010537:Peritoneum / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D019076:Transgenes / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
D005936:Glucans; D000077607:Icodextrin; D001616:beta-Galactosidase; D005947:Glucose