Maximizing the in vivo efficiency of gene transfer by means of nonviral polymeric gene delivery vehicles.
We have screened many synthetic and natural polymers for their ability to facilitate gene delivery in vivo into subcutaneous tissue. We postulated that gene delivery polymeric vehicles could control the chemical and biological stability of plasmid as well as their colloidal and surface properties, and this may lead to enhanced gene delivery in vivo. The screening was based on reporter gene (luciferase) expression using a plasmid containing the cytomegalovirus promoter. The control of charge density of resulting particles was achieved by selecting different ratios of polymer to plasmid mass as well as polymer chemistry. As opposed to in vitro observations, only polymers that lead to negatively charged particles exhibited an in vivo activity, in opposite to in vitro case. Such polymers exhibited relatively low positive charge chemistry (or neutral charge). The most potent polymeric vehicles were members of a Tetronic polymer series (synthetic polyethylene-polypropylene block copolymers; BASF, Mount Olive, NJ) or from a noncharged polyvinylpyrrolidine formulation. Plasmid dose response and time relationships were established for some polymers. Results were applied to the redesign of particles for biolistic (gene gun) plasmid gene delivery.
Prokop
Ales
A
Department of Chemical Engineering, Vanderbilt University School of Engineering, 107 Olin Hall, 24th Avenue S. and Garland Avenue, Nashville, Tennessee 37235, USA. ales.prokop@mcmail.vanderbilt.edu
Kozlov
Evgenii
E
Moore
William
W
Davidson
Jeffrey M
JM
D000818:Animals; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D018014:Gene Transfer Techniques / Q000295:instrumentation; D005822:Genetic Vectors / Q000008:administration & dosage; D007271:Injections, Intradermal; D008297:Male; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D011108:Polymers / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption / Q000502:physiology
D011108:Polymers