Rj. Mumper et Ap. Rolland, PLASMID DELIVERY TO MUSCLE - RECENT ADVANCES IN POLYMER DELIVERY SYSTEMS, Advanced drug delivery reviews, 30(1-3), 1998, pp. 151-172
Preclinical studies involving intramuscular injection of plasmid into
animals have revealed at least four significant variables that effect
levels of gene expression (i.e., > fivefold effect over controls), inc
luding the formulation, injection technique, species and pretreatment
of the muscle with myotoxic agents to induce muscle damage. The uptake
of plasmid formulated in saline has been shown to be a saturable proc
ess, most likely via a receptor-mediated event involving the T tubules
and caveolae. Pharmacokinetic studies have demonstrated that the bioa
vailability of injected plasmid to muscle cells is very low, due to ra
pid and extensive plasmid degradation by extracellular nucleases. We h
ave developed protective, interactive, non-condensing (PINC) delivery
systems designed to complex plasmids and to (i) protect plasmids from
rapid nuclease degradation, (ii) disperse and retain intact plasmid in
the muscle and (iii) facilitate the uptake of plasmid by muscle cells
. PINC systems result in up to at least a one log increase in both the
extent and levels of gene expression over plasmid formulated in salin
e. We have combined the PINC delivery systems with two different muscl
e-specific expression plasmids. After direct intramuscular injection o
f these gene medicines, we have shown both local myotrophic and neurot
rophic effects of expressed human insulin-like growth factor (hIGF-I)
and the secretion of biologically active human growth hormone (hGH) in
to the systemic circulation. (C) 1998 Elsevier Science B.V.