Cationic corticosteroids for gene delivery and as controlled release antiinflammatory agents
To our knowledge, there are no cationic DNA delivery agents designed to both deliver DNA and act as a drug on their own, and there are no FDA-approved small molecule pharmaceuticals that use short polycationic tails to alter their pharmacokinetics and pharmacodynamics. To address this problem, we developed a straightforward synthesis scheme to link spermine to the 21-C position of steroids via a 2-iminothiolane linkage to make cationic steroids. The initial cationic steroid synthesized, a dexamethasone-spermine conjugate (DS) was based on dexamethasone, a potent glucocorticoid recognized to enhance transgene expression in vivo by its anti-inflammatory activities. Four additional cationic steroids, with increasing octanol/water partition coefficient of the parent steroid (Log P), were formulated with dioleylphosphatidylethanolamine (DOPE) and used to lipofect ∼90% confluent bovine aortic endothelial cells. Transgene expression at 24 and 48 h, up to several times that observed with Lipofectamine, was analyzed with respect to the biochemical/biophysical variables, and a design equation for optimal expression and reduced toxicity at 24h and 48h post-lipofection was obtained for a Lipofection Index, LI = CR*LogP liposomes(LogPster/ABSΔ Log P)*[R/(R+1)]. DS was assayed for pharmacological activity. DS induced nuclear localization of the glucocorticoid receptor (GR), transactivation of GRE expression and, transrepression of NF-kB mediated expression. Pharmacokinetics of DS were similar to that of dexamethasone in intraperitoneal injection in mice. DS represents a new class of pharmacologically active DNA delivery lipids that may be useful in their own right as dissociated steroid depots for the topical treatment of inflammatory diseases such as arthritis and asthma. ^
Chemistry, Pharmaceutical|Engineering, Biomedical
Jeffrey Alan Miner Gruneich,
"Cationic corticosteroids for gene delivery and as controlled release antiinflammatory agents"
(January 1, 2002).
Dissertations available from ProQuest.