Apolipoprotein A-I, phospholipid vesicles, and cyclodextrins as potential anti-atherosclerotic drugs: delivery, pharmacokinetics, and efficacy.
High-density lipoprotein (HDL) is a reliable predictor for susceptibility to cardiovascular disease. Since apolipoprotein A-I (apoA-I) is the major protein of HDL, it is worthwhile to evaluate the potential of this protein to reduce the lipid burden of lesions observed in the clinic. While a large body of data emanates from in vitro and cell culture studies with apoA-I, few animal and lesser clinical trials examining the potential of this apolipoprotein to induce cholesterol (and other lipid) efflux exist. Lessons may be learned from studies with other lipid acceptors such as phospholipid vesicles (PLVs, liposomes) and cyclodextrins (CDs). Additionally, the combination of apoA-I with other effluxing agents, alteration of the composition of the lipoprotein, or a remodeling of the protein structure of the apolipoprotein to be administered in vivo may result in increased efficacy. The usage of this apolipoprotein in a therapeutic context has to follow the conventional sequence of events: an evaluation of the biodistribution, safety, and dose-response of the protein in animal trials before clinical trials. The review also considers the potential of cyclodextrins and PLVs to induce reverse cholesterol transport in vivo and discusses the potential of CDs as delivery agents for genetic constructs, such as plasmids and oligonucleotides.
Dass
C R
CR
Johnson and Johnson Research, Strawberry Hills, Australia. cdass@medau.jnj.com
D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000502:physiology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism*; D003505:Cyclodextrins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D010743:Phospholipids
D016632:Apolipoprotein A-I; D003505:Cyclodextrins; D008081:Liposomes; D010743:Phospholipids; D002784:Cholesterol