Apolipoprotein A-I, cyclodextrins and liposomes as potential drugs for the reversal of atherosclerosis. A review.
Several studies have revealed that high-density lipoprotein (HDL) is the most reliable predictor for susceptibility to cardiovascular disease. Since apolipoprotein A-I (apoA-I) is the major protein of HDL, it is worthwhile evaluating the potential of this protein to reduce the lipid burden of lesions observed in the clinic. Indeed, apoA-I is used extensively in cell culture to induce cholesterol efflux. However, while there is a large body of data emanating from in-vitro and cell-culture studies with apoA-I, little animal data and scant clinical trials examining the potential of this apolipoprotein to induce cholesterol (and other lipid) efflux exists. Importantly, the effects of oxysterols, such as 7-ketocholesterol (7KC), on cholesterol and other lipid efflux by apoA-I needs to be investigated in any attempt to utilise apoA-I as an agent to stimulate efflux of lipids. Lessons may be learnt from studies with other lipid acceptors such as cyclodextrins and phospholipid vesicles (PLVs, liposomes), by combination with other effluxing agents, by remodelling the protein structure of the apolipoprotein, or by altering the composition of the lipoprotein intended for administration in-vivo. Akin to any other drug, the usage of this apolipoprotein in a therapeutic context has to follow the traditional sequence of events, namely an evaluation of the biodistribution, safety and dose-response of the protein in animal trials in advance of clinical trials. Mass production of the apolipoprotein is now a simple process due to the advent of recombinant DNA technology. This review also considers the potential of cyclodextrins and PLVs for use in inducing reverse cholesterol transport in-vivo. Finally, the potential of cyclodextrins as delivery agents for nucleic acid-based constructs such as oligonucleotides and plasmids is discussed.
Johnson and Johnson Research, Strawberry Hills, Australia. cdass@medau.jnj.com
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Jessup
D016632:Apolipoprotein A-I / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003505:Cyclodextrins / Q000009:adverse effects / Q000627:therapeutic use*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage*; D010743:Phospholipids / Q000378:metabolism
D016632:Apolipoprotein A-I; D003505:Cyclodextrins; D004337:Drug Carriers; D008081:Liposomes; D010743:Phospholipids; D002784:Cholesterol