Recombinant lipoproteins: lipoprotein-like lipid particles for drug targeting.
Lipoproteins are endogenous particles that transport lipids through the blood to various cell types, where they are recognised and taken up via specific receptors. These particles are, therefore, excellent candidates for the targeted delivery of drugs to various tissues. For example, the remnant receptor and the asialoglycoprotein receptor (ASGPr), which are uniquely localised on hepatocytes, recognise chylomicrons and lactosylated high density lipopoteins (HDL), respectively. In addition, tumour cells of various origins overexpress the low density lipoprotein (LDL) receptor that recognises apolipoprotein E (apoE) on small triglyceride-rich particles and apoB-100 on LDL. Being endogenous, lipoproteins are biodegradable, do not trigger immune reactions, and are not recognised by the reticuloendothelial system (RES). However, their endogenous nature also hampers large-scale pharmaceutical application. In the past two decades, various research groups have successfully synthesised recombinant lipoproteins from commercially available natural and synthetic lipids and serum-derived or recombinant apolipoproteins, which closely mimic the metabolic behaviour of their native counterparts in animal models as well as humans. In this paper, we will summarise the studies that led to the development of these recombinant lipoproteins, and we will address the possibility of using these lipidic particles to selectively deliver a wide range of lipophilic, amphiphilic, and polyanionic compounds to hepatocytes and tumour cells. In addition, the intrinsic therapeutic activities of recombinant chylomicrons and HDL in sepsis and atherosclerosis will be discussed.
Rensen
P C
PC
Sylvius Laboratories, Amsterdam Center for Drug Research, Division of Biopharmaceutics, Leiden, University of Leiden, P.O. Box 9503, 2300 RA, Leiden, The Netherlands. p.rensen@lacdr.leidenuniv.nl
de Vrueh
R L
RL
Kuiper
J
J
Bijsterbosch
M K
MK
Biessen
E A
EA
van Berkel
T J
TJ
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy; D002914:Chylomicrons / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000008:administration & dosage* / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000737:chemistry; D012772:Shock, Septic / Q000188:drug therapy; D013501:Surface-Active Agents / Q000008:administration & dosage / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000378:metabolism
D002914:Chylomicrons; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011355:Prodrugs; D011994:Recombinant Proteins; D013501:Surface-Active Agents