Lipoproteins targeting

Porter, C.J., and W.N. Charman. 2001. Lipid-based formulations for oral administration Opportunities for bioavailability enhancement and lipoprotein targeting of lipophilic drugs. J Re cep t Signal Transduct Res 21 215. 

Opportunities for Bioavailability Enhancement and Lipoprotein Targeting of Lipophilic Drugs... 

Cholesterol, high-density lipoprotein Target value 30%... 

Proteins embedded in the shell of lipoproteins. They serve as scaffold for assembly of the lipoprotein particle in the endoplasmic reticulum. In addition, they control metabolism of lipoproteins in the circulation by interaction with enzymes such as lipases. Finally, apolipoproteins determine cellular uptake of the particles by interaction with specific lipoprotein receptors expressed on the surface of target cells. 

Szapary PO, Rader DJ (2004) The triglyceride-high-density lipoprotein axis an important target of therapy Am Heart J 148 211-221... 

The main transport form of lipids in the cir culation. They are spherical macromolecules of 10-1200 nm diameter-composed of a core of neutral lipids (mostly cholesterol ester and triglycerides) surrounded by an amphipathic shell of polar phospholipids and cholesterol. Embedded in the shell of lipoproteins are apolipoproteins that are essential for assembly of theparticles in tissues that secrete lipoproteins, and for their recognition by target cells. 

Reelin is an extracellular matrix protein, which is secreted by neuronal cells and binds to two lipoprotein receptors (VLDLR and ApoER2) that relay the Reelin signal inside target neurons by docking the tyrosine kinase adapter disabled-1 (Dabl). This allows neurons to complete migration and adopt their ultimate positions in laminar structures in the central nervous system. In... 

Patients with metabolic syndrome have an additional lipid parameter that needs to be assessed, namely non-high-density lipoprotein (non-HDL) cholesterol (total cholesterol minus HDL cholesterol). The target for non-HDL cholesterol is less than the patient s LDL cholesterol target plus 30 mg/dL (0.78 mmol/L). 

The use of LDL and other lipoproteins in drug targeting has been reviewed [170,172], Damle et al. [173] have shown that radiopharmaceuticals, such as iopanoic acid, a cholecystographic agent, could be incorporated in chylomicron remnants by esterification with cholesterol and used for liver imaging. About 87% of the chylomicron remnant-loaded iopanoic acid accumulated in the liver within 0.5 hour after administration, compared with 31% accumulated using a... 

At least four clinical candidates including GSK-256073 [112], MK-0354 [102], MK-1903 [113], and INCB-19062 [91], and one preclinical candidate MK-6892 [77] have been reported. Neither the structure of GSK-256073, nor the clinical data, has been reported. In Phase II clinical trials, neither GPR109A partial agonist MK-0354, nor the full agonist MK-1903 showed substantial lipoprotein effects, and both candidates were discontinued. INCB-19062 is targeted to a type II diabetes indication based upon the related role of FFA to insulin sensitization in type II diabetes, and the robust FFA lowering effect observed in a Phase I clinical trial devoid of FFA rebound. 

Targeted contrast agents are specific and directed to a specific molecular or cellular target with an appropriate targeting ligand molecule. Recombinant high density lipoprotein (HDL)-like nanoparticles, a specific contrast agent for MRI of atherosclerotic plaques, has been reported [86] (Fig. 25). 

The choice of target cells is another point worthy of discussion. In some instances, this choice is predetermined, e.g. treatment of the genetic condition, familial hypercholesterolaemia, would require insertion of the gene coding for the low-density lipoprotein receptor specifically in hepatocytes. 

As discussed above, obesity is associated with dyslipidemia, a condition where high levels of low-density lipoprotein cholesterol (LDL-C) is common. Elevated LDL-C is strongly associated with an elevated risk of coronary artery disease and for this reason a number of lipid-lowering therapies that target LDL-C have been developed. These include bile-acid sequestrants (BAS), statins (HMG-CoA reductase inhibitors), cholesterol absorption inhibitors, and fibrates. ... 

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