Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake

https://doi.org/10.1016/j.addr.2003.12.003Get rights and content

Abstract

We highlight the importance of the low-density lipoprotein (LDL) receptor family and its pharmaceutical implications in the field of drug delivery. The members of the LDL receptor family are a group of cell surface receptors that transport a number of macromolecules into cells through a process called receptor-mediated endocytosis. This process involves the receptor recognizing a ligand from the extracellular membrane (ECM), internalizing it through clathrin-coated pits and degrading it upon fusion with lysosomes. There are nine members of the receptor family, which include the LDL receptor, low-density lipoprotein-related protein (LRP), megalin, very low-density lipoprotein (VLDL) receptor, apoER2 and sorLA/LRP11, LRP1b, MEGF7, LRP5/6; the former six having been identified in humans. Each member is expressed in a number of different tissues and has a wide range of different ligands, not specific to the recognition of the LDL particle. Thus, rather than the original hypothesis that the receptor is only a mediator of cholesterol uptake, it may also be involved in a number of other physiological functions, including the progression of certain disease states and, potentially, cellular drug uptake. A number of studies have suggested that the LDL receptors are involved in endocytosis of drugs and drug formulations including aminoglycosides, anionic liposomes and cyclosporine A (CsA). This article reviews the importance of lipoproteins as a drug delivery system and how LDL receptors are relevant to the design and targeting of specific drugs.

Introduction

Lipoproteins are biological carriers in which lipids and proteins can be transported systemically. It is well established that specific drugs such as halofantrine (Hf), amphotericin B (AmpB) and cyclosporine A (CsA) associate with lipoproteins [9], [10], [11]. Therefore, by understanding the mechanism in which these lipoprotein-bound drugs can be taken up intracellularly may provide novel methods in drug targeting. There have been a number of studies suggesting that the LDL receptor and members of its superfamily may be playing a role in cellular drug uptake, specifically, aminoglycosides, type-I ribosome-inactivating proteins (RIP), anionic liposomes and cyclosporine A. Therefore, it would be of interest to examine the role of the LDL receptor family as a mechanism of cellular drug uptake.

Section snippets

Lipoproteins and their metabolism

Lipoproteins are a class of complex macromolecules consisting of both lipid and protein subgroups. Their main responsibility is to transport a number of water insoluble nutrients throughout the systemic circulation, mainly lipids in an aqueous environment. Lipoproteins are characterized by an insoluble core of cholesteryl ester and triglyceride surrounded by a shell of amphipathic phospholipids and specialized proteins called apolipoproteins [1], [2] (Fig. 1). They differ in their content of

Drug binding with lipoproteins

Plasma lipoproteins are primarily involved in the transport of lipids and proteins throughout systemic circulation. However, the biological significance of lipoproteins extends beyond lipid transport to the transport of hydrophobic drugs. Drugs such as CsA [9], Hf [11] and amphotericin B lipid complex (ABLC) [10] have been shown to associate extensively with plasma lipoproteins. These drugs have pharmacokinetic properties, tissue distribution and pharmacological activities that are affected by

The LDL receptor and its family members

The LDL receptor is an endocytic receptor that transports relevant macromolecules, mainly the cholesterol-rich lipoprotein LDL, into cells through a process called receptor-mediated endocytosis [54] (see Fig. 2). This process involves the cell surface receptor recognizing an LDL particle from the extracellular membrane (ECM), internalizing it through clathrin-coated pits and transporting it intracellularly via a vesicle [54], [55], [56]. Subsequently, the vesicle becomes degraded upon fusion

Drug interactions with LDL receptor family members

Recent studies have suggested the role of the LDL receptor family in the cellular uptake of drugs, including aminoglycosides, type-I ribosome inactivating protein, lipid-based formulations and cyclosporine A.

Conclusions

It is well established that certain drugs associate with lipoproteins. Thus lipoproteins can act as a natural drug delivery system for hydrophobic drugs or lipid-based formulations. Nevertheless, it is the association of these drugs with lipoproteins that may be able to explain their pharmacological activity, pharmacokinetic properties as well as its toxicities. Furthermore, by understanding the uptake mechanisms of these specific drug delivery systems, it can provide better therapeutic

Acknowledgements

We would like to acknowledge Kathy (Peteherych) Boulanger for contributing the diagrams from her thesis to this manuscript. Thank you to Dr. Kristina Sachs-Barrable for helping to review and for providing suggestions. In addition, we would like to thank the Canadian Institutes of Health Research (MOP #14484 to KMW) for the many years of funding.

References (148)

  • M.P. McIntosh et al.

    Differences in the lipoprotein binding profile of halofantrine in fed and fasted human or beagle plasma are dictated by the respective masses of core apolare lipoprotein lipid

    J. Pharm. Sci.

    (1999)
  • D.R. Brocks et al.

    The influence of lipid on stereoselective pharmacokinetics of halofantrine: important implications in food-effect studies involving drugs that bind to lipoproteins

    J. Pharm. Sci.

    (2002)
  • A.L. Kennedy et al.

    Preferential distribution of amphotericin B lipid complex into human HDL3 is a consequence of high density lipoprotein coat lipid content

    J. Pharm. Sci.

    (1999)
  • S.C. Hartsel et al.

    Heat-induced superaggregation of amphotericin B modifies its interaction with serum proteins and lipoproteins and stimulation of TNF-alpha

    J. Pharm. Sci.

    (2001)
  • T. Yamamoto et al.

    The human LDL receptor: a cysteine-rich protein with multiple alu sequences in its mRNA

    Cell

    (1984)
  • T. Yamamoto et al.

    The very low density lipoprotein receptor: a second lipoprotein receptor that may mediate uptake of fatty acids into muscle and fat cells

    Trends Cardiovasc. Med.

    (1993)
  • C.W. Heegaard et al.

    Very low density lipoprotein receptor binds and mediates endocytosis of urokinase-type plasminogen activator-type-1 plasminogen activator inhibitor complex

    J. Biol. Chem.

    (1995)
  • D.H. Kim et al.

    Human apolipoprotein E receptor 2: a novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in the brain

    J. Biol. Chem.

    (1996)
  • S. Novak et al.

    A new low-density lipoprotein receptor homologue with 8 ligand binding repeats in brain of chicken and mouse

    J. Biol. Chem.

    (1996)
  • T. Curran et al.

    Role of reelin in the control of brain development

    Brain Res. Brain Res. Rev.

    (1998)
  • M. Trommsdorff et al.

    Reeler/disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and apoE receptor 2

    Cell

    (1999)
  • J. Herz

    The LDL receptor gene family: (un)expected signal transducers in the brain

    Neuron

    (2001)
  • J.G. Neels et al.

    The second and fourth cluster of class A cysteine-rich repeats of the low density lipoprotein receptor-related protein share ligand-binding properties

    J. Biol. Chem.

    (1999)
  • C.X. Liu et al.

    The putative tumor suppressor LRP1b, a novel member of the low-density lipoprotein (LDL) receptor family, exhibits both overlapping and distinct properties with the LDL receptor-related protein

    J. Biol. Chem.

    (2001)
  • Y. Li et al.

    Low density lipoprotein (LDL) receptor-related protein 1b impairs urokinase receptor regeneration on the cell surface and inhibits cell migration

    J. Biol. Chem.

    (2002)
  • M. Nakayama et al.

    Identification of high-molecular-weight proteins with multiple EGF-like motifs by motif-trap screening

    Genomics

    (1998)
  • S.D. Brown et al.

    Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family

    Biochem. Biophys. Res. Commun.

    (1998)
  • Y. Dong et al.

    Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity

    Biochem. Biophys. Res. Commun.

    (1998)
  • P.J. Hey et al.

    Cloning of a novel member of the low-density lipoprotein receptor family

    Gene

    (1998)
  • N.S. Tolwinski et al.

    Wg/Wnt signal can be transmitted through arrow/LRP5,6 and axin independently of Zw3/Gsk3beta activity

    Dev. Cell

    (2003)
  • J. Mao et al.

    Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway

    Mol. Cell

    (2001)
  • Y. Gong et al.

    LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development

    Cell

    (2001)
  • L. Van Wesenbeeck et al.

    Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density

    Am. J. Hum. Genet.

    (2003)
  • J.C. Hsieh et al.

    Mesd encodes and LRP5/6 chaperone essential for specification of mouse embryonic polarity

    Cell

    (2003)
  • L. Jacobsen et al.

    Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein

    J. Biol. Chem.

    (1996)
  • S. Hirayama et al.

    Differentail exression of LR11 during proliferation and differentiation of cultured neuroblastoma cells

    Biochem. Biophys. Res. Commun.

    (2000)
  • H. Yamazaki et al.

    Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low density lipoprotein receptor family member

    J. Biol. Chem.

    (1996)
  • J. Shephard et al.

    Lipoproteins in health and disease: lipoprotein nomenclature and the classification of hyperlipoproteinemia

  • K.M. Wasan et al.

    Role of plasma lipoproteins in modifying the biological activity of hydrophobic drugs

    J. Pharm. Sci.

    (1998)
  • J.A. Harmony et al.

    Lipoprotein structure

  • A.M. Salter et al.

    The biochemistry of lipoproteins

    J. Inherit. Metab. Dis.

    (1988)
  • G.M. Kuster et al.

    Relation of cyclosporine blood levels to adverse effects on lipoproteins

    Transplantation

    (1994)
  • K.M. Wasan et al.

    Characteristics of lipid-based formulations that influence their biological behaviour within the plasma of patients

    Clin. Infect. Dis.

    (1996)
  • M.P. McIntosh et al.

    The degree of association of halofantrine with pre- and post-prandial plasma lipoproteins is determined by their apolar lipid content

    Pharm. Res.

    (1997)
  • W.M. Awni et al.

    The pharmacokinetics of cyclosporine: blood plasma distribution and binding studies

    Drug Metab. Dispos.

    (1984)
  • A.M. Gardier et al.

    Effects of plasma lipid levels on blood distribution and pharmacokinetics of cyclosporine A

    Ther. Drug Monit.

    (1993)
  • D. Sgoutas et al.

    Interaction of cyclosporine A with human lipoproteins

    J. Pharm. Pharmacol.

    (1986)
  • T. Hirano et al.

    Serum cholesterol levels and kidney transplantation outcome: attenuation of cyclosporine efficacy?

    Transplant

    (2001)
  • K.M. Wasan et al.

    Differences in lipoprotein lipid concentration and composition modify the plasma distribution of cyclosporine

    Pharm. Res.

    (1997)
  • M. Lemaire et al.

    Influence of blood components on the tissue uptake indices of cyclosporine in rats

    J. Pharmacol. Exp. Ther.

    (1988)
  • Cited by (133)

    • Low density lipoprotein receptor endocytosis in cardiovascular disease and the factors affecting LDL levels

      2023, Progress in Molecular Biology and Translational Science
      Citation Excerpt :

      LDLR helps in the metabolism of cholesterol through feedback inhibition of the hydroxymethylglutaryl CoA reductase enzyme,15 whereas, LDLR plays a vital role in lipid metabolism, cholesterol homeostasis, receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors.16 LDLR also plays an important role in drug delivery,17 LDLR-related protein-1 plays a significant role in inflammation in injuries to the nervous system, cancer, and atherosclerosis.18 LDLR gene is a mosaic protein of 839 amino acids which is located on chromosome 19 (19p13.

    • Nanotherapeutic treatment of the invasive glioblastoma tumor microenvironment

      2022, Advanced Drug Delivery Reviews
      Citation Excerpt :

      The low-density lipoprotein-(LDL) receptor family is a class of cell surface receptors crucial for transporting triglycerides and cholesterol via controlling the intracellular transport of apolipoprotein-containing lipoprotein particles [101]. These receptors are expressed in several different tissues and can also be found in the brain [102]. Specifically, the EC of the BBB expresses LDL and low-density lipoprotein receptor-related protein 1 (LRP1) receptors that govern lipoprotein transport into the brain [103].

    View all citing articles on Scopus
    View full text