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Nanobiotechnology Applications of Reconstituted High Density Lipoprotein Robert O Ryan1,2

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Nanobiotechnology Applications of Reconstituted High Density Lipoprotein Robert O Ryan1,2 Ryan Journal of Nanobiotechnology 2010, 8:28 http://www.jnanobiotechnology.com/content/8/1/28 REVIEW Open Access Nanobiotechnology applications of reconstituted high density lipoprotein Robert O Ryan1,2 Abstract High-density lipoprotein (HDL) plays a fundamental role in the Reverse Cholesterol Transport pathway. Prior to maturation, nascent HDL exist as disk-shaped phospholipid bilayers whose perimeter is stabilized by amphipathic apolipoproteins. Methods have been developed to generate reconstituted (rHDL) in vitro and these particles have been used in a variety of novel ways. To differentiate between physiological HDL particles and non-natural rHDL that have been engineered to possess additional components/functions, the term nanodisk (ND) is used. In this review, various applications of ND technology are described, such as their use as miniature membranes for solubilization and characterization of integral membrane proteins in a native like conformation. In other work, ND harboring hydrophobic biomolecules/drugs have been generated and used as transport/delivery vehicles. In vitro and in vivo studies show that drug loaded ND are stable and possess potent biological activity. A third application of ND is their use as a platform for incorporation of amphiphilic chelators of contrast agents, such as gadolinium, used in magnetic resonance imaging. Thus, it is demonstrated that the basic building block of plasma HDL can be repurposed for alternate functions. Background While its structural properties and composition can be The term high-density lipoprotein (HDL) describes a rather complex, in its most basic form, HDL are rela- continuum of plasma lipoprotein particles that possess a tively simple, containing only phospholipid and apolipo- multitude of different proteins and a range of lipid con- protein (apo). The most abundant and primary stituents [1]. The major physiological function of HDL apolipoprotein component of plasma HDL is apoA-I. is in Reverse Cholesterol Transport [RCT; [2]]. The Human apoA-I (243 amino acids) is well characterized well-documented inverse relationship between plasma in terms of its structural and functional properties. HDL concentration and incidence of cardiovascular dis- When incubated with certain phospholipid vesicles ease has generated considerable interest in development in vitro, apoA-I induces formation of rHDL. The key of strategies to increase HDL levels. Aside from exercise, structural element of apoA-I required for rHDL assem- moderate consumption of alcohol and a healthy lifestyle, bly is amphipathic a-helix. Indeed, other apolipopro- pharmacological approaches are being pursued with the teins, apolipoprotein fragments or peptides that possess goal of enhancing athero-protection [3]. In addition to this secondary structure, can also combine with phos- these strategies, direct infusion of reconstituted HDL pholipid to form rHDL. In general, the product particle (rHDL) into subjects has been performed [4]. The idea is a nanometer scale disk-shaped phospholipid bilayer is that parenteral administration of rHDL will promote whose periphery is circumscribed by two or more apoli- RCT, facilitating regression of atheroma. Indeed, Nissen poprotein molecules (Figure 1). Indeed, a defining char- et al. [5] reported Phase II clinical trial results showing acteristic of members of the class of exchangeable a decrease in intimal thickness in patients treated with apolipoprotein is an abilitytoformrHDL.Forthepur- rHDL harboring a variant apolipoprotein A-I. pose of this review, the protein/peptide component of discoidal rHDL is termed the “scaffold” in recognition of Correspondence: [email protected] its function in stabilization of the otherwise unstable 1Center for Prevention of Obesity, Cardiovascular Disease and Diabetes, edge of the bilayer. Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland CA 94609, USA Full list of author information is available at the end of the article © 2010 Ryan; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ryan Journal of Nanobiotechnology 2010, 8:28 Page 2 of 10 http://www.jnanobiotechnology.com/content/8/1/28 Figure 1 Schematic diagram of rHDL structural organization. The complex depicted is comprised of a disk-shaped phospholipid bilayer that is circumscribed by an amphipathic “scaffold” protein. Note: The exact structural organization of rHDL remains controversial. Recently, evidence consistent with an ellipsoidal shape has been presented [59-61]. Production of rHDL apolipoproteins [7] or designer peptides [8] can substi- Detailed structure-function studies of exchangeable apo- tute for full-length apolipoproteins in this reaction. lipoproteins have given rise to two general methods for Based on this description, it is evident that myriad com- discoidal rHDL formation: detergent dialysis and direct binations of phospholipid and scaffold can be employed conversion. Whereas the detergent dialysis method [6] toformulateuniquerHDL.These particles are readily has the advantage that a broad spectrum of bilayer characterized in terms of size by non-denaturing polya- forming phospholipids can be employed, a disadvantage crylamide gel electrophoresis and morphology by elec- relates to the potentially problematic detergent removal tron or atomic force microscopy (AFM). step, which can be achieved by specific absorption or Over the past decade, discoidal rHDL have been repur- exhaustive dialysis. On the other hand, while limited to posed for applications beyond its physiological role in fewer phospholipid substrates, the direct conversion lipoprotein metabolism. This review describes active method does not employ detergents. The types of phos- areas of research that have evolved from our basic under- pholipids commonly used in the direct conversion standing of rHDL structure and assembly. Whereas method are synthetic, saturated acyl chain glyceropho- rHDL has been modified to re-task it for alternate pur- spholipids such as dimyristoylphosphatidylcholine poses, its basic structural elements, including disk shape, (DMPC) or dimyristoylphosphatidylglycerol. These lipids nanometer scale size and a planar bilayer whose periph- undergoageltoliquidcrystallinephasetransitionin ery is stabilized by a scaffold, are preserved. In this man- the range of 23°C. Normally, the phospholipid substrate ner, rHDL serve as a platform capable of packaging is hydrated and induced to form vesicles, either by transmembrane proteins in a native-like membrane membrane extrusion or sonication. Incubation of the environment, solubilization and delivery of hydrophobic phospholipid vesicle substrate with an appropriate scaf- drugs/biomolecules and presentation of contrast agents fold protein (e.g. apoA-I) induces self-assembly of for magnetic resonance imaging of atherosclerotic rHDL. It is likely that the reaction proceeds most effi- lesions. In an effort to distinguish engineered rHDL from ciently in this temperature range because defects created classical rHDL, the term nanodisk (ND) is used to in the vesicle bilayer surface serve as sites for apolipo- describe rHDL formulated to possess a transmembrane protein penetration, bilayer disruption and transforma- protein, drug or non-natural hydrophobic moiety. tion to rHDL. Among the apolipoproteins that have been examined for their ability to transform phospholi- ND as a miniature membrane environment for pid bilayer vesicles into rHDL and function as a scaffold solubilization of transmembrane proteins are apoA-I, apoE, apoA-IV, apoA-V and apolipophorin The bilayer component of ND provides a native-like III. In addition, it is known that fragments of environment for study of transmembrane proteins in Ryan Journal of Nanobiotechnology 2010, 8:28 Page 3 of 10 http://www.jnanobiotechnology.com/content/8/1/28 isolation. The concepts being developed on this research membrane protein. This 247 amino acid, light-driven front are that Type 1, Type 2 or Type 3 membrane pro- proton pump possesses a covalently bound molecule of teins can be inserted into ND with retention of their retinal. Elegant electron crystallography methods were native conformation/biological activity. As with a cell developed and employed by Henderson and Unwin to membrane, the inserted protein would align such that decipher the structure of bacteriorhodopsin at near its transmembrane segment(s) spans the bilayer while atomic resolution [13]. The protein is comprised of a their soluble, extra-membranous portions, exist in the bundle of seven ~25 residue a-helical rods that span the aqueous environment (Figure 2). If correctly inserted, it bilayer while charged residues at the surface of the mem- is anticipated that specific biological or enzymatic prop- brane contact the aqueous solvent. In its native form bR erties of the protein will be preserved. The surface area exists as trimers that organize into a two-dimensional of a 20 nm diameter ND particle is ~300 nm2,ample hexagonal array in the plane of the membrane. In 2006, area to accommodate several molecules of a multiple Bayburt et al. [14] assembled bR into ND. Under the pass transmembrane protein. Advantages of ND versus conditions employed each ND contained three bR mole- detergent micelles include a more natural environment cules. Small angle
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