Methodist Journal


Nutritional Supplements and the Heart

Vol 15, Issue 3 (2019)



Dietary Supplements: Facts and Fallacies

See More

Drs. Raizner and Cooke Take the Lead in Special Issue on Supplements

See More


Recent Clinical Trials Shed New Light on the Cardiovascular Benefits of Omega-3 Fatty Acids

Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment

Coenzyme Q10

Red Yeast Rice for Hypercholesterolemia

Inorganic Nitrate Supplementation for Cardiovascular Health

Vitamin D and Calcium Supplements: Helpful, Harmful, or Neutral for Cardiovascular Risk?

Cardiovascular Risk of Proton Pump Inhibitors

Advanced Cardiac Imaging for Complex Adult Congenital Heart Diseases


A Rare Case of Pancreatitis-Induced Thrombosis of the Aorta and Superior Mesenteric Artery

Anomalous Origin of the Right Coronary Artery from the Left Main Coronary Artery in the Setting of Critical Bicuspid Aortic Valve Stenosis

Simultaneous Transfemoral Mitral and Tricuspid Valve in Ring Implantation: First Case Report with Edwards Sapien 3 Valve

Uneventful Follow-Up 2 Years after Endovascular Treatment of a High Flow Iatrogenic Aortocaval Fistula Causing Pulmonary Hypertension and Right Heart Failure


Snoopy’s Heart: A Case of Complete Congenital Absence of the Pericardium



Herbal Nephropathy


Rolling the Dice on Red Yeast Rice


The Kidney in Congenital Cyanotic Heart Disease


Talking Statins with Antonio Gotto


Letter to the Editor in Response to “Cardiac Autonomic Neuropathy in Diabetes Mellitus”

Vol 12, Issue 3 (2016)

Article Full Text


Native and Reconstituted Plasma Lipoproteins in Nanomedicine: Physicochemical Determinants of Nanoparticle Structure, Stability, and Metabolism

Jump to:
Article Citation:

Pownall HJ, Rosales C, Gillard BK, Ferrari M. Native and Reconstituted Plasma Lipoproteins in Nanomedicine: Physicochemical Determinants of Nanoparticle Structure, Stability, and Metabolism. Methodist DeBakey Cardiovasc J. 2016;12(3):146-150.



Although many acute and chronic diseases are managed via pharmacological means, challenges remain regarding appropriate drug targeting and maintenance of therapeutic levels within target tissues. Advances in nanotechnology will overcome these challenges through the development of lipidic particles, including liposomes, lipoproteins, and reconstituted high-density lipoproteins (rHDL) that are potential carriers of water-soluble, hydrophobic, and amphiphilic molecules. Herein we summarize the properties of human plasma lipoproteins and rHDL, identify the physicochemical determinants of lipid transfer between phospholipid surfaces, and discuss strategies for increasing the plasma half-life of lipoprotein- and liposome-associated molecules.

liposomes ,  reconstituted HDL ,  lipid metabolism ,  apolipoproteins ,  membrane dynamics ,  lipoprotein structure

Introduction: Nanotechnology in Medicine

Advances in nanotechnology have revealed its great potential in the diagnosis and treatment of major diseases, including atherosclerosis.1 However, there are many challenges in the development of new therapeutics, such as nonspecific distribution to and inadequate accumulation within target tissues. Some argue that site-specific delivery of therapeutics is a distant reality due to the biological barriers that a particle encounters following intravenous administration. These barriers include: (A) opsonization and subsequent sequestration by the phagocytosis, (B) nonspecific distribution, (C) hemorheological/blood vessel flow limitations, (D) pressure gradients, (E) cellular internalization, (F) escape from endosomal and lysosomal compartments, and (G) drug efflux pumps.2,3Some of these challenges might be overcome by using nanoparticles with natural in vivo compatibility. Liposomes have already been recognized as potential carriers of bioactive materials,4 and the extension of this nanoparticle method to lipoproteins is the logical next step.

A Review of the Plasma Lipoproteins
Figure 1. Oil drop model of plasma lipoproteins. Each lipoprotein comprises a neutral lipid core surrounded by a surface monolayer of proteins and phospholipids. LDL: low-density lipoprotein; HDL: high-density lipoprotein; VLDL: very low-density lipoprotein; PL: phospholipid; CE: cholesteryl ester

Plasma lipoproteins are lipid-protein complexes that transport lipids between various tissue sites for utilization as energy or for steroidogenic hormone production and storage.5 They are composed of lipids, cholesterol, cholesteryl esters, triglycerides, and phospholipids, mainly phosphatidylcholine plus specialized proteins called apolipoproteins (apos). Lipoproteins are classified according to the densities at which they are isolated: very low (VLDL), low (LDL), intermediate (IDL), and high-density lipoproteins (HDL). Following a fat-containing meal, the intestine secretes triglyceride (TG)-rich lipoproteins called chylomicrons, which are even smaller than VLDLs. The density of lipoproteins is inversely related to their size, with HDL being the smallest yet most dense lipoprotein. The classification of lipoproteins according to their densities is biologically arbitrary but widely accepted. Lipoproteins are not discrete particles, and each class extends over a range of sizes and density subclasses. For example, HDL occurs at two different density ranges: designated HDL3 and HDL2, the larger and usually less-abundant subclass. Figure 1 depicts simple models of the major plasma lipoproteins as oily neutral lipid cores of cholesteryl esters and triglycerides surrounded by a surface of phospholipids and apos. Lipoprotein size is determined by neutral lipid content: chylomicrons and VLDLs are triglyceride-rich, LDLs are cholesteryl ester-rich, and HDLs are rich in protein and phospholipids. The relevant properties and compositions of the human plasma lipoproteins are summarized in Table 1. Nearly all plasma lipids are found on each of the lipoproteins, but their stoichiometries differ across classes and subclasses. The table does not include minor components that have been recently discovered using a proteomics approach.6 

Table 1. Properties of human plasma lipoproteins. From Pownell et al.5

The secretion and digestion activities of lipoproteins differ by type. HDLs and VLDLs are secreted by the liver but chylomicrons are secreted by the intestine, and all three are remodeled by plasma activities. Chylomicron and VLDL triglycerides are hydrolyzed by lipoprotein lipase, an enzyme that is activated by apo CII. This activity converts chylomicrons into remnants that are hepatically removed. VLDLs are converted to IDLs that are then converted to LDLs by hepatic lipase activity and finally removed by liver hepatocytes bearing LDL receptors.

After entering the plasma, early forms of HDL are remodeled by three activities. First, cholesterol is esterified by lecithin:cholesterol acyltransferase, which is activated by apo AI, converting the discoidal nascent HDL to its mature spherical form. Second, the cholesteryl ester transfer protein exchanges the HDL cholesteryl esters for VLDL and chylomicron triglycerides, which may be hydrolyzed by hepatic lipase. Finally, the phospholipid transfer protein exchanges phospholipids among HDL subfractions. The mature forms of all native lipoproteins are essentially spherical.

The Apolipoproteins

The apolipoproteins comprise apo B-100, apo B-48, and the exchangeable apos that include apos AI, AII, AIV, AV, CI, CII, CIII, and E. Apo B-100 is hepatically secreted with VLDL as a 500-kDa protein. Apo B-48, which contains 48% of the amino terminus of apo B-100, is secreted by the intestine with chylomicrons. Apo B-100 contains a ligand sequence that attracts LDL—but not VLDL—to the hepatic LDL receptor, where it undergoes endocytosis and degradation. Apo B-48 lacks the LDL receptor ligand sequence; therefore, the disposal of chylomicrons involves lipolysis followed by apo E-mediated uptake of the remnants. The genes for the exchangeable apos, which belong to the same gene family,7 comprise four exons, the first three of which share homology. The members of this gene family are distinguished by exon IV, which codes for sequences that have unique structures and attendant activities. Activities of apos include lecithin:cholesterol acyltransferase activation (apos AI and CI),8 lipoprotein lipase activation (apo CII),9 and binding to the LDL receptor (apo E).10 Apo E occurs as three isoforms—E2, E3, and E4—with E2 being the normal-functioning isoform. E3 and E4 are associated with dyslipidemias and premature cardiovascular disease, and E4 is also a risk factor for Alzheimer’s disease.

Drug Delivery

The therapeutic efficacy of drugs is a function of two factors: the local biological effect on cells and cellular targeting and an acceptable safety and risk/benefit profile. Physicochemically, drugs fall into three broad classes—hydrophobic/water-insoluble, polar/water-soluble, and amphiphilic (i.e., drugs that bind to a surface-water interface). Water-soluble drugs are by nature practically systemic; tissue sites penetrated by plasma are readily accessible to water-soluble drugs. Although this does not ensure that the drugs are taken up by cells in all tissues, such an effect is highly likely.

Lipoproteins are potential vehicles for the delivery of hydrophobic and amphiphilic drugs that are more challenging to deliver systemically. These types of drug molecules are expected to associate with the core (hydrophobic) and surface (amphiphilic) of plasma lipoproteins. As natural components of plasma, all lipoproteins can cloak exogenous molecules, permitting a drug to evade an immunological response. In addition, lipoproteins are easily isolated in large quantities by flotation.11 HDL is especially attractive because of its longer plasma half-life compared to LDL and VLDL (~5 days versus ~3 days and ~5 hours, respectively). Reconstituted HDL (rHDL) is readily made in vitro by spontaneous association12 or by detergent-removal methods,13 and drugs can be incorporated into rHDL with the lipid components using either method.

The Hydrophobic Effect and Lipid Bioavailability
Figure 2. Lipid transfer reaction coordinate. (A) A monoacyl lipid resides in the outer phospholipid monolayer of a membrane or lipoprotein. (B) With sufficient free energy, the lipid escapes the membrane but remains noncovalently tethered, thereby reducing its rotational freedom. (C) As it diffuses into the surrounding aqueous phase, the lipid reaches a lower free energy.

The lipophilicity of molecules is a major determinant of their ability to cross biological membranes and other lipid surfaces, including lipoproteins (. This has been confirmed with studies of lipids and proteins in which their lipophilicity was altered by the covalent attachment of acyl chains of varying lengths. Studies of fatty acids, their methyl esters, alcohols, and alkanes showed that the rate of transfer for each of these four lipid classes is a predictable function of their hydrophobicity as determined by the number of methylene-methyl groups within each molecule.14 In contrast, the addition of double bonds increases the water solubility of amphiphiles and reduces the free energy of activation for transfer (Figure 2). Moreover, according to chemical kinetics and absolute rate theory, each methylene-methyl moiety contributes ~700 cal/mol to the free energy of activation for transfer between lipid surfaces, a value that varies only slightly among lipids with different functional groups. Increasing the acyl chain length by two methylene units decreases the transfer rate by a factor of eight, whereas each added double bond increases the rate by a factor of four.15 Similar data collected on pyrene-labeled phospholipids showed the same trend, with the specific type of polar head group making only a small difference in the transfer rates.16 The rate-limiting step for molecular transfer between lipid surfaces is desorption of the lipid from the membrane or lipoprotein surface; this process follows Kelvin’s law stating that the rate of evaporation of a rain drop is inversely related to the radius of the rain drop. Thus, molecular desorption from surfaces (i.e., lipid transfer and evaporation) are controlled by similar forces.

The principles developed from studies with pyrene-labeled lipids were validated with natural lipids. It was determined that the addition of more methylene units to a molecule increases its transfer time between lipid surfaces in a predictable way, whereas increasing the number of double bonds has the opposite effect.17 A qualitative perspective of this is given in Table 2. Of note, human plasma contains transfer proteins that transport phospholipids and cholesteryl esters between lipoproteins. Similarly, the rates of transfer of natural phospholipids follow Kelvin’s law. The transfer time of lipids from VLDL, the largest plasma lipoprotein, is five times longer than that from HDL, the smallest lipoprotein. 

Table 2. Lipid transfer half-times.

Similar to liposomes, plasma lipoproteins have variable plasma half-lives dependent on the hydrophobicity of their major protein components. For example, free cholesterol binds to LDL but transfers to other lipoproteins on a time scale of minutes, which is orders of magnitude shorter than that of apo B-100 with a plasma half-life of approximately 3 days. The cholesteryl ester transfer protein, which transfers cholesteryl esters between lipoproteins, can reduce its plasma half-life by transfer from HDL to VLDL. Interestingly, mice do not express a cholesteryl ester transfer protein.

The transfer mechanisms of phospholipids differ from cholesteryl esters in some ways. Human plasma contains lipid transfer proteins for both cholesteryl esters and phospholipids. The cholesteryl ester transfer protein transfers HDL- and LDL-cholesteryl ester to VLDL in exchange for triglyceride,18 while the phospholipid transfer protein disproportionates HDL into larger and smaller particles.19,20 Both types of transfer proteins likely accelerate the turnover of their target lipids. However, the greatest threat to the life of a plasma phospholipid is lipolysis by hepatic lipase, endothelial lipase, lipoprotein lipase, phospholipases, and lecithin:cholesterol acyltransferase, all of which have phospholipase activities.21,22 Thus, the integrity and survival of a lipoprotein or liposome in plasma depends on its resistance to phospholipolytic activity and a long lipid transfer time. Increasing the transfer time is readily accomplished by increasing the number of methylene units attached to the phospholipid. This can be calculated from log T1/2 = 0.234n – 0.189m – 5.32, where T1/2 is the transfer half-life in minutes, n is the number of methylene + methyl moieties in the acyl chains, and m is the number of double bonds. For example, the calculated T1/2 of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) from HDL is 280 min, which is relatively short compared to the lifetimes of HDL and LDL. However, replacing the palmitoyl chain of POPC with a behenoyl, which has 20 carbons and no double bonds, increases the transfer time to ~50 hours.

Another challenge to increasing transfer time is that plasma phospholipases rapidly convert a phosphatidylcholine to a fatty acid and a lysophosphatidylcholine, both of which transfer in a matter of milliseconds. One solution is to formulate liposomes and rHDL from apos and phospholipids in which the ester linkages are replaced by ether bonds that are phospholipase-resistant. Ether phospholipids have physical properties similar to those of their ester analogs but resist phospholipolytic activity.23,24 These findings led to studies of phospholipid turnover in rats, which revealed the effects of phospholipid chain length and substitution of ether on the plasma half-life of ester phospholipids.25 Phosphatidylcholine saturated with 28 (dimyristoylphosphatidylcholine, DMPC), 32 (dipalmitoylphosphatidylcholine, DPPC), and 36 acyl carbons (desaturated phosphatidylcholine, DSPC) along with monounsaturated phosphatidylcholine with 34 acyl carbons (POPC) were compared. The phosphatidylcholine esters have affinities that are similar to their ether analogs. In vitro, the lecithin:cholesterol acyltransferase reactivity of these lipids increased: DMPC > DPPC > POPC > DSPC. Following injection into rats, the plasma half-lives of the ester and ether phosphatidylcholines increased: DMPC < DPPC < DSPC < POPC. However, the respective plasma half-lives of the ether phosphatidylcholines were 80%, 60%, 85%, and 110% longer than their ester analogs. The plasma half-life of a phosphatidylcholine increases with increasing acyl chain length and by replacing the acyl ester bonds with ether bonds. 

To summarize, an ideal lipid for liposome-based therapies would (1) be resistant to phospholipases, (2) contain two long acyl chains, making it very lipophilic, and (3) be saturated so that it could not be readily oxidized. Diphytanoyl phosphatidylcholine contains two 20-carbon branched acyl chains and satisfies these criteria.26

Increasing the Plasma Lifetimes of Proteins

Ponsin et al. tested whether the plasma half-life of an apo could be controlled by the covalent attachment of acyl chains of varying lengths. This was tested comparing a small, synthetic, lipid-associating peptide apo analog (LAP-20; 2 kDa; 20 amino acid residues) with apo AI (28 kDa). Similar to apo AI, LAP-20 binds HDL and activates lecithin:cholesterol acyltransferase.27 Moreover, increasing the length of the acyl chain attached to the LAP-20 amino terminus increased binding to rHDL by three orders of magnitude.28 The plasma half-lives of the various acylated LAP-20, measured in rats, increased as the acyl chain length was increased from 0 to 16 and the site of LAP-20 degradation shifted from the kidneys to the liver.29

Comparison of in vitro and in vivo data suggested that the plasma half-life of a protein can be controlled by graded acylation and that the plasma half-life of LAP-20 could be greatly extended by hyperacylation. This was tested with a diacyl LAP-20 that was shown to be nontransferable and a valid biomarker for HDL.30 Interestingly, the rate of clearance of diLAP-labeled HDL was slower than that of apo AI. A fraction of native human apo AI is cleared by the kidneys, whereas the liver was the preferred site for diLAP-labeled uptake.

Reconstituted HDL

Reconstituted HDL (rHDL) therapy for atherosclerosis and other disorders has been the focus of numerous studies, some of which showed that apo AI and phospholipids self-assemble into rHDL,31–33 enhance cholesterol efflux from cells,33,34 and have purported antiatherosclerotic effects.35 For example, rHDL treatment reverses atherosclerotic plaques36–38 and also improves endothelial function in patients with isolated low HDL cholesterol.39

Figure 3.Electron cryomicroscopy reconstruction of reconstituted HDL (rHDL). (A) Isosurface representation of rHDL viewed in an en face orientation. The diameter of the particle is ~360 Å. (B) Isosurface representation of the rHDL particle viewed laterally; the thickness is ~45 Å, the same as that of a single dimyristoylphosphatidylcholine bilayer. (C, D) Isosurface representation of rHDL scaled to diameter = 96 Å, but preserving thickness viewed in en face and lateral orientations assuming the same thickness but different density.

Reconstituted HDL has been studied by Raman spectroscopy, 13C NMR, calorimetry, chemical cross-linking, molecular dynamics, hydrogen-deuterium exchange, and electron microscopy. Studies have shown that increasing rHDL’s free cholesterol content up to 20 mol% increases its size from ~10 to ~40 nm.40 An early model of rHDL was a bilayer disc circumscribed by two antiparallel apo AI molecules in a head-to-tail configuration.41 An alternative structure, the superhelical model, was based on small-angle neutron scattering and molecular dynamics simulations.42,43 However, electron cryomicroscopy and image reconstruction of rHDL containing 15 mol% cholesterol and 8 apo AI molecules per particle40 shows rHDL as a 360 Å disc with a thickness of ~45 Å, which corresponds to the expected dimensions of a phospholipid bilayer.44 Although negative stain electron microscopy studies support a discoidal model, this approach can introduce artifacts, especially in lipidated molecules. In addition, molecules do not always remain in their native conformations when using native stain electron microscopy. However, with the electron cryomicroscopy method, the rapid freezing of the sample locks the particle in its native conformation.


Native and reconstituted lipoproteins bind to a myriad of hydrophobic and amphiphilic molecules with an affinity that is determined by the number of methylene and methyl groups. Reconstituted HDL are particularly attractive vehicles for drugs because they can be easily prepared and can accommodate a variety of lipophilic molecules. Preparing these and other carriers with ether phospholipids, which allow lipoproteins to cloak exogenous molecules, is likely to greatly increase their time in the plasma and, therefore, their therapeutic potential.

Key Points
  • The plasma lifetime of molecules that associate with liposomes or lipoproteins can be controlled in a predictable way by the covalent attachment of acyl chains of varying lengths. This approach can be used to make nontransferable analogs of lipids and proteins.

  • The in vivo plasma lifetime of a phospholipid increases with its hydrophobicity and can be further increased by replacing ester bonds with nonhydrolyzable ether bonds.

  • The sizes of rHDL prepared from apolipoprotein AI and phospholipids can be increased by the addition of free cholesterol; electron cryomicroscopy shows that rHDL, which are potential nanoparticle carriers of hydrophobic drugs, are discoidal.

Conflict of Interest Disclosure

The authors have completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported.

1. World Health Organization [Internet]. Geneva, SwitzerlandWorld Health Organizationc2016. Cardiovascular diseases: fact sheet N°317; 2015 Jan [cited 2016 May 8]. Available from:
2. Tellides G Pober JS. Inflammatory and immune responses in the arterial media. Circ Res. 2015 Jan 16; 116( 2): 312– 22.[Crossref]
3. Sampson UK , Fazio S , Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep. 2012 Feb; 14( 1): 1– 10[Crossref]
4. Tabas I , Williams KJ , Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007 Oct 16; 116( 16): 1832– 44[Crossref]
5. Chinetti-Gbaguidi G , Colin S , Staels B. Macrophage subsets in atherosclerosis. Nat Rev Cardiol. 2015 Jan; 12( 1): 10– 7.[Crossref]
6. Moore KJ , Sheedy FJ , Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013 Oct; 13( 10): 709– 21[Crossref]
7. McLaren JE , Michael DR , Ashlin TG , Ramji DP. Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog Lipid Res. 2011 Oct; 50( 4): 331– 47[Crossref]
8. Shashkin P , Dragulev B , Ley K. Macrophage differentiation to foam cells. Curr Pharm Des. 2005; 11( 23): 3061– 72[Crossref]
9. Feng B , Yao PM , Li Y , et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol. 2003 Sep; 5( 9): 781– 92[Crossref]
10. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005 Nov; 25( 11): 2255– 64[Crossref]
11. Lyaker MR , Tulman DB , Dimitrova GT , Pin RH , Papadimos TJ. Arterial embolism. Int J Crit Illn Inj Sci. 2013 Jan; 3( 1): 77– 87.[Crossref]
12. Libby P. Collagenases and cracks in the plaque. J Clin Invest. 2013 Aug; 123( 8): 3201– 3[Crossref]
13. Robbins CS , Hilgendorf I , Weber GF , et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med. 2013 Sep; 19( 9): 1166– 72[Crossref]
14. Gomez D Owens GK. Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc Res. 2012 Jul 15; 95( 2): 156– 64.[Crossref]
15. Marx SO , Totary-Jain H , Marks AR. Vascular smooth muscle cell proliferation in restenosis. Circ Cardiovasc Interv. 2011 Feb 1; 4( 1): 104– 11[Crossref]
16. Frink RJ. Inflammatory atherosclerosis: characteristics of the injurious agent. Sacramento, CAHeart Research Foundation2002. Chapter 2, The smooth muscle cell. The pivot in atherosclerosis. 111 p.
17. Allahverdian S , Chehroudi AC , McManus BM , Abraham T , Francis GA. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation. 2014 Apr 15; 129( 15): 1551– 9.[Crossref]
18. Feil S , Fehrenbacher B , Lukowski R , et al. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res. 2014 Sep 12; 115( 7): 662– 7[Crossref]
19. Shankman LS , Gomez D , Cherepanova OA , et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med. 2015 Jun; 21( 6): 628– 37[Crossref]
20. Anderson HC. Matrix vesicles and calcification. Curr Rheumatol Rep. 2003 Jun; 5( 3): 222– 6[Crossref]
21. Nakano-Kurimoto R , Ikeda K , Uraoka M , et al. Replicative senescence of vascular smooth muscle cells enhances the calcification through initiating the osteoblastic transition. Am J Physiol Heart Circ Physiol. 2009 Nov; 297( 5): H1673– 84.[Crossref]
22. Kataoka Y , Puri R , Hammadah M , et al. Spotty calcification and plaque vulnerability in vivo: frequency-domain optical coherence tomography analysis. Cardiovasc Diagn Ther. 2014 Dec; 4( 6): 460– 9.
23. Gotto AM Jr. The cardiology patient page. Statins: powerful drugs for lowering cholesterol: advice for patients. Circulation. 2002Apr 2; 105( 13): 1514– 6[Crossref]
24. Hayek S , Canepa Escaro F , Sattar A , et al. Effect of ezetimibe on major atherosclerotic disease events and all-cause mortality. Am J Cardiol. 2013 Feb 15; 111( 4): 532– 9[Crossref]
25. Ruparelia N , Digby JE , Choudhury RP. Effects of niacin on atherosclerosis and vascular function. Curr Opin Cardiol. 2011 Jan; 26( 1): 66– 70[Crossref]
26. Everett BM , Smith RJ , Hiatt WR. Reducing LDL with PCSK9 Inhibitors–The Clinical Benefit of Lipid Drugs. N Engl J Med. 2015Oct 22; 373( 17): 1588– 91[Crossref]
27. Yusuf S , Sleight P , Pogue J , Bosch J , Davies R , Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med.2000 Jan 20; 342( 3): 145– 53[Crossref]
28. Mason RP. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil. Vasc Health Risk Manag. 2011; 7: 405– 16[Crossref]
29. Ambrose JA Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol.2004 May 19; 43( 10): 1731– 7[Crossref]
30. Bäck M Hansson GK. Anti-inflammatory therapies for atherosclerosis. Nat Rev Cardiol. 2015 Apr; 12( 4): 199– 211[Crossref]
31. Tardif JC , L’allier P L , Ibrahim R , et al. Treatment with 5-lipoxygenase inhibitor VIA-2291 (Atreleuton) in patients with recent acute coronary syndrome. Circ Cardiovasc Imaging. 2010 May; 3( 3): 298– 307[Crossref]
32. Fisk M , Gajendragadkar PR , Mäki-Petäjä KM , Wilkinson IB , Cheriyan J. Therapeutic potential of p38 MAP kinase inhibition in the management of cardiovascular disease. Am J Cardiovasc Drugs. 2014 Jun; 14( 3): 155– 65[Crossref]
33. Petri MH , Tellier C , Michiels C , Ellertsen I , Dogné JM , Bäck M. Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells. Biochem Biophys Res Commun. 2013 Nov15; 441( 2): 393– 8[Crossref]
34. Ridker PM. The JUPITER trial: results, controversies, and implications for prevention. Circ Cardiovasc Qual Outcomes. 2009 May; 2( 3): 279– 85[Crossref]
35. Laplante M Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012 Apr 13; 149( 2): 274– 93[Crossref]
36. Martinet W , De Loof H , De Meyer GR. mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques. Atherosclerosis. 2014 Apr; 233( 2): 601– 7[Crossref]
37. Axel DI , Kunert W , Göggelmann C , et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation. 1997 Jul 15; 96( 2): 636– 45[Crossref]
38. Dzau VJ , Braun-Dullaeus RC , Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med. 2002 Nov; 8( 11): 1249– 56[Crossref]
39. Suri SS , Fenniri H , Singh B. Nanotechnology-based drug delivery systems. J Occup Med Toxicol. 2007 Dec 1; 2: 16[Crossref]
40. Godin B , Hu Y , La Francesca S , Ferrari M. Cardiovascular nanomedicine: challenges and opportunities. In: Homeister JW , Willis MS , editors. Molecular & translational vascular medicine. New YorkSpringer Science & Business Media2012. p. 249– 281[Crossref]
41. Allen TM Cullis PR. Drug delivery systems: entering the mainstream. Science. 2004 Mar 19; 303( 5665): 1818– 22[Crossref]
42. Tabas I Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science. 2013 Jan 11; 339( 6116): 166– 72[Crossref]
43. Moore KJ Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011 Apr 29; 145( 3): 341– 55[Crossref]
44. Sanchez-Gaytan BL , Fay F , Lobatto ME , et al. HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages. Bioconjug Chem. 2015 Mar 18; 26( 3): 443– 51[Crossref]
45. Tang J , Lobatto ME , Hassing L , et al. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Sci Adv. 2015 Apr; 1( 3): e1400223[Crossref]
46. Tarin C , Carril M , Martin-Ventura JL , et al. Targeted gold-coated iron oxide nanoparticles for CD163 detection in atherosclerosis by MRI. Sci Rep. 2015 Nov 30; 5: 17135[Crossref]
47. Zhang J , Nie S , Martinez-Zaguilan R , Sennoune SR , Wang S. Formulation, characteristics and antiatherogenic bioactivities of CD36-targeted epigallocatechin gallate (EGCG)-loaded nanoparticles. J Nutr Biochem. 2016 Apr; 30: 14– 23[Crossref]
48. Bagalkot V , Badgeley MA , Kampfrath T , Deiuliis JA , Rajagopalan S , Maiseyeu A. Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals. J Control Release. 2015 Nov 10; 217: 243– 55[Crossref]
49. Parodi A , Quattrocchi N , van de Ven AL , et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat Nanotechnol. 2013 Jan; 8( 1): 61– 8[Crossref]
50. Fang J , Nakamura H , Maeda H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. 2011 Mar 18; 63( 3): 136– 51[Crossref]
51. Lobatto ME , Fayad ZA , Silvera S , et al. Multimodal clinical imaging to longitudinally assess a nanomedical anti-inflammatory treatment in experimental atherosclerosis. Mol Pharm. 2010 Dec 6; 7( 6): 2020– 9[Crossref]
52. Fredman G , Kamaly N , Spolitu S , et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci Transl Med. 2015 Feb 18; 7( 275): 275ra20[Crossref]
53. Lee GY , Kim JH , Choi KY , et al. Hyaluronic acid nanoparticles for active targeting atherosclerosis. Biomaterials. 2015; 53: 341– 8[Crossref]
54. Molinaro R , Corbo C , Martinez JO , et al. Biomimetic proteolipid vesicles for targeting inflamed tissues. Nat Mater. 2016 Sep; 15( 9); 1037– 46[Crossref]

Add Comments

Please login to dialogue with author.