Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis

Abstract

Atherosclerosis remains one of the most common causes of death in the United States and throughout the world because of the lack of early detection. Macrophage apoptosis is a major contributor to the instability of atherosclerotic lesions. Development of an apoptosis targeted high-density lipoprotein (HDL)-mimicking nanoparticle (NP) to carry contrast agents for early detection of vulnerable plaques and the initiation of preventative therapies that exploit the vascular protective effects of HDL can be attractive for atherosclerosis. Here, we report the construction of a synthetic, biodegradable HDL-NP platform for detection of vulnerable plaques by targeting the collapse of mitochondrial membrane potential that occurs during apoptosis. This HDL mimic contains a core of biodegradable poly(lactic-co-glycolic acid), cholesteryl oleate, and a phospholipid bilayer coat that is decorated with triphenylphosphonium (TPP) cations for detection of mitochondrial membrane potential collapse. The lipid layer provides the surface for adsorption of apolipoprotein (apo) A-I mimetic 4F peptide, and the core contains diagnostically active quantum dots (QDs) for optical imaging. In vitro uptake, detection of apoptosis, and cholesterol binding studies indicated promising detection ability and therapeutic potential of TPP-HDL-apoA-I-QD NPs. In vitro studies indicated the potential of these NPs in reverse cholesterol transport. In vivo biodistribution and pharmacokinetics indicated favorable tissue distribution, controlled pharmacokinetic parameters, and significant triglyceride reduction for i.v.-injected TPP-HDL-apoA-I-QD NPs in rats. These HDL NPs demonstrate excellent biocompatibility, stability, nontoxic, and nonimmunogenic properties, which prove to be promising for future translation in early plaque diagnosis and might find applications to prevent vulnerable plaque progression.espite advances in both primary and secondary prevention, atherosclerosis (1) remains one of the leading causes of morbidity and mortality in the Western world because of the lack of early detection and targeted therapy. In general, atherosclerosis is a result of excess cholesterol circulating in the bloodstream. At the cellular level, atherosclerotic plaque formation is caused by cholesterol consumption and foam cell formation by macrophages situated within the intimal layers of the arteries (2). The term "vulnerable plaque" designates a plaque at high risk of disruption leading to thrombosis. Identification of vulnerable plaques before the thrombus formation is essential to enable the development of treatment modalities. One intriguing possibility for the development of image-guided therapies of coronary heart diseases (CHDs) is through high-density lipoproteins (HDLs), because of its function in the reverse cholesterol transport (RCT) pathway (3, 4). Along with apolipoprotein (apo) E, which promotes cholesterol efflux from foam cells, apoA-I-containing HDL facilitate the transport of cholesterol from lesions. Development of targeted HDL nanoparticles ...

Functionality of HDL: Antioxidation and Detoxifying Effects

“…There are, as yet, no detailed studies confirming HDL neutralisation and clearance of engineered nanoparticles. However, the concept of incorporating lipophilic drugs assembled with apoA-I and phospholipids into soluble, HDL-like nanoparticles for drug delivery is presently widely explored (Marrache and Dhar 2013;Shin et al 2013). They could serve a number of therapeutic purposes, for example, targeting tissues expressing high amounts of SR-BI, such as cancer cells (Marrache and Dhar 2013;Shin et al 2013).…”

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…For example, nanoparticles prepared by blending a poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol)-triphenylphosphonium block copolymer (PLGAb-PEG-TPP) with nontargeted poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG-OH) or poly(d,l-lactic-co-glycolic acid) (PLGA-COOH) were found to exhibit compete endosomal escape and were found to localize in the mitochondria of Hela cells. [154] This behavior was attributed to the cationic charge that facilitated endosomal escape through buffering effect and provided mitochondria localization. The use of the TPP functional nanoparticles for the delivery of Lonidamine and α-tocopheryl succinate resulted in a significant improvement of the therapeutic index as compared to administration of these drugs with the nontargeted TPP-modified nanoparticles or the free drug.…”

“…Fluorescence microscopy analysis of treated HeLa cells indicated significantly greater mitochondrial uptake of targeted nanoparticles as compared to nontargeted ones as shown in Figure 5. [154] …”

“…The use of the TPP functional nanoparticles for the delivery of Lonidamine and α-tocopheryl succinate resulted in a significant improvement of the therapeutic index as compared to administration of these drugs with the nontargeted TPP-modified nanoparticles or the free drug. [154] More recently, α-tocopheryl succinate was delivered in combination with obatoclax (a Bcl-2 inhibitor) using TPP-coated positively charged nanoparticles. The nanoparticles entered into acidic lysosomes via macropinocytosis, followed by lysosomal escape and accumulated into mitochondria over a period of 24 h. [155] In another example, conjugation of (4-carboxybutyl)triphenylphosphonium (4-carboxybutyl TPP) to PCL diol resulted in the formation of amphiphilic TPP-b-PCL-b-TPP polymers, which self-assembled into less than 50 nm cationic nanoparticles.…”

Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy

“…22 As a biodegradable polymer that has been exploited widely in developing nanoparticles approved by the US Food and Drug Administration, poly (lactic-co-glycolic acid) (PLGA) may likely be a favored alternative to the lipid core for HDL-based nanoplatform. [23][24][25] Thus, we anticipated that a core-shell rHDL (PLGA-rHDL) composed of a PLGA core functionalized with a phospholipid bilayer would be of enormous potential benefits in treating atherosclerosis: (i) PLGA core is capable of not only encapsulating high amounts of cardiovascular drugs without additional exogenous cholesterol but also maintaining a stable spherical structure of PLGA-rHDL; (ii) the slow-release property of PLGA polymer would be extremely favorable for the chronic disease treatment; and (iii) the phospholipid bilayer of core-shell rHDL would reinforce the fusion between nanoparticle and cell membranes as well as provide a larger space for receiving more cholesterol, thereby promoting cholesterol removal from iMΦ.…”