High-Density Lipoproteins: Nature’s Multifunctional Nanoparticles

Abstract

High-density lipoproteins (HDL) are endogenous nanoparticles involved in the transport and metabolism of cholesterol, phospholipids, and triglycerides. HDL is well known as the ―good‖ cholesterol because it not only removes excess cholesterol from atherosclerotic plaques but also has anti-inflammatory and anti-oxidative properties, which protect the cardiovascular system. Circulating HDL also transports endogenous proteins, vitamins, hormones, and microRNA to various organs. Compared with other synthetic nanocarriers, such as liposomes, micelles, inorganic and polymeric nanoparticles, HDL has unique features that allow them to deliver cargo to specific targets more efficiently. These attributes include their ultra-small size (8-12 nm in diameter), high tolerability in humans (up to 8 g of protein per infusion), long circulating half-life (12-24 hours), and intrinsic targeting properties to different recipient cells. Various recombinant ApoA proteins and ApoA mimetic peptides have been recently developed for the preparation of reconstituted HDL that exhibits properties similar to endogenous HDL and has a potential for industrial scale-up. In this review, we will summarize: a) clinical pharmacokinetics and safety of reconstituted HDL products, b) comparison of HDL with inorganic and other organic nanoparticles, c) the rationale for using HDL as drug delivery vehicles for important therapeutic indications, d) the current state-of-the-art in HDL production, and e) HDL-based drug delivery strategies for small molecules, peptides/proteins, nucleic acids, and imaging agents targeted to various organs.

Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma

“…21 In addition, hydrophobic molecules can be preferentially incorporated in sHDL, while hydrophilic molecules require covalent attachment to sHDL or chemical modification in order to be loaded in sHDL. 15,36 In the current study, we optimized the sHDL lipid composition to maximize encapsulation efficiency.…”

“…Most biomimetic HDL nanoparticles are assembled using the full-length ApoA 1 protein, 15 which is technically difficult and costly to produce, making ApoA 1 -based HDL delivery not commercially feasible. In addition, given the amphiphilic nature of the protein, ApoA 1 tends to aggregate and bind to endotoxin and host cell proteins, resulting in low production yields and difficulty in scaling up.…”

“…In addition, the same methodology has been used to prepare ETC642-blank sHDL, which has been examined in single-and multiple-dose clinical trials for treatment of cardiovascular diseases. 15,24,25 Therefore, prior clinical experience could facilitate the translation of 22A peptide-based sHDL drug delivery nanodisks.…”

“…This size and shape closely resembled the characteristics of endogenous HDL nanoparticles. 15 To examine drug-release kinetics, WGA-TA-sHDL nanoparticles were placed in a dialysis bag and incubated in sink conditions in 200 mL of PBS containing 0.1% Tween 80 for 24 hours. To compare nanoparticle release with free drug, the same amount of WGA-TA-sHDL was dissolved in 50% dimethyl sulfoxide and placed in a dialysis bag.…”

“…24,25 In clinical studies, ETC642 was found to have long plasma residence (~8 hours) and to be safe when administered at 30 mg/kg peptide (90 mg/kg total components) by weekly intravenous (IV) administration. 15,26 Prior clinical safety data with ETC642 can facilitate clinical translation of sHDLmediated drug delivery for treatment of adrenal diseases.…”