Role of Liposome Size, Surface Charge, and PEGylation on Rheumatoid Arthritis Targeting Therapy

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic, progressive autoimmune disease. The vascular permeability of inflamed joints in RA makes it a natural candidate for passive targeting, similar to the enhanced permeability and retention (EPR) effect in solid tumors. Thus, various therapeutic drugs have been encapsulated in nanocarriers to achieve longer in vivo circulation times and improve RA targeting. Although liposomes are the most widely used nanocarriers for RA treatment, the effects of physical and chemical characteristics of liposomes, such as particle sizes, surface charge, polyethylene glycol (PEG) chain length, and PEG concentration, on their passive RA targeting effect have not been fully elucidated. Here, we systematically investigated the effects of physical and chemical properties of liposomes on circulation time and conducted preliminary studies on their passive targeting mechanisms. A series of liposomes with different particle sizes (70, 100, 200, and 350 nm), surface charges (positive, negative, slight positive, and slight negative), PEG chain lengths (1, 2, and 5 kDa), and concentrations (5, 10, and 20% w/w of total lipid) were prepared by lipid film dispersion and extrusion. The pharmacokinetics of liposomes with different formulas were evaluated with a fluorescence microplate reader. A collagen-induced arthritis (CIA) mouse model was utilized to mimic RA pathological conditions and to evaluate the targeting and efficacy of liposomes with different properties using a near-infrared fluorescence imaging system. Uptake of fluorescent liposomes by various synovial cells was measured by flow cytometry. The results indicated that liposomes with 100 nm diameter, a slight negative charge, and 10% incorporation of 5 kDa PEG had better in vivo circulation time and inflamed joint targeting than did other liposomes. Dexamethasone (Dex) was encapsulated into optimized liposomes as an active ingredient for RA treatment. Pharmacodynamic studies demonstrated that Dex liposomes could significantly improve the antiarthritic efficacy of Dex in a CIA mouse model of RA. This study also found that the retention mechanism of RA was mainly increased because of the uptake of liposomes by fibroblasts and macrophages in inflamed joints. This study provides a persuasive explanation for passive RA targeting by liposomes and advances our ability to treat RA with nanomedicine.

Leveraging Electrostatic Interactions for Drug Delivery to the Joint

“…118 In a study that investigated the role of surface charge of liposomes in their biodistribution after intravenous injection into a preclinical model of RA, both strongly anionic and cationic liposomes were easily adsorbed by complement proteins, engulfed by RES, and accumulated in the liver tissue. 119 As previously mentioned, liposomes with high charge density were more easily recognized by complement proteins and consequently cleared by the RES in this study. 119 In contrast, liposomes with slight positive charges were in circulation for a longer period, likely due to their interactions with serum proteins; whereas liposomes with slight negative charges accumulated in the RA paws to a greater extent.…”

“…119 As previously mentioned, liposomes with high charge density were more easily recognized by complement proteins and consequently cleared by the RES in this study. 119 In contrast, liposomes with slight positive charges were in circulation for a longer period, likely due to their interactions with serum proteins; whereas liposomes with slight negative charges accumulated in the RA paws to a greater extent. 119 In yet another investigation utilizing a preclinical model of RA, a positively charged cystine-dense peptide demonstrated localization to cartilaginous tissues such as joint cartilage and intervertebral disks after systemic delivery (oral gavage).…”

Methoxy polyethylene glycol–cholesterol modified soy lecithin liposomes for poorlywater‐solubleanticancer drug delivery

“…In addition, as shown in Figure 4(b), PTX/SLP@mPEG varied in surface charge when different mPEG‐Chol ratios were used. The zeta value gradually decreased from −56.4 to −45.4 mV as the mPEG‐Chol ratio increased, which is in concordance with previous studies that PEG exerts an important effect on liposome properties 38,40 …”

A Nano-Platform for in situ Investigations of Ovarian Follicles

“…8B). The insert in Figure 8B Herein, the sizes of the synthesized liposomes were comparable to those in previous reports [20,30,31], while the injected volumes (5 µl in pigs and 200 µl in mares) and incubation time (24 h) were lesser or equal to those reported in previous studies [4,32]. Hence, the absence of morphological changes in both equine and porcine ovarian follicles' structures following intrafollicular injections was highly important, with the prospect of performing local deliveries (i.e., intrauterine or intrafollicular) of molecules at minimal effective doses to reach the targeted cells during ovarian follicle treatments [33].…”