Hyaluronic Acid-Functionalized Mesoporous Silica Nanoparticles Loading Simvastatin for Targeted Therapy of Atherosclerosis

Abstract

Atherosclerosis (AS) constitutes a major threat to human health, yet most current therapeutics are hindered in achieving desirable clinical outcomes by low bioavailability or serious side effects. Herein, we constructed an enzyme-responsive and macrophage-targeting drug delivery system (SIM@HA-MSN) which can potentially modulate the microenvironment of the atherosclerotic plaques characterized by excessive inflammation and overexpression of hyaluronidase (HAase) for precise AS treatment. More specifically, mesoporous silica nanoparticles (MSNs) were loaded with a lipid-lowering drug simvastatin (SIM) and further gated with hyaluronic acid (HA) coating, which endowed the nanosystem with HAase responsiveness and targetability to inflammatory macrophages. Our results showed that a high loading efficiency (>20%) and excellent enzyme-responsive release of SIM were simultaneously achieved for the first time by silica-based nanocarriers through formulation optimizations. Moreover, in vitro experiments confirmed that SIM@HA-MSN possessed robust targeting, anti-inflammatory, and anti-foaming effects, along with low cytotoxicity and excellent hemocompatibility. In addition, preliminary animal experiments demonstrated the as-established nanosystem had a long plasma-retention time and good biocompatibility in vivo. Taken together, SIM@HA-MSN with HA playing triple roles including gatekeeping, lesion-targeting, and long-circulating holds great potential for the management of atherosclerosis.

Hepatic‐Targeted Nano‐enzyme with Resveratrol Loading for Precise Relief of Nonalcoholic Steatohepatitis

“…Latterly, the massive carboxyl groups in PAA were then applied for covalent conjugation of Gal by a conventional EDC/NHS reaction (H−CeO 2 −Gal). Owing to the cavity and stacked mesopores in H−CeO 2 −Gal, Res could be successfully encapsulated in H−CeO 2 −Gal (Res@H−CeO 2 −Gal) with the loading efficiency as ∼20±0.37 %, comparable with that of reported mesoporous silica nanoparticles loading simvastatin (21.32±1.31 %) [20] . In order to investigate the stability Res@H−CeO 2 −Gal under aqueous solutions (water and PBS 1X) and physiological buffer (cell culture medium) for various durations.…”

“…Owing to the cavity and stacked mesopores in HÀ CeO 2 À Gal, Res could be successfully encapsulated in HÀ CeO 2 À Gal (Res@HÀ CeO 2 À Gal) with the loading efficiency as ~20 � 0.37 %, comparable with that of reported mesoporous silica nanoparticles loading simvastatin (21.32 � 1.31 %). [20] In order to investigate the stability Res@HÀ CeO 2 À Gal under aqueous solutions (water and PBS 1X) and physiological buffer (cell culture medium) for various durations. Interestingly, after dynamic laser scanning analysis, the sizes of Res@HÀ CeO 2 À Gal (~120 nm) in different conditions presented little fluctuations even for 48 h co-culture, which were consistence with TEM and SEM images (Figure 2C).…”

Natural Biopolymers as Smart Coating Materials of Mesoporous Silica Nanoparticles for Drug Delivery

“…In tumoral areas, the biopolymer coating can be efficiently removed by the hydrolysis catalyzed in the first extent by hyaluronidase-2 (Hyal-2), present on cancer cells membranes, and then by hyaluronidase-1 (Hyal-1) after mediated endocytosis [ 223 ]. Due to the significantly high concentration of hyaluronidase in senescent aortic plaques, hyaluronic acid-coated MSNs have also been proposed for the treatment of atherosclerosis and the enzyme-responsive release of simvastatin [ 147 ] and rosuvastatin [ 148 ] in senescent foamy macrophages was recently reported. In both studies hyaluronic acid-coated MSNs were able to efficiently inhibit foamy macrophages proliferation and arrest plaque progression.…”

“…In both studies hyaluronic acid-coated MSNs were able to efficiently inhibit foamy macrophages proliferation and arrest plaque progression. Moreover, the active targeting of hyaluronic acid coating toward CD44 receptor of inflammatory macrophages was also demonstrated [ 147 ]. Similarly, the overproduction of hyaluronidase by bacteria in infection sites was exploited for the development of responsive DDS for the treatment of resistant bacterial infections [ 149 ].…”

Towards a simple in vitro surface chemistry pre-screening method for nanoparticles to be used for drug delivery to solid tumours

“…In a recent study, hyaluronic acid-functionalized MSNs with a particle diameter of about 180 nm were shown to exhibit a long blood circulation time, much longer than corresponding cationic amino-functionalized particles. 23 In another study, an increase on the blood circulation time and in the tumour targetability of pure hyaluronic acid-based nanoparticles via PEGylation was demonstrated in vivo , where these effects were dependent on the degree of PEGylation. 24 A fast accumulation of amino-functionalized MSNs in the liver upon intravenous injection is in agreement with previous reports.…”