Targeting delivery of simvastatin using ICAM-1 antibody-conjugated nanostructured lipid carriers for acute lung injury therapy

Abstract

Acute lung injury (ALI) is a critical illness without effective therapeutic modalities currently. Recent studies indicated potential efficacy of statins for ALI, while high-dose statins was suggested to be significant for attenuating inflammation in vivo. Therefore, a lung-targeted drug delivery system (DDS) delivering simvastatin (SV) for ALI therapy was developed, attempting to improve the disease with a decreased dose and minimize potential adverse effects. SV-loaded nanostructured lipid carriers (SV/NLCs) with different size were prepared primarily. With particle size increasing from 143.7 nm to 337.8 nm, SV/NLCs showed increasing drug-encapsulated efficiency from 66.70% to 91.04%. Although larger SV/NLCs exhibited slower in vitro cellular uptake by human vascular endothelial cell line EAhy926 at initial stage, while in vivo distribution demonstrated higher pulmonary accumulation of the larger ones. Thus, the largest size SV/NLCs (337.8 nm) were conjugated with intercellular adhesion molecule 1 (ICAM-1) antibody (anti-ICAM/SV/NLCs) for lung-targeted study. The anti-ICAM/SV/NLCs exhibited ideal lung-targeted characteristic in lipopolysaccharide-induced ALI mice. In vivo i.v. administration of anti-ICAM/SV/NLCs attenuated TNF-a, IL-6 and inflammatory cells infiltration more effectively than free SV or non-targeted SV/NLCs after 48-h administration. Significant histological improvements by anti-ICAM/SV/NLCs were further revealed by H&E stain. Therefore, ICAM-1 antibody-conjugated NLCs may represent a potential lung-targeted DDS contributing to ALI therapy by statins.

Simvastatin preparations promote PDGF‐BB secretion to repair LPS‐induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway

“…The simvastatin nanoparticles (SV‐NPs), a new formulation of simvastatin using nanostructured lipid carriers, were prepared by solvent diffusion method in an aqueous system as described previously . Briefly, 97.5 mg monostearin (Shanghai Chemical Reagent Co., Ltd. Shanghai, China), 30 mg Medium‐chain triglycerides (MCT, Gattefosse, Saint‐Priest, France), 15 mg PEG2000‐stearic acid (Tokyo Kasei Kogyo Co., Ltd., Tokyo, Japan) and 7.5 mg simvastatin were completely dissolved into 0.75 mL ethanol in water bath at 60°C.…”

Anti-ICAM-1 antibody-modified nanostructured lipid carriers: a pulmonary vascular endothelium-targeted device for acute lung injury therapy

“…Near-infrared DiR fluorescent probe was from Life Technologies (Carlsbad, CA). Octadecylamine-fluorescein isothiocyanate (ODA-FITC) and amino-terminated polyethylene glycol monostearate (NH 2 -PEG 2000 -SA) were synthesized previously [20]. All other solvents were of analytical or chromatographic grade.…”

“…The humidified cell incubator was set at 37 °C with 5% CO 2 . To establish in vitro cell model of inflammatory pathological endothelium with over-expressed ICAM-1, the EAs were incubated with 400 ng/mL of LPS for 24 h as our previous study reported [20].…”

Nanomedicine-Based Therapeutics to Combat Acute Lung Injury

“…18 The above characteristics offer targets for site-specific delivery and the microenvironment for responsive drug release. To this end, the nanomedicine for ALI has broad alternative therapeutic strategies, including the delivery of anti-inflammatory agents to the disease site, [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] the direct scavenging of inflammatory factors, [35][36][37][38][39][40][41][42][43][44][45][46][47] the regulating of inflammatory cell activities, [48][49][50][51][52][53][54][55][56][57][58][59] or the modulating of inflammatory signaling pathways. [60][61][62][63][64][65]…”

“…2 To target the endothelium and epithelium, intercellular adhesion molecule-1 (ICAM-1), 87 plateletendothelial cell adhesion molecule (PECAM-1) 88 and surfactant protein (SP) 89 can be bio-conjugated by corresponding antibodies for active targeting nanotherapy. [20][21][22]24,28,35,56,60,63 Nanomedicine can restore barrier integrity and prevent cell death by influencing inflammatory pathways 20,21,44,60,63,65,[70][71][72] and alleviating oxidative stress. 28,35,36,42,54,56 The influence of nanomedicine on cellular architecture can be assessed by a pragmatic optimized air-liquid interface system, which showed comparable results as those in an in vivo study.…”