Role of dexamethasone/captopril co-loaded immunoliposome-nanoparticle hybrids on the regulation of macrophage polarization in mice with glomerulonephritis / 药学学报

In this study, dexamethasone (DXMS) and captopril (CAP) were co-loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles with a surface coating of a phospholipid bilayer, and then the core-shell nanoparticles were modified with polyethylene glycol and integrin α8 antibody to obtain immunoliposome-nanoparticle hybrids (DXMS/CAP@PLGA-ILs). The role of nanoparticles on the renal targeting, anti-inflammatory effects, and macrophage differentiation were investigated. The results showed that the particle size of the nanoparticles was 115.9 ± 2.89 nm, and the core-shell structure could be observed under an electron microscope. The drug loading capacity of DXMS and CAP was 5.72% ± 0.37% and 7.51% ± 0.07%, respectively. The results of in vitro experiments showed that DXMS/CAP@PLGA-ILs could reduce the secretion of specific cytokines and the mRNA expression of markers in M2-type macrophages, thus promoting the differentiation of M2-type macrophages in the direction of unpolarized macrophages. In vivo experiments in mice showed that DXMS/CAP@PLGA-ILs had a significant renal targeting effect, which could restore the renal index, serum creatinine, and urea nitrogen levels of mesangial proliferative glomerulonephritis in mice. Moreover, DXMS/CAP@PLGA-ILs could reduce both the secretion of inflammatory cytokines and the mRNA expression levels of M1 and M2 macrophage markers in the kidney. All the animal experiments were in accordance with the regulations of Animal Ethics Committee of Sichuan Agricultural University. In conclusion, renal-targeting DXMS/CAP@PLGA-ILs could effectively regulate the polarization of macrophages and had an "anti-inflammatory/anti-fibrosis" therapeutic effect, providing a new strategy and basis for the targeted therapy of glomerulonephritis.

Synthesis and Evaluation of Low Molecular Weight Chitosan-Acetylcysteine Conjugate for Renal Targeting Therapy / 中国药学杂志

OBJECTIVE: To synthesize low molecular weight chitosan-acetylcysteine (LMWC-NAC) conjugate and investigate its renal targeting profile and the rapeutic effects in model mice with acute kidney injury (AKI).METHODS: NAC was conjugated to LMWC by EDC/NHS reaction and the LMWC-NAC conjugate was identified by 1H-NMR. The cellular uptake of LMWC-NAC conjugate and megalin receptor involved in this process was investigated in vitro. In addition, the tissue distribution of ICG-labelled LMWC-NAC conjugate was investigated in nude mice. AKI were induced by LPS intraperitoneal injection (20 mg·kg-1).The parameters including Scr, BUN, inflammatory factors (TNF-α and IL-1β), and oxidative stress (MDA) were determined and renal histology was observed. RESULTS: LMWC-NAC conjugate was successfully synthesized by the amide interaction.The in vitrostudies demonstrated that the uptake of LMWC-NAC conjugate was mediated by the megalin receptor on HK-2 cells, and the tissue distribution experiment indicated that LMWC-NAC conjugate was mainly accumulated in the kidney.LMWC-NAC conjugate significantly suppressed Scr, BUN, inflammatory factors and oxidative stress (P<0.01) and improved kidney injury. CONCLUSION: LMWC-NAC conjugate showed good renal targeting profile and effect in recovering renal functions, which indicates the potential of LMWC-NAC conjugate as a safe and efficient drug delivery system for the treatment of AKI.