Background Anti-dsDNA antibody-targeting peptide mimic ALW has been reported to be a potential strategy in attenuating lupus-like disease in MRL/lpr mice. However, the therapeutic effect of peptide has been hampered due to its unstable architecture and non-renal targeting. Here, we describe a strategy of D-amino acid modified peptide and further engineered it by nanoparticle delivery system to overcome the obstacles in lupus nephritis therapy.
Methods The binding efficiency of D-form mimic peptide (D-ALW) to anti-dsDNA antibodies was assessed in vitro by surface plasma resonance and enzyme-linked immunosorbent assay (ELISA). The inhibition capacity of D-ALW affinity to autoantigens, mesangial cells and glomeruli was determined by inhibitory ELISA, flow cells, and glomerular binding assay. The proteolysis resistance of D-ALW was measured by high-performance liquid chromatography. The peptide D-ALW engineered by PEG-PLGA nanoparticles was injected into BALB/c mice to determine its attenuation in blood and biodistributions in tissue. Polyethylene glycol coated poly lactic-co-glycolic acid was used for the preparation of D-ALW nanoparticles, which were then administered to MRL/lpr mice. The serum anti-dsDNA IgG, complement 3 (C3), proteinuria, renal histopathologic, and renal IgG deposition were analyzed accordingly.
Results D-ALW, but not L-form ALW, can efficiently resist the proteolysis and possess a higher ability of binding to anti-dsDNA antibody IgG isotypes and blocking the binding of the anti-dsDNA antibody to multiple antigens, mesangial cells or glomeruli in vitro. In vivo studies showed that, compared to D-ALW, D-ALW nanoparticles with specific diameter and charge largely enhanced half-life in sera and accumulation in kidneys. D-ALW nanoparticles even improved the renal IgG deposition and glomerular fibrosis in MRL/lpr mice, accompanied by prolonged life-span.
Conclusions This study demonstrated that D-form ALW peptide possesses high efficiency and stability. D-ALW nanoparticles with special kidney-targeting ability can ameliorate the nephritis in MRL/lpr mice, possibly through inhibiting pathogenic renal IgG deposition and fibrosis.
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