Glycol chitosan-based tacrolimus-loaded nanomicelle therapy ameliorates lupus nephritis

Abstract

Background Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Faslpr mutation were also treated with HGC vehicle and used as healthy controls. Results Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-β1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone. Conclusion Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice.

The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis

“…Additionally, it improved renal function, decreased tissue injury and fibrosis, and reduced renal oxidative damage and inflammation, which were associated with inhibiting the NF-ƙB signaling pathway ( Hassan et al, 2021 ). In a classical model of lupus nephritis, the administration of MRL/lpr, which are hydrophobically modified glycol chitosan nanomicelles loaded with tacrolimus, decreased glomerulosclerosis and suppressed intrarenal inflammation via the NF-ƙB signaling pathway ( Kim et al, 2021 ). Suo et al (2021) reported that bortezomib improved renal allograft tubulointerstitial fibrosis by inhibiting the NF-ƙB-TNF-α-Akt-mTOR-P70S6K-Smurf2 pathway via IƙBα protein stabilization.…”

The applications of functional materials-based nano-formulations in the prevention, diagnosis and treatment of chronic inflammation-related diseases

“…Treatment with a combination of short and low doses of them can attenuate the systemic symptoms in collagen-induced arthritis mice, driven by the downregulation of T helper cells (Th) 17 bc2-specific antigenic responses and enhancement of Th2-type T cell responses (Mangal et al, 2022). Meanwhile, chitosan NPs have also yielded noteworthy 2020), Kim et al (2021) Nrf2, nuclear factor E2-related factor 2; Keap 1, kelch-like ECH, associated protein 1; ARE, antioxidant response element; RXRα, retinoic X receptor α; Cul3, cullin-based E3 ligase; RBX1, ring box protein 1; sMaf, small Maf proteins; AREs, antioxidant response elements; EpRE, electrophile response element; β-TrCP, beta-transducin repeats-containing protein; NPs, nanoparticles; p38 MAPK, mitogen-activated protein kinase p38 antibody; TRAF2, tumor necrosis factor receptor-associated factor 2; MKK3, p38 MAPK, kinase 3; ATF-2, activating transcription factor 2; HSP27, heat shock protein 27; MAPKAPK, MAPK-activated protein kinase; MNK, MAPK, signaling integrated kinase; JAK, janus kinase; STAT3, signal transducers and activators of transcription 3; G-CSF, granulocyte colony-stimulating factor; EPO, erythropoietin; TPO, thrombopoietin; EGFR, epidermal growth factor receptor; NF-κB, nuclear factor κB; Rel, REL, protooncogene; IκBα, inhibitor kappa B alpha; TNFR, tumor necrosis factor receptor; IL, interleukin; TNF-α, tumor necrosis factor-alpha; TLR, toll-like receptor; TIR, toll-interleukin 1 receptor; Myd88, myeloid differentiation primary response protein 88; TIRAP, TIR, domain-containing adapter protein; IRAK, IL-1, receptor-associated kinase; TRAF6, TNF, receptor associated factor 6; PI3K, phosphatidylinositol-3-kinase; AKT, serine/threonine kinase; PIP2, phosphatidylinositol-4, 5-bisphosphate; PDK1, 3-phosphoinositide-dependent protein kinase 1; TSC, tuberous sclerosis complex; PTEN, protein tyrosine phosphatase; TGF-β, transforming growth factor beta; SMAD, drosophila mothers against decapentaplegic protein; TGF-βR, TGF-β, receptor; BMP, bone morphogenetic protein; GDF, growth differentiation factors.…”

Renal Cell-Targeted Drug Delivery Strategy for Acute Kidney Injury and Chronic Kidney Disease: A Mini-Review

“…CS/HA pDNA effectively alleviated fibrosis and restored renal function in unilateral ureteral obstruction (UUO) mouse models of CKD. Kim et al developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (HGC-TAC) for LN therapy. HGC-TAC nanomicelle has a diameter of 370 ± 22 nm and a positive charge of 24 ± 4 mV.…”

“…CS/HA pDNA effectively alleviated fibrosis and restored renal function in unilateral ureteral obstruction (UUO) mouse models of CKD. Kim et al152 developed hydrophobically…”