RESUMEN
Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-ß1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-ß1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.
Asunto(s)
Abietanos , Doxorrubicina , Fibrosis , Glomerulonefritis , Riñón , Liposomas , Ratones Endogámicos BALB C , Animales , Ratones , Liposomas/química , Abietanos/farmacología , Abietanos/química , Fibrosis/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Masculino , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/inducido químicamente , Glomerulonefritis/patología , Factor de Crecimiento Transformador beta1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Modelos Animales de Enfermedad , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/inducido químicamenteRESUMEN
In this study, we evaluated and screened the effects of the molecular weight (MW) and molar ratio of poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (PEtOz-CHMC) on the pH sensitivity, stability, and antitumor efficacy of liposomes. The pH sensitivity of PEtOz-CHMC with different MWs and molar ratios was screened by drug release and cytotoxicity experiments at different pH levels. Results indicated that the liposomes coated with PEtOz1k-CHMC (7% molar ratio) and PEtOz2k-CHMC (5% molar ratio) exhibited the desirable pH responsiveness. When the MW of PEtOz was relatively low, 7% of the modified ratio obtained the strongest stability, but the turbidity of the liposomes did not obviously change when the molar ratio of PEtOz-CHMC was further increased. A375 cells were used as models to investigate the cellular uptake and intracellular localization of coumarin-6-loaded liposomes (C6-L), PEGylated liposomes (PEG-C6-L), and PEtOzylated liposomes. PEtOz1k-C6-L and PEtOz2k-C6-L presented remarkably stronger fluorescence intensity at low pH than at pH 7.4, whereas C6-L and PEG-C6-L did not achieve any obvious diversity at different pH conditions. Compared with C6-L and PEG-C6-L, PEtOz-C6-L showed efficient intracellular trafficking, including endosomal/lysosomal escape and cytoplasmic release. Pharmacokinetic experiments demonstrated that half-lives of PEG2k-C6-L, PEtOz2k-C6-L, and PEtOz1k-C6-L were 11.89-, 7.00-, and 5.29-fold times higher than those of C6-L, respectively. Among the liposomes, the DOX·HCl-loaded liposomes coated with PEtOz2k-CHMC demonstrated the strongest antitumor efficacy against B16 tumor xenograft models in vivo. These findings provide the feasibility of using PEtOz-CHMC with optimal pH sensitivity and long circulation to extend the application of liposomes to efficient anticancer drug delivery.