Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes

Abstract

Previously, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes were reported to specifically target mesangial cells (MCs) in glomeruli. To further gain a better understanding of the characteristics and potential application for glomerular diseases of TRX-20-modified liposomes, we synthesized TRX-20 and prepared TRX-20-modified liposomes (TRX-LPs) with different molar ratios – 6% (6%-TRX-LP), 11% (11%-TRX-LP), and 14% (14%-TRX-LP) – of TRX-20 to total lipid in the present study. All TRX-LPs exhibited concentration-dependent toxicity against the MCs at a lipid concentration ranging from 0.01 to 1.0 mg/mL with IC 50 values of 3.45, 1.13, and 0.55 mg/mL, respectively. Comparison of the cell viability of TRX-LPs indicated that high levels of TRX-20 caused severe cell mortality, with 11%-TRX-LP showing the higher cytoplasmic accumulation in the MCs. Triptolide (TP) as a model drug was first loaded into 11%-TRX-LP and the liposomes were further modified with PEG 5000 (PEG-TRX-TP-LP) in an attempt to prolong their circulation in blood and enhance TP-mediated immune suppression. Due to specific binding to MCs, PEG-TRX-TP-LP undoubtedly showed better anti-inflammatory action in vitro, evidenced by the inhibition of release of nitric oxide (NO) and tumor necrosis factor-α from lipopolysaccharide-stimulated MCs, compared with free TP at the same dose. In vivo, the PEG-TRX-TP-LP effectively attenuated the symptoms of membranous nephropathic (MN) rats and improved biochemical markers including proteinuria, serum cholesterol, and albumin. Therefore, it can be concluded that the TRX-modified liposome is an effective platform to target the delivery of TP to glomeruli for the treatment of MN.

The Effect of Triptolide in Rheumatoid Arthritis: From Basic Research towards Clinical Translation

“…Nevertheless, the current targeted delivery systems of TP are mostly renal-targeted and tumor-targeted. For example, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes [ 122 ], PF-A299–585 [ 123 ], 2-Glucosamine [ 124 ], and lysozyme [ 125 ] were reported to specifically deliver TP to the kidney. Carbonic anhydrase IX (CA IX) [ 126 ], AS1411 [ 127 ], and nanoformulations coated with folate [ 128 ] were used to specifically deliver TP to lung cancer, pancreatic cancer, and hepatocellular carcinoma cells, respectively.…”

Targeting strategies for drug delivery to the kidney: From renal glomeruli to tubules

“…41 Our recent study has indeed demonstrated the effectiveness of targeted drug delivery to the glomerulus to restrain local inflammatory and pathological reactions to produce better therapeutic results. 13 Glomerular pathological processes are intricate and involve all glomerular cell types, including the mesangial cells (MCs), podocytes, endothelial cells, parietal epithelial cells, and infiltrating inflammatory cells. [43][44][45][46][47] MCs constitute 30% to 40% of the total glomerular cell population, and they execute many critical functions, an example of which is the maintenance of glomerular hemodynamics and the structural integrity of the microvascular bed.…”

“…However, the concentration of TRX-20 required for the active targeting also contributed to a significant level of toxicity. 13 Future research will aim to develop liposomes systems with an acceptable safety profile at the concentrations required for targeting applications.…”

“…While the data have been promising, they also highlighted many uncertainties, the chief of which is that most of the systems in their current forms could not be directly applied to treat human kidney diseases. 13,36,65 Future research will need to address the important knowledge and technology gaps relating to the cytotoxicity of the NPs on healthy glomerular cells, the impact of long-term chronic exposure of the kidney and other organs to the NPs, the molecular mechanisms of actions and related toxicodynamics underlying the adverse effects of the NPs.…”

Surface-enhanced Raman scattering investigation of targeted delivery and controlled release of gemcitabine

“…Additionally, through multifunctionalization, nanocarriers can contain not only anticancer payloads but also ligands that preferentially bind to surface receptor proteins of cancer cells and mediate endocytosis of the nanocarrier. These key advantages have recently attracted considerable interest 7764 santiago et al and led to the development of various nanocarrier-based systems, including micellar, [11][12][13] liposome, 14,15 polymer, [16][17][18] noble metal, 4,5,19 and other 2,20 nanocarriers. Here, we present an investigation into a nanocarrier-based targeted drug delivery system for the anticancer drug gemcitabine (GEM) administration.…”