Abstract
The targeted delivery of therapeutics to the kidneys has a profound potential for the management of renal fibrosis. Thus, we developed a drug delivery system that targets mesangial cells by conjugating anti-alpha8 integrin to the surface of liposomes. We coloaded emodin (EMO) and diammonium glycyrrhizinate (DAG) to the immunoliposomes for combined therapy. The coloaded immunoliposomes were small size (92.4±0.4 nm), narrowly distributed, and with nearly neutral zeta potential and good stability. The encapsulation rate of EMO and DAG in immunoliposomes was 45.5±2.0% and 44.3±1.1%, respectively. Using a BCA assay, the actual number of antibody molecules attached to a single liposome was determined as being approximately 41. An in vitro release study showed that EMO and DAG could be ratiometrically released from the immunoliposomes, which means that an optimized synergistic ratio of the two drugs could be achieved. Studies on cellular uptake studies demonstrated an approximately 3-fold increase for immunoliposomes in HBZY-1 cells compared to nonconjugated liposomes. In vitro cell growth inhibition and Western Blot assay revealed that the coloaded immunoliposomes exhibited a stronger and synergistic in vitro antifibrosis effect against NIH3T3 and HBZY-1 cells in vitro. Taken together, it indicated that anti-alpha8 integrin-modified immunoliposomes for codelivery of EMO and DAG have great potential for targeting the kidneys for the treatment of renal fibrosis.
Highlights
Renal fibrosis, which is the final common outcome of progressive kidney diseases, represents an attractive target for therapy in numerous chronic kidney diseases
Phenotypic transformation of glomerular mesangial cells is activated after injury, followed by the production of several signaling molecules are produced such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), which contribute to excessive proliferation of mesangial cells and increases in matrix synthesis [7]
In this investigation, thiolated anti-alpha8 integrin was successfully conjugated to the DSPE-PEG2000-MAL present on the surface of liposomes with a conjugation efficiency of 60:8 ± 2:0%, corresponding to approximately 41 anti-alpha8 integrin molecules per liposome
Summary
Renal fibrosis, which is the final common outcome of progressive kidney diseases, represents an attractive target for therapy in numerous chronic kidney diseases. Renal fibrosis is characterized by the activation and proliferation of renal interstitial fibroblasts, excessive accumulation of extracellular matrix (ECM) in the renal stroma, and destruction of renal tissue [3, 4]. Numerous investigations have demonstrated that the development of renal fibrosis is closely associated with mesangial cells [5, 6]. Glomerular mesangial cells are involved in glomerular inflammatory response, repair of basement membrane, and the initiation of ECM overproduction, which are signs of progress of renal fibrosis. Mesangial cells (MCs) proliferation and extracellular matrix accumulation are involved in the occurrence of glomerular inflammation and aggravate its progression to chronic diseases. Specific inhibition of mesangial cell activation and proliferation is of great significance in the treatment of renal fibrosis
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