Clinical implication of encapsulated vitamin D nanoparticle in continuous ambulatory peritoneal dialysis

摘要

ABSTRACT PURPOSE Peritoneal dialysis (PD) is an established replacement therapy of end stage renal disease (ESRD) Unfortunately the limitation of long-term PD is peritoneal fibrosis resulting in technique failure Epithelial-mesenchymal transition (EMT) of mesothelial cells (MCs) is the process of initiate and reversible during peritoneal fibrosis and sequential extracellular matrix (ECM) accumulation also is the key change Recently we have found that vitamin D to be one novel potential therapy in PD related peritoneal damage But the most limitation in animal studies is that therapeutic dose of vitamin D can induce vessel calcification and hypercalcemia and this defect will limit its applicability Nanomedicine the application of nanotechnology to medicine enables the development of nanoparticle (NP) therapeutic carriers These drug carriers can passively target to specific site to enhance permeability and retention effect and there are plenty of NP platforms have been approved by the Food and Drug Administration (FDA) or tested in clinical trials Therefore they are ideally suited for the delivery of specific drug as target therapy For this reason we’ll provide the hypothesis that site target specific nanoparticle delivery system can reinforce vitamin D therapeutic effect on peritoneal fibrosis and alleviate its side effect EXPERIMENTAL DESIGN First we used 1 2-Distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino-(polyethylene glycol)2000] (DSPE-PEG) L-a-phosphatidylcholine (PC) and Calcitriol (1? 25(OH)2D3) to construct nanoparticles (D-NPs) which will package with 1? 25(OH)2D3 as a delivery system To confirm the function and safety of D-NPs we treated primary human MCs with TGF-b1 which could induce EMT and were reversed by D-NPs Final we conjugated antibodies (Glycoprotein M6A GPM6A) to D-NPs These particles (Ab-D-NPs) were implanted to mice by intraperitoneal (IP) injection and stagnated in the abdominal cavity and then alleviated the side effect that induced by high-dose vitamin D intraperitoneal injection RESULTS We created the vitamin D nanoparticle delivery system and then provided a possibility that low concentration of the vitamin D with high-efficiency therapy could alleviate the side effect of vitamin D through intraperitoneal injection in mice As yet we have constructed drug delivery vehicles with a sub-200 nm size which were loaded with vitamin D and released with a slow manner These vitamin D nanoparticles were taken up by human peritoneal mesothelial cell line (HMrSV5 cells) in the time course and were safety for HMrSV5 cells and MCs by the XTT assay Whereas fluorescence encapsulated NPs conjugated antibodies allow tissue specific fluorescent imaging and calcitriol encapsulated NPs conjugated antibodies could alleviate the side effect of intraperitoneal vitamin D injection in vivo CONCLUSIONS Nanotechnology have shown that nanoparticles have a great potential as drug carriers and our finding reveal that vitamin D loaded particles are feasible and safe to deliver vitamin D to the peritoneum and to alleviate hypercalcemia in a mouse model in vivo Thus the effect of nanoparticles vitamin D delivery systems in the prevention of intraperitoneal vitamin D injection may be a potential strategy in future

獎項日期	2017 8月 16
原文	English
監督員	Yuan-Yow Chiou (Supervisor)