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Abstract: SA-PO647

Dexamethasone-Loaded Macrophage-Derived Microvesicles: A Novel Approach for Enhanced Anti-Inflammatory Efficacy for Renal Disease

Session Information

  • Pharmacology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Tang, Tao-Tao, Zhong Da Hospital, Southeast University,, Nanjing, JIANGSU , China
  • Lv, Linli, Zhong Da Hospital, Southeast University,, Nanjing, JIANGSU , China
  • Jingyuan, Cao, Zhong Da Hospital, Southeast University,, Nanjing, JIANGSU , China
  • Feng, Ye, Zhong Da Hospital, Southeast University,, Nanjing, JIANGSU , China
  • Li, Zuolin, Zhong Da Hospital, Southeast University,, Nanjing, JIANGSU , China
  • Liu, Bi-Cheng, Zhong Da Hospital, Southeast University,, Nanjing, JIANGSU , China
Background

Although glucocorticoids are the mainstays in the treatment of renal disease, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are nano-sized extracellular vesicles with a membrane lipid bilayer that are shed by cells and efficiently entering other cells. Here, we investigated whether macrophage-derived MVs can function as efficient carriers of dexamethasone (DEX), and the anti-inflammatory efficacy of the novel DEX delivery system was assessed in both in vitro and in vivo models of renal disease.

Methods

MVs were prepared from the supernatants of RAW 264.7 cells treated with DEX by centrifugation. In vivo, the therapeutic potential of DEX-packaging MVs (MV-DEX) was assessed in LPS and Adriamycin (ADR) induced nephropathy model. In vitro, the therapeutic efficacy was assessed in glomerular endothelial cells (GECs).

Results

The mean diameter of MV-DEX was 140.7±4.8 nm and the average drug content was 6.2μg/1×1010 MVs. Compared with GECs without LPS stimulation, more MVs were accumulated in the inflamed GECs. Consistently, the higher renal radiance signal of DID-labelled MVs was observed in LPS and ADR model. The extent of average radiance was positively correlated with renal TNF-α or IL-6 protein levels. In vitro, we found that the mRNA levels of proinflammatory cytokines, protein expression of NF-κB p65 and p-p65, and levels of TNF-α and IL-6 in the supernatants were significantly inhibited by MV-DEX treatment. Inflammation was blunted with free DEX, however, to a much lesser extent than with MV-DEX therapy. In LPS model, treatment with MV-DEX increased the animal survival rate. In ADR model, albuminuria, glomerulosclerosis and foot process effacement were remarkedly ameliorated with MV-DEX threatment. In both models, the mRNA levels of proinflammatory cytokines, protein expression of p65 and p-p65, and infiltration of inflammatory cells were inhibited after MV-DEX treatment. Interestingly, MV-DEX treatment showed better therapeutic efficacy than free DEX both in vivo and in vitro.

Conclusion

Our studies firstly demonstrated that macrophage-derived MVs could efficiently deliver DEX into inflamed kidney and exhibit a superior ability to suppress renal inflammation compared to routine DEX therapy.