Skip to main content

Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis.

Publication ,  Journal Article
Tang, T-T; Lv, L-L; Wang, B; Cao, J-Y; Feng, Y; Li, Z-L; Wu, M; Wang, F-M; Wen, Y; Zhou, L-T; Ni, H-F; Chen, P-S; Gu, N; Crowley, SD; Liu, B-C
Published in: Theranostics
2019

Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently. Methods: RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice. Results: Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin αLβ2 (LFA-1) and α4β1 (VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy. In vitro, MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-κB activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis). Conclusion: In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications.

Duke Scholars

Published In

Theranostics

DOI

EISSN

1838-7640

Publication Date

2019

Volume

9

Issue

16

Start / End Page

4740 / 4755

Location

Australia

Related Subject Headings

  • RAW 264.7 Cells
  • Mice, Inbred C57BL
  • Mice
  • Macrophages
  • Kidney Diseases
  • Kidney
  • Integrins
  • Fibrosis
  • Endothelial Cells
  • Drug Delivery Systems
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Tang, T.-T., Lv, L.-L., Wang, B., Cao, J.-Y., Feng, Y., Li, Z.-L., … Liu, B.-C. (2019). Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis. Theranostics, 9(16), 4740–4755. https://doi.org/10.7150/thno.33520
Tang, Tao-Tao, Lin-Li Lv, Bin Wang, Jing-Yuan Cao, Ye Feng, Zuo-Lin Li, Min Wu, et al. “Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis.Theranostics 9, no. 16 (2019): 4740–55. https://doi.org/10.7150/thno.33520.
Tang, Tao-Tao, et al. “Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis.Theranostics, vol. 9, no. 16, 2019, pp. 4740–55. Pubmed, doi:10.7150/thno.33520.
Tang T-T, Lv L-L, Wang B, Cao J-Y, Feng Y, Li Z-L, Wu M, Wang F-M, Wen Y, Zhou L-T, Ni H-F, Chen P-S, Gu N, Crowley SD, Liu B-C. Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis. Theranostics. 2019;9(16):4740–4755.

Published In

Theranostics

DOI

EISSN

1838-7640

Publication Date

2019

Volume

9

Issue

16

Start / End Page

4740 / 4755

Location

Australia

Related Subject Headings

  • RAW 264.7 Cells
  • Mice, Inbred C57BL
  • Mice
  • Macrophages
  • Kidney Diseases
  • Kidney
  • Integrins
  • Fibrosis
  • Endothelial Cells
  • Drug Delivery Systems