Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis
Authors: Bin Wang
Ning Gu
Le-Ting Zhou
Jing-Yuan Cao
Feng-Mei Wang
Steven D Crowley
Bi-Cheng Liu
Zuo-Lin Li
Hai-Feng Ni
Yi Wen
Tao-Tao Tang
Min Wu
Lin-Li Lv
Ping-Sheng Chen
Ye Feng
Journal: Theranostics (2019)
Discipline: CLINICAL MEDICINE
Keywords: dexamethasone; drug delivery; macrophage-derived microvesicles; renal fibrosis; renal inflammation.
Affiliations: Institute of Nephrology, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing, China., State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, China., Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, United States.

Abstract:  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. 

Retracted: No

PubPeer comments:
 This chapter contains several [**tortured phrases**] that make some passages hard to parse. These typically result from an attempt to avoid plagiarism detection using a paraphrasing software. So far, the following have been spotted: * **discourse acknowledgement OR discourse acknowledgment** instead of the established _u2018voice recognitionu2019_ * **help vector machine** instead of the established _u2018support vector machine (SVM)u2019_ * **intense lymphocytic leukemia** instead of the established _u2018acute lymphocytic leukemiau2019_ * **k-implies bunching** instead of the established _u2018k-means clusteringu2019_ * **man-made consciousness** instead of the established _u2018artificial intelligenceu2019_ * **profound neural system** instead of the established _u2018deep neural networku2019_ * **proof of idea** instead of the established _u2018proof of conceptu2019_ * **profound learning** instead of the established _u2018deep learningu2019_ Can the authors explain why they departed from the established phrases? How come these incorrect wordings survived proofreading by the coauthors, editors, referees, copy editors, and typesetters? Found by the [_Problematic Paper Screener_] . ,