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Design and in vivo characterization of kidney-targeting multimodal micelles for renal drug delivery

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Abstract

One in three Americans is at risk for developing chronic kidney disease (CKD) and end-stage renal disease (ESRD), leading to the need for dialysis or a kidney transplant. Small-molecule drugs have been proposed as therapies to manage kidney diseases, but high dosages are often required to achieve therapeutic efficacy, generating off-target side effects, some of which are lethal. To address these limitations, we developed a novel, kidney-targeting multimodal micelle (KM) system for drug delivery applications. Specifically, we incorporated the kidney-targeting peptide (Lysine-Lysine-Glutamic acid-Glutamic acid-Glutamic acid)3-Lysine) ((KKEEE)3K) into micelles. This peptide binds to megalin, a multi-ligand cell surface receptor present on renal tubule cells. When incubated with human kidney proximal tubule cells, KMs were found to be biocompatible in vitro. In vivo, KMs showed higher accumulation in the kidneys as compared to a non-targeted (NT) control upon intravenous injection in wild-type C57BL/6J mice. Histological evaluation showed no signs of tissue damage, while blood urea nitrogen (BUN) and creatinine levels were within normal ranges, validating the preservation of kidney health upon micelle administration. To our knowledge, this is the first utilization of (KKEEE)3K in a nanoparticle formulation, and our study offers strong evidence that this novel nanoparticle platform can be used as a candidate drug delivery carrier to direct therapeutics to diseased tissue in CKD.

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Acknowledgements

The authors would like to acknowledge the financial support from the University of Southern California (USC) Provost Fellowship awarded to J. W., the National Heart, Lung, and Blood Institute (NHLBI), R00HL124279 awarded to E. J. C., and the U.S. Dept. of Defense grant W81XWH-15-1-0420 to K. R. H. The authors also would like to thank the Center for Electron Microscopy and Microanalysis (CEMMA) at USC for assistance in TEM imaging.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA

    Jonathan Wang, Christopher Poon, Deborah Chin, Sarah Milkowski, Vivian Lu & Eun Ji Chung

  2. Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Kenneth R. Hallows & Eun Ji Chung

  3. USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Kenneth R. Hallows

  4. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA

    Eun Ji Chung

  5. Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Eun Ji Chung

  6. Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, 90089, USA

    Eun Ji Chung

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  1. Jonathan Wang
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Correspondence to Eun Ji Chung.

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Wang, J., Poon, C., Chin, D. et al. Design and in vivo characterization of kidney-targeting multimodal micelles for renal drug delivery. Nano Res. 11, 5584–5595 (2018). https://doi.org/10.1007/s12274-018-2100-2

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