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Combining Metformin and Drug-Loaded Kidney-Targeting Micelles for Polycystic Kidney Disease.

Authors
  • Jiang, Kairui1
  • Huang, Yi1
  • Chung, Eun Ji1, 2, 3, 4, 5, 6, 7
  • 1 Department of Biomedical Engineering, University of Southern California, 1002 Childs Way, MCB 357, Los Angeles, CA 90089 USA.
  • 2 Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA USA.
  • 3 Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA USA.
  • 4 Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, CA USA.
  • 5 Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA USA.
  • 6 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA.
  • 7 Bridge Institute, University of Southern California, Los Angeles, CA USA.
Type
Published Article
Journal
Cellular and molecular bioengineering
Publication Date
Feb 01, 2023
Volume
16
Issue
1
Pages
55–67
Identifiers
DOI: 10.1007/s12195-022-00753-9
PMID: 36660586
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease that leads to eventual renal failure. Metformin (MET), an AMP-activated protein kinase (AMPK) activator already approved for type 2 diabetes, is currently investigated for ADPKD treatment. However, despite high tolerability, MET showed varying therapeutic efficacy in preclinical ADPKD studies. Thus, newer strategies have combined MET with other ADPKD small molecule drug candidates, thereby targeting multiple ADPKD-associated signaling pathways to enhance therapeutic outcomes through potential drug synergy. Unfortunately, the off-target side effects caused by these additional drug candidates pose a major hurdle. To address this, our group has previously developed kidney-targeting peptide amphiphile micelles (KMs), which displayed significant kidney accumulation in vivo, for delivering drugs to the site of the disease. To mitigate the adverse effects of ADPKD drugs and evaluate their therapeutic potential in combination with MET, herein, we loaded KMs with ADPKD drug candidates including salsalate, octreotide, bardoxolone methyl, rapamycin, tolvaptan, and pioglitazone, and tested their in vitro therapeutic efficacy when combined with free MET. Specifically, after determining the 40% inhibitory concentration for each drug (IC40), the size, morphology, and surface charge of drug-loaded KMs were characterized. Next, drug-loaded KMs were applied in combination with MET to treat renal proximal tubule cells derived from Pkd1flox/-:TSLargeT mice in 2D proliferation and 3D cyst model. MET combined with all drug-loaded KMs demonstrated significantly enhanced efficacy as compared to free drugs in inhibiting cell proliferation and cyst growth. Notably, synergistic effects were found for MET and KMs loaded with either salsalate or rapamycin as determined by Bliss synergy scores. Together, we show drug synergy using drug-loaded nanoparticles and free MET for the first time and present a novel nanomedicine-based combinatorial therapeutic approach for ADPKD with enhanced efficacy. The online version contains supplementary material available at 10.1007/s12195-022-00753-9. © The Author(s) under exclusive licence to Biomedical Engineering Society 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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