{"title":"Combining Metformin and Drug-Loaded Kidney-Targeting Micelles for Polycystic Kidney Disease.","authors":"Kairui Jiang, Yi Huang, Eun Ji Chung","doi":"10.1007/s12195-022-00753-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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 <i>in vivo</i>, for delivering drugs to the site of the disease.</p><p><strong>Methods: </strong>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 <i>in vitro</i> therapeutic efficacy when combined with free MET. Specifically, after determining the 40% inhibitory concentration for each drug (IC<sub>40</sub>), 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 <i>Pkd1flox/-:TSLargeT</i> mice in 2D proliferation and 3D cyst model.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s12195-022-00753-9.</p>","PeriodicalId":9687,"journal":{"name":"Cellular and molecular bioengineering","volume":"16 1","pages":"55-67"},"PeriodicalIF":2.3000,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9842834/pdf/","citationCount":"3","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular and molecular bioengineering","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1007/s12195-022-00753-9","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/2/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"BIOPHYSICS","Score":null,"Total":0}
引用次数: 3
Abstract
Introduction: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Supplementary information: The online version contains supplementary material available at 10.1007/s12195-022-00753-9.
期刊介绍：
The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas:
Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example.
Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions.
Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress.
Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.
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