{"title":"结合二甲双胍和药物载体肾靶向胶束治疗多囊性肾病","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":"{\"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. 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引用次数: 3
摘要
简介常染色体显性多囊肾（ADPKD）是最常见的遗传性肾病，会导致最终的肾功能衰竭。二甲双胍（MET）是一种 AMP 激活蛋白激酶（AMPK）激活剂，已被批准用于治疗 2 型糖尿病，目前正被研究用于 ADPKD 的治疗。然而，尽管 MET 具有很高的耐受性，但在 ADPKD 临床前研究中却显示出不同的疗效。因此，新的策略是将 MET 与其他 ADPKD 小分子候选药物相结合，从而靶向多种 ADPKD 相关信号通路，通过潜在的药物协同作用提高治疗效果。遗憾的是，这些额外的候选药物造成的脱靶副作用构成了一大障碍。为了解决这个问题，我们小组之前开发了肾脏靶向肽双亲胶束（KMs），这种胶束在体内有显著的肾脏蓄积，可以将药物输送到发病部位：为了减轻 ADPKD 药物的不良反应并评估其与 MET 结合的治疗潜力，我们在 KMs 中添加了 ADPKD 候选药物，包括沙利度、奥曲肽、甲基巴多隆、雷帕霉素、托伐普坦和吡格列酮，并测试了它们与游离 MET 结合后的体外疗效。具体来说，在确定了每种药物的 40% 抑制浓度（IC40）后，对药物负载 KM 的大小、形态和表面电荷进行了表征。接着，在二维增殖和三维囊肿模型中，将药物负载的 KMs 与 MET 结合使用，以治疗来自 Pkd1flox/-:TSLargeT 小鼠的肾近曲小管细胞：结果：在抑制细胞增殖和囊肿生长方面，与游离药物相比，MET 与所有载药 KMs 的联合药效都明显增强。值得注意的是，根据 Bliss 协同作用评分，MET 与含有莎草酸或雷帕霉素的 KMs 具有协同作用：总之，我们首次展示了使用药物负载纳米颗粒和游离 MET 的药物协同作用，并提出了一种新型的基于纳米药物的组合治疗 ADPKD 的方法，其疗效得到了增强：在线版本包含补充材料，可在10.1007/s12195-022-00753-9获取。
Combining Metformin and Drug-Loaded Kidney-Targeting Micelles for Polycystic Kidney Disease.
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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