Abstract 111: A Kidney Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Cisplatin-induced Nephrotoxicity

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
John D Imig ◽  
Md A Khan ◽  
Adeniyi M Adebesin ◽  
John R Falck
Keyword(s):  
Folic Acid ◽  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Kidney Tissue ◽  
Renal Tissue ◽  
Epoxyeicosatrienoic Acid ◽  
High Concentration ◽  
Lower Effective Dose

Epoxyeicosatrienoic acid (EET) analogs have exceptional therapeutic potential to combat cardiovascular and kidney diseases. EET analogs combat damage in acute and chronic kidney disease models. Biological actions attributed to EET analogs such as vasodilation, anti-inflammation, anti-apoptosis, and anti-fibrosis are ideally suited to treat kidney diseases. Although EET analogs have performed well in several in vivo models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect in the kidney and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated an EET analog to folic acid because there is a high concentration of folate receptors in renal tissue. The EET analog was conjugated to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. (10mg/kg/hr) for 6 hours via the rat jugular vein. Plasma and kidney tissue were collected and EET-A or EET-F01 measured by LC-MS-MS. EET-A plasma level was 1.6 ng/mL, but EET-A was undetectable in the kidney. On the other hand, EET-F01 was 6.5 ng/mL in plasma and 26.7 ng/mL in kidney tissue. These data demonstrate that EET-F01 targets the kidney. Experiments were conducted to compare EET-F01 and EET-A to decrease cisplatin-induced nephrotoxicity. A single injection of cisplatin (7 mg/kg ip) was administered to WKY rats treated with vehicle, EET-A (10 mg/kg ip) or EET-F01 (20 mg/kg or 2 mg/kg ip) for five days. Cisplatin increased BUN (125 ± 11 mg/dL) and NAG (12 ± 4 IU/L) compared to control (36 ± 9 mg/dL and 4 ± 1 IU/L). EET-F01 was as effective as EET-A in decreasing BUN, NAG, and renal histological injury five days following cisplatin administration. Despite it almost 2x-greater molecular weight compared with EET-A, EET-F01 was effective in lowering BUN and NAG at 20 mg/kg/d and at a 10-fold lower dose of 2 mg/kg/d. These data clearly demonstrate that EET-F01 targets the kidney and allows for a lower effective dose. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

scholarly journals Kidney-Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Inflammation, Oxidative Stress, and Cisplatin-Induced Nephrotoxicity

2021 ◽  
Vol 22 (6) ◽  
pp. 2793
Author(s):  
John D. Imig ◽  
Md Abdul Hye Khan ◽  
Anna Burkhan ◽  
Guan Chen ◽  
Adeniyi Michael Adebesin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Targeted Delivery ◽  
Kidney Diseases ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Thiobarbituric Acid ◽  
Epoxyeicosatrienoic Acid ◽  
Lower Effective Dose ◽  
Cisplatin Nephrotoxicity ◽  
Kidney Injury Molecule 1

Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-β-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

scholarly journals A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Soudeh Moghadasi ◽  
Marischa Elveny ◽  
Heshu Sulaiman Rahman ◽  
Wanich Suksatan ◽  
Abduladheem Turki Jalil ◽  
...  
Keyword(s):  
Regenerative Medicine ◽  
Ethical Issues ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Experimental Models ◽  
Live Cells ◽  
Target Cells ◽  
Intercellular Interaction ◽  
Micro Rnas

AbstractRecently, mesenchymal stem/stromal cells (MSCs) due to their pro-angiogenic, anti-apoptotic, and immunoregulatory competencies along with fewer ethical issues are presented as a rational strategy for regenerative medicine. Current reports have signified that the pleiotropic effects of MSCs are not related to their differentiation potentials, but rather are exerted through the release of soluble paracrine molecules. Being nano-sized, non-toxic, biocompatible, barely immunogenic, and owning targeting capability and organotropism, exosomes are considered nanocarriers for their possible use in diagnosis and therapy. Exosomes convey functional molecules such as long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs), proteins (e.g., chemokine and cytokine), and lipids from MSCs to the target cells. They participate in intercellular interaction procedures and enable the repair of damaged or diseased tissues and organs. Findings have evidenced that exosomes alone are liable for the beneficial influences of MSCs in a myriad of experimental models, suggesting that MSC- exosomes can be utilized to establish a novel cell-free therapeutic strategy for the treatment of varied human disorders, encompassing myocardial infarction (MI), CNS-related disorders, musculoskeletal disorders (e.g. arthritis), kidney diseases, liver diseases, lung diseases, as well as cutaneous wounds. Importantly, compared with MSCs, MSC- exosomes serve more steady entities and reduced safety risks concerning the injection of live cells, such as microvasculature occlusion risk. In the current review, we will discuss the therapeutic potential of MSC- exosomes as an innovative approach in the context of regenerative medicine and highlight the recent knowledge on MSC- exosomes in translational medicine, focusing on in vivo researches.

Resolution of renal inflammation: a new role for NF-κB1 (p50) in inflammatory kidney diseases

2009 ◽  
Vol 297 (2) ◽  
pp. F429-F439 ◽  
Author(s):  
Ulf Panzer ◽  
Oliver M. Steinmetz ◽  
Jan-Eric Turner ◽  
Catherine Meyer-Schwesinger ◽  
Claudia von Ruffer ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Kidney Diseases ◽  
Renal Tissue ◽  
Induction Phase ◽  
Nuclear Compartment ◽  
Renal Inflammation ◽  
Proinflammatory Gene ◽  
And Function ◽  
Proinflammatory Gene Expression

In renal tissue injury, activation of the transcription factor NF-κB has a central role in the induction of proinflammatory gene expression, which are involved in the development of progressive renal inflammatory disease. The function of NF-κB during the switch from the inflammatory process toward resolution, however, is largely unknown. Therefore, we assessed the time-dependent activation and function of NF-κB in two different models of acute nephritis. Our experiments demonstrate a biphasic activation of NF-κB in the anti-Thy-1 model of glomerulonephritis in rats and the LPS-induced nephritis in mice, with a first peak during the induction phase and a second peak during the resolution period. After induction of glomerular immune injury in rats, predominantly NF-κB p65/p50 heterodimer complexes are shifted to the nucleus whereas during the resolution phase predominantly p50 homodimers could be demonstrated in the nuclear compartment. In addition, we could demonstrate that p50 protein plays a pivotal role in the resolution of LPS-induced renal inflammation since NF-κB p50 knockout mice demonstrate significantly higher chemokine expression, prolonged renal inflammatory cell infiltration with consecutive tissue injury, and reduced survival. In conclusion, our studies indicate that NF-κB subunit p50 proteins have critical in vivo functions in immunologically mediated renal disease by downregulating inflammation during the resolution period.

scholarly journals Extracellular vesicles as immune mediators in response to kidney injury

2018 ◽  
Vol 314 (1) ◽  
pp. F9-F21 ◽  
Author(s):  
Eva Feigerlová ◽  
Shyue-Fang Battaglia-Hsu ◽  
Thierry Hauet ◽  
Jean-Louis Guéant
Keyword(s):  
Extracellular Vesicles ◽  
Therapeutic Potential ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Bioactive Molecules ◽  
Renal Diseases ◽  
Cytokine Signaling ◽  
Renal Tubular ◽  
Tissue Recovery

Important progress has been made on cytokine signaling in response to kidney injury in the past decade, especially cytokine signaling mediated by extracellular vesicles (EVs). For example, EVs released by injured renal tubular epithelial cells (TECs) can regulate intercellular communications and influence tissue recovery via both regulating the expression and transferring cytokines, growth factors, as well as other bioactive molecules at the site of injury. The effects of EVs on kidney tissue seem to vary depending on the sources of EVs; however, the literature data are often inconsistent. For example, in rodents EVs derived from mesenchymal stem cells (MSC-EVs) and endothelial progenitor cells (EPC-EVs) can have both beneficial and harmful effects on injured renal tissue. Caution is thus needed in the interpretation of these data as contradictory findings on EVs may not only be related to the origin of EVs, they can also be caused by the different methods used for EV isolation and the physiological and pathological states of the tissues/cells under which they were obtained. Here, we review and discuss our current understanding related to the immunomodulatory function of EVs in renal tubular repair in the hope of encouraging further investigations on mechanisms related to their antiinflammatory and reparative role to better define the therapeutic potential of EVs in renal diseases.

Effective tumor-targeted delivery of etoposide using chitosan nanoparticles conjugated with folic acid and sulfobetaine methacrylate

RSC Advances ◽  
2016 ◽  
Vol 6 (94) ◽  
pp. 91192-91200 ◽  
Author(s):  
Song Hua ◽  
Jiahua Yu ◽  
Jun Shang ◽  
Haowen Zhang ◽  
Jie Du ◽  
...  
Keyword(s):  
Folic Acid ◽  
Targeted Delivery ◽  
Tumor Targeting ◽  
Chitosan Nanoparticles

FA–CS(VP-16)-g-PSBMA nanoparticles were synthesized and showed effective tumor-targeting properties and promising anti-tumor capacity in vivo.

Novel folate-targeted docetaxel-loaded nanoparticles for tumour targeting: in vitro and in vivo evaluation

RSC Advances ◽  
2016 ◽  
Vol 6 (69) ◽  
pp. 64306-64314 ◽  
Author(s):  
M. H. Han ◽  
Z. T. Li ◽  
D. D. Bi ◽  
Y. F. Guo ◽  
H. X. Kuang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Folic Acid ◽  
Cancer Therapy ◽  
Targeted Delivery ◽  
Tumour Targeting ◽  
Breast Cancer Therapy ◽  
In Vivo Evaluation ◽  
Targeted Delivery System

Cholesterol-PEG1000-FA (folic acid) was synthesized as a stabilizer to encapsulate DTX, for the construction of a promising targeted delivery system for breast cancer therapy.

Folic acid conjugated chitosan for targeted delivery of siRNA to activated macrophages in vitro and in vivo

2014 ◽  
Vol 2 (48) ◽  
pp. 8608-8615 ◽  
Author(s):  
Chuanxu Yang ◽  
Shan Gao ◽  
Jørgen Kjems
Keyword(s):  
Folic Acid ◽  
Targeted Delivery ◽  
Activated Macrophages

scholarly journals Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

2020 ◽  
Author(s):  
Mariana Conceição ◽  
Laura Forcina ◽  
Oscar P. B. Wiklander ◽  
Dhanu Gupta ◽  
Joel Z. Nordin ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Signalling Pathway ◽  
Peptide Sequence ◽  
Target Cells ◽  
Dimerization Domain ◽  
Decoy Receptor ◽  
Stat3 Phosphorylation

AbstractThe cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.

scholarly journals DARPin_9-29-Targeted Gold Nanorods Selectively Suppress HER2-Positive Tumor Growth in Mice

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5235
Author(s):  
Galina M. Proshkina ◽  
Elena I. Shramova ◽  
Marya V. Shilova ◽  
Ivan V. Zelepukin ◽  
Victoria O. Shipunova ◽  
...  
Keyword(s):  
Gold Nanorods ◽  
Targeted Delivery ◽  
Photothermal Therapy ◽  
Near Infrared ◽  
Therapeutic Potential ◽  
Infrared Light ◽  
Strong Reduction ◽  
Her2 Positive ◽  
Excellent Stability

Near-infrared phototherapy has great therapeutic potential for cancer treatment. However, for efficient application, in vivo photothermal agents should demonstrate excellent stability in blood and targeted delivery to pathological tissue. Here, we demonstrated that stable bovine serum albumin-coated gold mini nanorods conjugated to a HER2-specific designed ankyrin repeat protein, DARPin_9-29, selectively accumulate in HER2-positive xenograft tumors in mice and lead to a strong reduction in the tumor size when being illuminated with near-infrared light. The results pave the way for the development of novel DARPin-based targeted photothermal therapy of cancer.

Oral Targeted Delivery by Nanoparticles Enhances Efficacy of an Hsp90 Inhibitor by Reducing Systemic Exposure in Murine Models of Colitis and Colitis-Associated Cancer

2019 ◽  
Vol 14 (1) ◽  
pp. 130-141 ◽  
Author(s):  
Mei Yang ◽  
Fang Zhang ◽  
Chunhua Yang ◽  
Lixin Wang ◽  
Junsik Sung ◽  
...  
Keyword(s):  
Delivery System ◽  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Systemic Exposure ◽  
Hsp90 Inhibitor ◽  
Systemic Administration ◽  
Raw 264.7 Cells ◽  
In Vivo Models ◽  
Promising Therapeutic Approach

AbstractBackground and AimsHeat shock protein 90 [Hsp90]-targeted therapy has been proposed as a promising strategy for the treatment of ulcerative colitis [UC] and colitis-associated cancer [CAC]. Systemic administration of the Hsp90 inhibitor, 17-AAG, was found to be profoundly protective in preclinical mouse models of inflammatory bowel disease [IBD]. However, the therapeutic potential of 17-AAG is limited by potential side effects associated with its systemic exposure and the modest bioavailability afforded by its oral administration.MethodsTo address these issues, we used a versatile single-step surface-functionalizing technique to prepare a 17-AAG oral delivery system using PLGA/PLA-PEG-FA nanoparticles [NP-PEG-FA/17-AAG].ResultsNP-PEG-FA could be efficiently taken up by mouse Colon-26 cells and activated Raw 264.7 cells in vitro and by inflamed mouse colitis tissues in vivo. The therapeutic efficacy of orally administrated NP-PEG-FA/17-AAG was evaluated in in vivo models using dextran sulphate sodium [DSS]-induced UC and azoxymethane [AOM]/DSS-induced CAC, and the results indicated that NP-PEG-FA/17-AAG significantly alleviated the symptoms of UC and CAC. More importantly, our inflamed colitis-targeted 17-AAG nano-formulation reduced systemic exposure and provided a degree of therapeutic response similar to that obtained by systemic administration [intraperitoneal] of 17-AAG, but at a ten-fold lower dose.ConclusionsWe describe a convenient, orally administrated 17-AAG delivery system that exhibits enhanced efficacy in UC and CAC therapy while reducing systemic exposure. This system may represent a promising therapeutic approach for treating UC and CAC.

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