Dual-Targeted Theranostic Delivery of miRs Arrests Abdominal Aortic Aneurysm Development

Wang, Xiaowei; Searle, Amy; Hohmann, Jan David; Liu, Ao Leo; Abraham, Meike-Kristin; Palasubramaniam, Jathushan; Lim, Bryan; Yu, Yao; Wallert, Maria; Yu, Eefang; Chen, Yung-Chih; Peter, Karlheinz

doi:10.1016/j.ymthe.2018.02.010

Cited by 45 publications

(31 citation statements)

References 34 publications

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“…23 In another study, microRNA mimics were coupled with microbubbles, which enable imaging as well as ultrasound-guided burst delivery, and an antibody against VCAM-1 to specifically target endothelial cells. 24 Thus, in the near future with an improved technique of cell-specific microRNA mimic delivery, cardiac-specific short-term overexpression of miR-212/132 could be used to prevent doxorubicin-induced cardiotoxicity. Another limitation of the AAV9 viral system that we used is that, despite higher cardiotropism, it also transduces other organs, and we cannot completely rule out effects mediated by transduction of other cell types or tissues.…”

Section: Discussionmentioning

confidence: 99%

miR-212/132 Cluster Modulation Prevents Doxorubicin-Mediated Atrophy and Cardiotoxicity

et al. 2019

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Improved therapy of cancer has significantly increased the lifespan of patients. However, cancer survivors face an increased risk of cardiovascular complications due to adverse effects of cancer therapies. The chemotherapy drug doxorubicin is well known to induce myofibril damage and cardiac atrophy. Our aim was to test potential counteracting effects of the prohypertrophic miR-212/132 family in doxorubicin-induced cardiotoxicity. In vitro, overexpression of the pro-hypertrophic miR-212/132 cluster in primary rodent and human iPSC-derived cardiomyocytes inhibited doxorubicin-induced toxicity. Next, a disease model of doxorubicin-induced cardiotoxicity was established in male C57BL/6N mice. Mice were administered either adeno-associated virus (AAV)9-control or AAV9-miR-212/132 to achieve myocardial overexpression of the miR-212/132 cluster. AAV9-mediated overexpression limited cardiac atrophy by increasing left ventricular mass and wall thickness, decreased doxorubicin-mediated apoptosis, and prevented myofibril damage. Based on a transcriptomic profiling we identified fat storage-inducing transmembrane protein 2 (Fitm2) as a novel target and downstream effector molecule responsible, at least in part, for the observed miR-212/132 anti-cardiotoxic effects. Overexpression of Fitm2 partially reversed the effects of miR-212/132. Overexpression of the miR-212/132 family reduces development of doxorubicin-induced cardiotoxicity and thus could be a therapeutic entry point to limit doxorubicin-mediated adverse cardiac effects.

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Section: Discussionmentioning

confidence: 99%

miR-212/132 Cluster Modulation Prevents Doxorubicin-Mediated Atrophy and Cardiotoxicity

et al. 2019

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“…MB-assisted imaging or targeted drug delivery can be achieved by bursting the MBs after their adhesion to the target wall. In this study, the effect of acoustic forces on the MB adhesion to the target wall was neglected due to their small impact on the MBs motion 7,67,68 . The current study addressed the SDM adhesion on the intended surface using the MBs ligands and AAA receptors.…”

Section: Discussionmentioning

confidence: 99%

Targeted Drug Delivery of Microbubble to Arrest Abdominal Aortic Aneurysm Development: A Simulation Study Towards Optimized Microbubble Design

Shamloo

Ebrahimi

Amani

et al. 2020

Sci Rep

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Abdominal aortic aneurysm (AAA) is an irreversible bulge in the artery with higher prevalence among the elderlies. increase of the aneurysm diameter by time is a fatal phenomenon which will lead to its sidewall rupture. invasive surgical treatments are vital in preventing from AAA development. these approaches however have considerable side effects. Targeted drug delivery using microbubbles (MBs) has been recently employed to suppress the AAA growth. the present study is aimed to investigate the surface adhesion of different types of drug-containing MBs to the inner wall of AAA through ligandreceptor binding, using fluid-structure interaction (FSI) simulation by using a patient CT-scan images of the vascular system. The effect of blood flow through AAA on MBs delivery to the intended surface was also addressed. For this purpose, the adherence of four types of MBs with three different diameters to the inner surface wall of AAA was studied in a patient with 40-mm diameter aneurysm. The effects of the blood mechanical properties on the hematocrit (Hct) percentage of patients suffering from anemia and diabetes were studied. Moreover, the impact of variations in the artery inlet velocity on blood flow was addressed. Simulation results demonstrated the dependency of the surface density of MBs (SDM) adhered on the AAA lumen to the size and the type of MBs. It was observed that the amount of SDM due to adhesion on the AAA lumen for one of the commercially-approved MBs (Optison) with a diameter of 4.5 μm was higher than the other MBs. Furthermore, we have shown that the targeted drug delivery to the AAA lumen is more favorable in healthy individuals (45% Hct) compared to the patients with diabetes and anemia. Also, it was found that the targeted drug delivery method using MBs on the patients having AAA with complicated aneurysm shape and negative inlet blood flow velocity can be severely affected. Abdominal aortic aneurysm (AAA) is one of the most common types of cardiovascular diseases (CVDs) occurring in the middle part of the aorta. AAA is originated from the changes in the mechanical properties of the vessel wall leading to permanent focal dilation of 50% 1. At present, small AAAs, with a diameter of less than 55 mm in men and less than 50 mm in women, are examined with regular monitoring in terms of size. At this point, the growth rate is approximately 3-10 mm/year. The patient needs surgery in case of AAA excessive enlargement beyond these values 2-4. However, the minimally invasive or so-called endovascular method also has some complications, including difficulty and complexity of the operation when AAA is closed to one of the visceral veins. Also, about 20 percent of grafts cannot completely remove the damaged vessel from the circulatory system 5,6. Another problem with the endovascular method is the durability of this method due to endoleak (continuous blood leakage around stents), which results in shorter durability of this type of treatment 5. Despite these drawbacks and challenges, effective treatment is still...

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“…In a novel preclinical study, a biotechnological theranostic approach was used in the AngII-ApoE -/- mouse model [ 92 ]. MicroRNA-126 was previously shown to downregulate vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells and to exert anti-inflammatory effects by reduced leukocyte adhesion.…”

Section: Use Of New Imaging Methods To Study Aaa Rupturementioning

confidence: 99%

“…MicroRNA-126 was previously shown to downregulate vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells and to exert anti-inflammatory effects by reduced leukocyte adhesion. The investigators used ultrasound-microbubbles coupled with VCAM-1-targeted antibodies (scFvmVCAM-1) and microRNA-126 mimic theranostic microbubbles (TargMB-M126) [ 92 ]. They showed that TargMB-M126 inhibited AngII-induced AAA.…”

Section: Use Of New Imaging Methods To Study Aaa Rupturementioning

confidence: 99%

Risk Factors and Mouse Models of Abdominal Aortic Aneurysm Rupture

Krishna

Morton

et al. 2020

IJMS

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Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults. In clinical practice, the most established predictor of AAA rupture is maximum AAA diameter. Aortic diameter is commonly used to assess AAA severity in mouse models studies. AAA rupture occurs when the stress (force per unit area) on the aneurysm wall exceeds wall strength. Previous research suggests that aortic wall structure and strength, biomechanical forces on the aorta and cellular and proteolytic composition of the AAA wall influence the risk of AAA rupture. Mouse models offer an opportunity to study the association of these factors with AAA rupture in a way not currently possible in patients. Such studies could provide data to support the use of novel surrogate markers of AAA rupture in patients. In this review, the currently available mouse models of AAA and their relevance to the study of AAA rupture are discussed. The review highlights the limitations of mouse models and suggests novel approaches that could be incorporated in future experimental AAA studies to generate clinically relevant results.

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Dual-Targeted Theranostic Delivery of miRs Arrests Abdominal Aortic Aneurysm Development

Cited by 45 publications

References 34 publications

miR-212/132 Cluster Modulation Prevents Doxorubicin-Mediated Atrophy and Cardiotoxicity

miR-212/132 Cluster Modulation Prevents Doxorubicin-Mediated Atrophy and Cardiotoxicity

Targeted Drug Delivery of Microbubble to Arrest Abdominal Aortic Aneurysm Development: A Simulation Study Towards Optimized Microbubble Design

Risk Factors and Mouse Models of Abdominal Aortic Aneurysm Rupture

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