Magnetic resonance imaging of intra‐pancreatic ductal nanoparticle delivery to islet cells

Wang, Ping; Ross, Alana; Yoo, Byunghee; Yang, Jixiang; Farrar, Christian T.; Ran, Chongzhao; Pantazopoulos, Pamela; Medarova, Zdravka; Moore, Anna

doi:10.1002/dmrr.2881

Cited by 7 publications

(10 citation statements)

References 18 publications

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“…The sequences of miRNA mimics, inhibitors and scramble controls used for the synthesis of the nanodrugs are included in Supplemental Table 1. Nanoparticles with a size of ~30 nm were used for conjugation to the oligonucleotides 28 . Synthesis of the prototype nanodrugs have been previously described by us 6,29 and involved: (1) synthesis of dextran-coated magnetic nanoparticles 30 ; (2) conjugation of Cy5.5 fluorescent dye.…”

Section: Synthesis and Characterization Of Mir-216a Nanodrugsmentioning

confidence: 99%

“…Mice were considered diabetic if blood glucose readings reached above 250 mg/dL on two consecutive measurements. Nanodrugs (MN-ASO, MN-ASOscr, MN-miRNA and MN-miRNAscr, 15 mg iron/kg) were injected into the diabetic animals after a laparotomy and exposure of the duodenum and the pancreas using a 31-gauge blunt-ended infusion catheter (World Precision Instruments, Sarasota, FL) inserted in the pancreatic duct through the sphincter of Oddi 28 . The catheter was connected to a quintessential stereotaxic injector (Stoelting, Wood Dale, IL) to allow for a stable infusion of the nanoparticles over a 15 min period 28 .…”

Section: Intrapancreatic Ductal Injection Of the Nanodrugs And Assessmentioning

confidence: 99%

“…Nanodrugs (MN-ASO, MN-ASOscr, MN-miRNA and MN-miRNAscr, 15 mg iron/kg) were injected into the diabetic animals after a laparotomy and exposure of the duodenum and the pancreas using a 31-gauge blunt-ended infusion catheter (World Precision Instruments, Sarasota, FL) inserted in the pancreatic duct through the sphincter of Oddi 28 . The catheter was connected to a quintessential stereotaxic injector (Stoelting, Wood Dale, IL) to allow for a stable infusion of the nanoparticles over a 15 min period 28 . The process was monitored by in vivo MR imaging using a 9.4 T Bruker scanner equipped with a Rat Array MRI CryoProbes coil and using standard T2 weighted gradient echo pulse sequences and T2 maps.…”

Section: Intrapancreatic Ductal Injection Of the Nanodrugs And Assessmentioning

confidence: 99%

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miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

Wang

Liu

Zhao

et al. 2020

Sci Rep

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Aberrant expression of miRNAs in pancreatic islets is closely related to the development of type 1 diabetes (T1D). The aim of this study was to identify key miRNAs dysregulated in pancreatic islets during T1D progression and to develop a theranostic approach to modify their expression using an MRI-based nanodrug consisting of iron oxide nanoparticles conjugated to miRNA-targeting oligonucleotides in a mouse model of T1D. Isolated pancreatic islets were derived from NOD mice of three distinct age groups (3, 8 and 18-week-old). Total RNA collected from cultured islets was purified and global miRNA profiling was performed with 3D-Gene global miRNA microarray mouse chips encompassing all mouse miRNAs available on the Sanger miRBase V16. Of the miRNAs that were found to be differentially expressed across three age groups, we identified one candidate (miR-216a) implicated in beta cell proliferation for subsequent validation by RT-PCR. Alterations in miR-216a expression within pancreatic beta cells were also examined using in situ hybridization on the frozen pancreatic sections. For in vitro studies, miR-216a mimics/inhibitors were conjugated to iron oxide nanoparticles and incubated with beta cell line, βTC-6. Cell proliferation marker Ki67 was evaluated. Expression of the phosphatase and tensin homolog (PTEN), which is one of the direct targets of miR-216a, was analyzed using western blot. For in vivo study, the miR-216a mimics/inhibitors conjugated to the nanoparticles were injected into 12-week-old female diabetic Balb/c mice via pancreatic duct. The delivery of the nanodrug was monitored by in vivo MRI. Blood glucose of the treated mice was monitored post injection. Ex vivo histological analysis of the pancreatic sections included staining for insulin, PTEN and Ki67. miRNA microarray demonstrated that the expression of miR-216a in the islets from NOD mice significantly changed during T1D progression. In vitro studies showed that treatment with a miR-216a inhibitor nanodrug suppressed proliferation of beta cells and increased the expression of PTEN, a miR-216a target. In contrast, introduction of a mimic nanodrug decreased PTEN expression and increased beta cell proliferation. Animals treated in vivo with a mimic nanodrug had higher insulinproducing functionality compared to controls. These observations were in line with downregulation of PTEN and increase in beta cell proliferation in that group. Our studies demonstrated that miR-216a could serve as a potential therapeutic target for the treatment of diabetes. miR-216a-targeting theranostic nanodrugs served as exploratory tools to define functionality of this miRNA in conjunction with in vivo MR imaging.

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Section: Synthesis and Characterization Of Mir-216a Nanodrugsmentioning

confidence: 99%

Section: Intrapancreatic Ductal Injection Of the Nanodrugs And Assessmentioning

confidence: 99%

Section: Intrapancreatic Ductal Injection Of the Nanodrugs And Assessmentioning

confidence: 99%

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miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

Wang

Liu

Zhao

et al. 2020

Sci Rep

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“…Within the islet the microvasculature becomes more permeable during insulitis and inflammation, as demonstrated by the uptake of nanoparticles into the islet microenvironment of non-obese diabetic (NOD) mice 14 or STZ-treated mice 15 , which model T1D. Magnetic resonance imaging (MRI) has been used to visualize magnetic nanoparticles (MNPs) uptake and retention within the inflamed islets during the development of T1D in rodent models [14][15][16][17] and in human T1D 18,19 . As such, measurements of increased islet vascular permeability and changes in these measurements over time could be used more broadly to diagnose and monitor islet infiltration and decline during the progression of T1D.…”

Section: Introductionmentioning

confidence: 99%

“…This includes accumulation of ~100-300 nm diameter NBs within tumors as a result of increased tumor vascular permeability [23][24][25] . Such NBs are echogenic at clinically relevant ultrasound frequencies (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), allowing regions of high permeability microvasculature to be imaged non-invasively and in real time.…”

Section: Introductionmentioning

confidence: 99%

Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis and β-cell mass decline in mouse models of type 1 diabetes

Ramirez

Abenojar

Hernandez

et al. 2019

Preprint

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Type 1 diabetes (T1D) is characterized by the infiltration of autoreactive T-cells into the islet of Langerhans, and depletion of insulin-secreting β-cells. This immune cell infiltration (insulitis) first occurs during an asymptomatic phase of T1D that can take place many years prior to clinical diagnosis. Methods to diagnose insulitis and changes in β-cell mass during this asymptomatic phase are limited, thus precluding early therapeutic intervention. While therapeutic treatments can delay T1D progression, treatment efficacy is limited and widely varying, and a method to track this efficacy is also lacking. During T1D progression, the islet microvasculature increases permeability as a result of insulitis, in both mouse models of T1D and humans with T1D. This increased permeability can allow nanoparticles, such as contrast agents for diagnostic imaging, to access the islet microenvironment. Contrast enhanced ultrasound (CEUS) uses shell-stabilized gas bubbles to provide high acoustic backscatter in vasculature and tissue and is clinically approved. A novel, sub-micron sized 'nanobubble' (NB) ultrasound contrast agent has been developed and shown to extravasate and accumulate in tumors, where microvascular permeability is high. To test whether CEUS can be used to measure increased islet microvasculature permeability and indicate the asymptomatic phase of T1D, we applied CEUS measurements with NBs in pre-clinical T1D models. NOD mice and mice receiving an adoptive-transfer of diabetogenic splenocytes showed accumulation of NBs specifically within the pancreatic islets, and only in the presence of insulitis. This accumulation was measured by both ultrasound contrast and histological analysis, and accumulation only occurred for sub-micron sized bubbles. Importantly, accumulation was detected as early as 4w in NOD mice. Thus, CEUS with sub-micron sized NB contrast agent may provide a predicative marker for disease progression early in asymptomatic T1D, as well as monitoring of disease prevention or reversal.

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miRNA Theranostic Nanoparticles Promote Pancreatic Beta Cell Proliferation in Type 1 Diabetes Model

Nigam

Moore

Wang

2022

Methods in Molecular Biology

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Magnetic resonance imaging of intra‐pancreatic ductal nanoparticle delivery to islet cells

Abstract: Our results demonstrate that pancreatic ductal injection accompanied by image guidance could serve as an alternative pathway for nanoparticle delivery. We expect to utilize this intraductal delivery method for theranostic applications in type 1 diabetes.

Cited by 7 publications

References 18 publications

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis and β-cell mass decline in mouse models of type 1 diabetes

miRNA Theranostic Nanoparticles Promote Pancreatic Beta Cell Proliferation in Type 1 Diabetes Model

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