Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes

Ramirez, David G.; Abenojar, Eric; Hernandez, Christopher; Lorberbaum, David S.; Papazian, Lucine; Passman, Samantha; Pham, Vinh; Exner, Agata A.; Benninger, Richard K.P.

doi:10.1038/s41467-020-15957-8

Cited by 42 publications

(39 citation statements)

References 45 publications

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“…4j): islets in which no insulitis was observed (score 0) showed similar DiO fluorescent coverage as islets in which substantial insulitis is observed (score 3). This is consistent with other reports in which the vascular permeability reflects the overall diseased state of the pancreas rather that the local level of disease (15). Consistent with measurements above, there was no relationship between fluorescent coverage and insulitis for non-vaporized nanodroplets, whether analyzed by pancreas or by islet ( Fig.S2).…”

Section: Nanodroplet Accumulation Within Pancreas Of Nod Mice Is Restsupporting

confidence: 92%

“…4). When examined, this has been observed with other contrast agents that extravasate and accumulate within the islet in models of T1D (13,15,24). Thus while islet microvascular permeability is a good indication of pre-symptomatic T1D (13,14), it does not necessarily reflect spatial variations in insulitis across the pancreas, at least in mouse models of T1D.…”

Section: Nanodroplet Accumulation In Pre-symptomatic T1d Correlates Wmentioning

confidence: 96%

“…Sub-micron sized particles selectively accumulate in the islets of Langerhans in mouse models of type1 diabetes (T1D) via the enhanced permeability and retention (EPR) effect that can occur in inflamed tissues (12,15). Nanodroplet phase change agents are sub-micron sized that can accumulate in tumors, and can be vaporized within the tissue to provide significant ultrasound contrast.…”

Section: Sub-micron Nanodroplets Accumulate and Can Be Vaporized Withmentioning

confidence: 99%

“…Sub-micron sized nanobubble ultrasound contrast agents have been developed. These agents act via the EPR effect to accumulate in tumors and inflamed tissue, including the immune infiltrated pancreas (15,16). However one potential limitation with sub-micron sized bubbles is their low scattering cross section, requiring a larger number of bubbles to be infused to generate measurable signal.…”

Section: Introductionmentioning

confidence: 99%

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Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents

Ramirez¹,

Upadhyay²,

Pham³

et al. 2020

Preprint

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Type1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing beta-cells within the pancreatic islets of Langerhans (insulitis), resulting in loss of glucose homeostasis. Early diagnosis during pre-symptomatic T1D would allow for therapeutic intervention prior to substantial loss of beta-cell mass at T1D onset. There are limited methods to track the progression of insulitis and beta-cell mass decline in pre-symptomatic T1D. During insulitis, the islet microvasculature increases permeability, such that sub-micron sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Sub-micron sized nanodroplet (ND) phase-change agents can be vaporized into micron-sized bubbles; serving as a circulating microbubble precursor. We tested if NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in NOD mice and NOD;Rag1ko controls, and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10w NOD mice following ND infusion and vaporization, but was absent in both the non-infiltrated kidney of NOD mice and pancreas of Rag1ko controls. High contrast elevation also correlated with rapid diabetes onset. In pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression to guide and assess preventative therapeutic interventions for T1D.

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Section: Nanodroplet Accumulation Within Pancreas Of Nod Mice Is Restsupporting

confidence: 92%

Section: Nanodroplet Accumulation In Pre-symptomatic T1d Correlates Wmentioning

confidence: 96%

Section: Sub-micron Nanodroplets Accumulate and Can Be Vaporized Withmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents

Ramirez¹,

Upadhyay²,

Pham³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Contrast-enhanced ultrasound has also been used for detecting inslulitis in pre-clinical models of T1D, which shows accumulation of nanobubbles specifically within pancreatic islets, correlating with insulitis. Thus, nanobubble ultrasound imaging provides a marker for disease progression for T1D [46].…”

Section: Optical Imaging and Ultrasound Imagingmentioning

confidence: 99%

Current Progress and Perspective: Clinical Imaging of Islet Transplantation

Richards

Sun

Hayat

et al. 2020

Life

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Islet transplantation has great potential as a cure for type 1 diabetes. At present; the lack of a clinically validated non-invasive imaging method to track islet grafts limits the success of this treatment. Some major clinical imaging modalities and various molecular probes, which have been studied for non-invasive monitoring of transplanted islets, could potentially fulfill the goal of understanding pathophysiology of the functional status and viability of the islet grafts. In this current review, we summarize the recent clinical studies of a variety of imaging modalities and molecular probes for non-invasive imaging of transplanted beta cell mass. This review also includes discussions on in vivo detection of endogenous beta cell mass using clinical imaging modalities and various molecular probes, which will be useful for longitudinally detecting the status of islet transplantation in Type 1 diabetic patients. For the conclusion and perspectives, we highlight the applications of multimodality and novel imaging methods in islet transplantation.

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Pharmacokinetic modeling of PSMA‐targeted nanobubbles for quantification of extravasation and binding in mice models of prostate cancer

et al. 2022

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Contrast-enhanced ultrasound (CEUS) by injection of microbubbles (MBs) has shown promise as a cost-effective imaging modality for prostate cancer (PCa) detection. More recently, nanobubbles (NBs) have been proposed as novel ultrasound contrast agents. Unlike MBs, which are intravascular ultrasound contrast agents, the smaller diameter of NBs allows them to cross the vessel wall and target specific receptors on cancer cells such as the prostate-specific membrane antigen (PSMA). It has been demonstrated that PSMA-targeted NBs can bind to the receptors of PCa cells and show a prolonged retention effect in dual-tumor mice models. However, the analysis of the prolonged retention effect has so far been limited to qualitative or semi-quantitative approaches. Methods: This work introduces two pharmacokinetics models for quantitative analysis of time-intensity curves (TICs) obtained from the CEUS loops. The first model is based on describing the vascular input by the modified local density random walk (mLDRW) model and independently interprets TICs from each tumor lesion. Differently, the second model is based on the reference-tissue model, previously proposed in the context of nuclear imaging, and describes the binding kinetics of an indicator in a target tissue by using a reference tissue where binding does not occur. Results: Our results show that four estimated parameters, 𝛽, 𝛽∕𝜆, 𝛽 + ∕𝛽 − , for the mLDRW-input model, and 𝛾 for the reference-based model, were significantly different (p-value <0.05) between free NBs and PSMA-NBs. These parameters estimated by the two models demonstrate different behaviors between PSMAtargeted and free NBs. Conclusions: These promising results encourage further quantitative analysis of targeted NBs for improved cancer diagnostics and characterization.

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Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes

Cited by 42 publications

References 45 publications

Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents

Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents

Current Progress and Perspective: Clinical Imaging of Islet Transplantation

Pharmacokinetic modeling of PSMA‐targeted nanobubbles for quantification of extravasation and binding in mice models of prostate cancer

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