Squalene-PEG-Exendin as High-Affinity Constructs for Pancreatic Beta-Cells

Babič, Andréj; Vinet, Laurent; Chellakudam, Vineetha; Janikowska, Karolina; Allémann, Éric; Lange, Norbert

doi:10.1021/acs.bioconjchem.8b00186

Cited by 8 publications

(5 citation statements)

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“…Other strategies to reduce renal uptake are introduction of a cleavable linker to allow renal excretion of the radionuclides, 80 inhibition of neutral endopeptidases to increase metabolic stability of the peptide in the circulation, 79,[81][82][83][84] and incorporation of highly lipophilic groups 34 (efficacies of these strategies are summarized in Table 5). Furthermore, groups have conjugated exendin to PEG, [85][86][87] albumin, 88 an albumin binding domain, 89 a nonglycosylated human Fc fragment, 90 or nanoparticles [91][92][93] to increase circulation time. Since these strategies potentially increase uptake of the exendin-4 conjugates in other organs such as the liver, biodistribution and potency for imaging should be assessed for every compound.…”

Section: Kidney Dosimetry and Methods To Reduce Kidney Uptake Of Exmentioning

confidence: 99%

Exendin‐4 analogs in insulinoma theranostics

Jansen

Lith

Boss

et al. 2019

Labelled Comp Radiopharmac

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Insulinomas are neuroendocrine tumors arising from the pancreatic beta cells. Currently, surgical resection is the therapy of choice, and therefore, preoperative localization of insulinomas is essential. Nearly all insulinomas show overexpression of the glucagon‐like peptide‐1 receptor (GLP‐1R), and therefore, radiolabeled GLP‐1 peptide analog exendin‐4 can be used for diagnosis and preoperative localization with nuclear imaging. Here, we present an overview of the development and clinical implementation of exendin‐4–based tracers for single‐photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging of insulinomas, and we address the potential use of this molecule for optical imaging. At last, we discuss the possibilities and pitfalls of the use of exendin‐4–based tracers for therapeutic applications such as peptide receptor radionuclide therapy (PRRT) or targeted photodynamic therapy (tPDT), giving a future outlook on the use of exendin‐4 in insulinoma theranostics.

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Section: Kidney Dosimetry and Methods To Reduce Kidney Uptake Of Exmentioning

confidence: 99%

Exendin‐4 analogs in insulinoma theranostics

Jansen

Lith

Boss

et al. 2019

Labelled Comp Radiopharmac

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“…Several potential strategies for reducing non-specific uptake and kidney uptake have therefore been discussed, including the incorporation of highly lipophilic groups, albumin and albumin-binding domains, and nanoparticles (94,(96)(97)(98). Certain modifications such as [ 18 Exendin-4 conjugated with polyethylene glycol might prove to be a promising alternative, given that PEGylation is a wellestablished technique for increasing the probe's molecular weight and stability in circulation and for improving its specific uptake (100).…”

Section: Visualization Of B Cells: Glucagon-like Peptide-1 Receptor-targeted Imagingmentioning

confidence: 99%

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

2021

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Pancreatic beta (β)-cell dysfunction and reduced mass play a central role in the development and progression of diabetes mellitus. Conventional histological β-cell mass (BCM) analysis is invasive and limited to cross-sectional observations in a restricted sampling area. However, the non-invasive evaluation of BCM remains elusive, and practical in vivo and clinical techniques for β-cell-specific imaging are yet to be established. The lack of such techniques hampers a deeper understanding of the pathophysiological role of BCM in diabetes, the implementation of personalized BCM-based diabetes management, and the development of antidiabetic therapies targeting BCM preservation and restoration. Nuclear medical techniques have recently triggered a major leap in this field. In particular, radioisotope-labeled probes using exendin peptides that include glucagon-like peptide-1 receptor (GLP-1R) agonist and antagonist have been employed in positron emission tomography and single-photon emission computed tomography. These probes have demonstrated high specificity to β cells and provide clear images accurately showing uptake in the pancreas and transplanted islets in preclinical in vivo and clinical studies. One of these probes, 111indium-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4), has captured the longitudinal changes in BCM during the development and progression of diabetes and under antidiabetic therapies in various mouse models of type 1 and type 2 diabetes mellitus. GLP-1R-targeted imaging is therefore a promising tool for non-invasive BCM evaluation. This review focuses on recent advances in non-invasive in vivo β-cell imaging for BCM evaluation in the field of diabetes; in particular, the exendin-based GLP-1R-targeted nuclear medicine techniques.

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“…GLP-1R is expressed specifically on β-cells and the GLP-1R agonist Ex4 has been utilized extensively for quantifying and visualizing β-cell mass. 26,28 ENTPD3 has recently been shown to be a marker for mature human and stem cell derived β-like cells; however, it has not been tested as a target for β-cell specific drug delivery . 56,57 To assess the NCs ability to target βcells in vitro, Cy5 encapsulated NCs were cultured with human islets from 2-3 independent donors for 24hr either uncoated or coated with BSA (5mg/ml), HA (0.2mg/ml), guinea pig IgG (1µl/ml), guinea pig ENTPD3 antibody (1µl/ml) or HA-Ex4 (0.2mg/ml).…”

Section: Feasible To Fabricate Bkc-pcl-ncs and Encapsulatementioning

confidence: 99%

“…11,25 Nanoparticles targeted to the pancreatic islet β-cell have previously been utilized as a non-invasive strategy for quantifying and visualizing β-cell mass. 26,27 Notably, iron nanoparticles coated with Exendin-4 (Ex4), an agonist for the glucagon-like peptide 1 receptor (GLP-1R) that is expressed on the surface of β-cells, was successful for targeting the pancreatic islet in vivo. 26,28,29 Although these magnetic nanoparticles could potentially be used as an early diagnostic tool for diabetes detection, 30,31 implementing nanoparticles for targeted drug delivery to protect and promote the proliferation of pancreatic β-cells has not been fully investigated.…”

mentioning

confidence: 99%

“…26,27 Notably, iron nanoparticles coated with Exendin-4 (Ex4), an agonist for the glucagon-like peptide 1 receptor (GLP-1R) that is expressed on the surface of β-cells, was successful for targeting the pancreatic islet in vivo. 26,28,29 Although these magnetic nanoparticles could potentially be used as an early diagnostic tool for diabetes detection, 30,31 implementing nanoparticles for targeted drug delivery to protect and promote the proliferation of pancreatic β-cells has not been fully investigated. The GLP-1R is an attractive target for β-cell specific drug delivery as it's expression is specific to the β-cell within the islet, the FDA-approved agonist Ex4 exhibits high potency for the GLP-1R, and the internalization of GLP-1R upon ligand binding in pancreatic β-cells has been well characterized.…”

mentioning

confidence: 99%

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Peptide Coated Polycaprolactone-Benzalkonium Chloride Nanocapsules for Targeted Drug Delivery to the Pancreatic β-Cell

Collins,

Barra,

Holcomb

et al. 2024

Preprint

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Targeting of current therapies to treat or prevent loss of pancreatic islet β-cells in Type 1 Diabetes (T1D) may provide improved efficacy and reduce off target effects. Current efforts to target the β-cell are limited by a lack of β-cell specific targets and the inability to test multiple targeting moieties with the same delivery vehicle. Here we fabricate a novel tailorable polycaprolactone nanocapsule (NC) where multiple different targeting peptides can be interchangeably attached for β-cell specific delivery. Incorporation of a cationic surfactant in the NC shell allows for the attachment of Exendin-4 and an antibody for ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) for β-cell specific targeting. The average NC size ranges from 250-300nm with a polydispersity index under 0.2. The NCs are non-toxic, stable in media culture, and can be lyophilized and reconstituted. NCs coated with targeting peptide were taken up by human cadaveric islet β-cells and human stem cell-derived β-like cells (sBC)in vitrowith a high level of specificity. Furthermore, NCs successfully delivered both hydrophobic and hydrophilic cargo to human β-cells. Finally, Exendin-4 coated NCs were stable and targeted the mouse pancreatic islet β-cellin vivo. Our unique NC design allows for the interchangeable coating of targeting peptides for future screening of targets with improved cell specificity. The ability to target and deliver thera-peutics to human pancreatic β-cells opens avenues for improved therapies and treatments to help the delay onset, prevent, or reverse T1D.

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Squalene-PEG-Exendin as High-Affinity Constructs for Pancreatic Beta-Cells

Cited by 8 publications

References 50 publications

Exendin‐4 analogs in insulinoma theranostics

Exendin‐4 analogs in insulinoma theranostics

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

Peptide Coated Polycaprolactone-Benzalkonium Chloride Nanocapsules for Targeted Drug Delivery to the Pancreatic β-Cell

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