Stable Evans Blue Derived Exendin-4 Peptide for Type 2 Diabetes Treatment

Liu, Yi; Wang, Guohao; Zhang, Huimin; Ma, Ying; Lang, Lixin; Jacobson, Orit; Kiesewetter, Dale O.; Zhu, Lei; Gao, Shi; Ma, Qingjie; Chen, Xiaoyuan

doi:10.1021/acs.bioconjchem.5b00625

Cited by 26 publications

(32 citation statements)

References 29 publications

(50 reference statements)

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“…4 ). Like MEB 43 , in the presence of albumin, the originally self-quenched MEB fluorescence of MEB–CpG was recovered and the fluorescence lifetime was prolonged, indicating albumin binding of MEB–CpG. The fluorescence of MEB–CpG was less than MEB upon albumin binding (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 96%

Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy

et al. 2017

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Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund’s adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+ cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.

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Section: Resultsmentioning

confidence: 96%

Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy

et al. 2017

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“…We subsequently postulated that the properties of the binding of EB and its derivatives to albumin can be used to retain drugs or tracers in the blood. We prepared a truncated EB derivative of exendin-4 that proved effective for long-term glucose control (5).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, slow release of the drug over time would allow continual uptake at the biologic target. We demonstrated this enhanced blood half-life and drug efficacy for a derivative of exendin-4 (5,6).…”

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confidence: 80%

Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents

et al. 2016

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One of the major design considerations for a drug is its pharmacokinetics in the blood. A drug with a short half-life in the blood is less available at a target organ. Such a limitation dictates treatment with either high doses or more frequent doses, both of which may increase the likelihood of undesirable side effects. To address the need for additional methods to improve the blood half-life of drugs and molecular imaging agents, we developed an "add-on" molecule that contains 3 groups: a truncated Evans blue dye molecule that binds to albumin with a low micromolar affinity and provides a prolonged half-life in the blood; a metal chelate that allows radiolabeling for imaging and radiotherapy; and maleimide for easy conjugation to drug molecules. Methods: The truncated Evans blue molecule was conjugated with the chelator NOTA or DOTA, and the resulting conjugate was denoted as NMEB or DMEB, respectively. As a proof of concept, we coupled NMEB and DMEB to c(RGDfK), which is a small cyclic arginine-glycine-aspartic acid (RGD) peptide, for targeting integrin a v b 3 . NMEB and DMEB were radiolabeled with 64 Cu and 90 Y, respectively, and tested in xenograft models. Results: The resulting radiolabeled conjugates showed a prolonged circulation half-life and enhanced tumor accumulation in integrin a v b 3 -expressing tumors. Tumor uptake was markedly improved over that with NOTA-or DOTA-conjugated c(RGDfK). Tumor radiotherapy experiments in mice with 90 Y-DMEB-RGD showed promising results; existing tumors were eliminated. Conclusion: Conjugation of our novel add-on molecule, NMEB or DMEB, to potential tracers or therapeutic agents improved blood half-life and tumor uptake and could transform such agents into theranostic entities. Thegoalofdr ug development is to achieve high activity and specificity for a desired biologic target. However, many potential pharmaceuticals that meet these criteria fail as therapeutics because of unfavorable pharmacokinetics, in particular, rapid blood clearance, which prevents the achievement of therapeutic concentrations. For some drugs, the administration of large or frequently repeated doses is required to achieve and maintain therapeutic levels (1) but can, in turn, increase the probability of undesired side effects. One chemical modification that delays the rate of drug clearance and has been effective for some drugs is the addition of polyethylene glycol (PEG) (2). However, recent studies showed that PEGylation of drugs has disadvantages, including immunogenicity caused by the development of anti-PEG antibodies, heterogeneity of the PEGylated drugs, and decreased biologic activity and bioavailability of the drugs (1,3).To address the need for additional methods to improve the blood half-life of drugs and molecular imaging agents, we made use of molecules with a high affinity for albumin. We previously developed a radiolabeled truncated derivative of Evans blue (EB) that allowed imaging of the blood volume because of the affinity of EB for albumin (4). This result encouraged us to e...

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“…Other modifications of existing exendin‐4 can also be achieved by the conjugation of exogenous molecules to the incretin peptide. For example, a conjugation with maleimide derivatives of Evans blue dye produces an exendin peptide with longer half‐life and better hypoglycaemic effects . Another example is the conjugation of fatty acids with lysine residues of exendin‐4 to form a sterically stable micelle for an extensive absorption .…”

Section: Challenges Of Exendin‐4 As Anti‐diabetic Drugmentioning

confidence: 99%

Exendin‐4 from Heloderma suspectum venom: From discovery to its latest application as type II diabetes combatant

Yap

Misuan

2018

Basic Clin Pharma Tox

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Type II diabetes mellitus (T2DM) is a chronic non-communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and incretin mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin-4 is a short incretinmimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon-like peptide 1 (GLP-1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl-peptidase-4 and has a longer half-life than the endogenous GLP-1; thus, it is further developed as an incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N-terminal domain (NTD) of GLP-1 receptor while the C-terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto-inhibited state of the receptor to its auto-activated state. Exendin-4 enhances the physiological functions of β-cells and the up-regulation of GLP-1 receptors, thus reducing the plasma glucose levels. Moreover, exendin-4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin-4 have also been extrapolated into several clinical trials. Although exendin-4 has a reasonable subcutaneous bioavailability, its half-life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin-4 and the structure-function relationships of exendin-4 with GLP-1 receptor. The review also highlights some challenges and future directions in the improvement of exendin-4 as an anti-diabetic drug.

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Stable Evans Blue Derived Exendin-4 Peptide for Type 2 Diabetes Treatment

Cited by 26 publications

References 29 publications

Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy

Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy

Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents

Exendin‐4 from Heloderma suspectum venom: From discovery to its latest application as type II diabetes combatant

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