Objective To fulfil an unmet therapeutic need for treating type 2 diabetes by developing an innovative oral drug delivery nanosystem increasing the production of glucagon-like peptide-1 (GLP-1) and the absorption of peptides into the circulation.
Design We developed a nanocarrier for the oral delivery of peptides using lipid-based nanocapsules. We encapsulated the GLP-1 analogue exenatide within nanocapsules and investigated in vitro in human L-cells (NCl-H716) and murine L-cells (GLUTag cells) the ability of the nanosystem to trigger GLP-1 secretion. The therapeutic relevance of the nanosystem in vivo was tested in high-fat diet (HFD)-induced diabetic mice following acute (one administration) or chronic treatment (5 weeks) in obese and diabetic mice.
Results We demonstrated that this innovative nanosystem triggers GLP-1 secretion in both human and murine cells as well as in vivo in mice. This strategy increases the endogenous secretion of GLP-1 and the oral bioavailability of the GLP-1 analogue exenatide (4% bioavailability with our nanosystem).
The nanosystem synergizes its own biological effect with the encapsulated GLP-1 analogue leading to a marked improvement of glucose tolerance and insulin resistance (acute and chronic). The chronic treatment decreased diet-induced obesity, fat mass, hepatic steatosis, together with lower infiltration and recruitment of immune cell populations and inflammation.
Conclusion We developed a novel nanosystem compatible with human use that synergizes its own biological effect with the effects of increasing the bioavailability of a GLP-1 analogue. The effects of the formulation were comparable to the results observed for the marketed subcutaneous formulation. This nanocarrier-based strategy represents a novel promising approach for oral peptide delivery in incretin-based diabetes treatment.
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Contributors Conceptualisation, AB and PDC; Methodology, YX, AB, MVH, FS and PDC; Investigations, YX, VP, AB, PDC; Resources, AB and PDC; Writing-original draft, YX and AB; Supervision, AB and PDC; Funding, AB, VP and PDC.
Funding YX is the recipient of a grant from the China Scholarship Council (CSC). AB is a research associate from the FRS-FNRS (Fonds de la Recherche Scientifique) Belgium. This work was supported by the Fonds de la Recherche Scientifique-FNRS under Grants n°J.0220.16 (recipient V.P.) and T.0013.19 (recipient AB). PDC is senior research associate from FRS-FNRS under grants: WELBIO-CR-2017-C02 and The Excellence Of Science (EOS 30770923) and is a recipient of the Funds Baillet Latour (Grant for Medical Research 2015).
Competing interests PDC is a co-founder of A-Mansia Biotech SA.
Patient consent for publication Not required.
Ethics approval All animal experiments were approved by and performed in accordance with the local animal committee (2014/UCL/MD/033 and 2017/UCL/MD/005) and as specified by the Belgian Law of 29 May 2013 on the protection of laboratory animals.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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