L cell stimulation: a novel strategy for oral peptide delivery in incretin-based diabetes treatment

ObjectiveTo 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.DesignWe 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.ResultsWe 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.ConclusionWe 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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Oral peptide delivery: challenges and the way ahead

Drug Discovery Today ◽

10.1016/j.drudis.2021.01.001 ◽

2021 ◽

Author(s):

Sunil Kumar Dubey ◽

Shraddha Parab ◽

Neha Dabholkar ◽

Mukta Agrawal ◽

Gautam Singhvi ◽

...

Keyword(s):

Peptide Delivery ◽

Oral Peptide Delivery ◽

The Way

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New perspectives in oral peptide delivery

Drug Discovery Today ◽

10.1016/j.drudis.2021.01.020 ◽

2021 ◽

Author(s):

Alessandra T. Zizzari ◽

Dimanthi Pliatsika ◽

Flavio M. Gall ◽

Thomas Fischer ◽

Rainer Riedl

Keyword(s):

Peptide Delivery ◽

Oral Peptide Delivery

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Oral peptide delivery by tetraether lipid liposomes

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2011.05.066 ◽

2011 ◽

Vol 415 (1-2) ◽

pp. 150-157 ◽

Cited By ~ 39

Author(s):

Johannes Parmentier ◽

Bernhard Thewes ◽

Felix Gropp ◽

Gert Fricker

Keyword(s):

Peptide Delivery ◽

Oral Peptide Delivery ◽

Tetraether Lipid ◽

Lipid Liposomes

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Towards Developing Bioresponsive, Self-Assembled Peptide Materials: Dynamic Morphology and Fractal Nature of Nanostructured Matrices

Materials ◽

10.3390/ma11091539 ◽

2018 ◽

Vol 11 (9) ◽

pp. 1539 ◽

Cited By ~ 2

Author(s):

Kyle Koss ◽

Larry Unsworth

Keyword(s):

Fine Structure ◽

Focal Point ◽

Peptide Delivery ◽

Bioactive Molecules ◽

Matrix Metalloproteinase 2 ◽

Fractal Nature ◽

Self Assembling ◽

Delivery Platform ◽

Peptide Materials ◽

Novel Strategy

(Arginine-alanine-aspartic acid-alanine)4 ((RADA)4) nanoscaffolds are excellent candidates for use as peptide delivery vehicles: they are relatively easy to synthesize with custom bio-functionality, and assemble in situ to allow a focal point of release. This enables (RADA)4 to be utilized in multiple release strategies by embedding a variety of bioactive molecules in an all-in-one “construct”. One novel strategy focuses on the local, on-demand release of peptides triggered via proteolysis of tethered peptide sequences. However, the spatial-temporal morphology of self-assembling nanoscaffolds may greatly influence the ability of enzymes to both diffuse into as well as actively cleave substrates. Fine structure and its impact on the overall effect on peptide release is poorly understood. In addition, fractal networks observed in nanoscaffolds are linked to the fractal nature of diffusion in these systems. Therefore, matrix morphology and fractal dimension of virgin (RADA)4 and mixtures of (RADA)4 and matrix metalloproteinase 2 (MMP-2) cleavable substrate modified (RADA)4 were characterized over time. Sites of high (glycine-proline-glutamine-glycine+isoleucine-alanine-serine-glutamine (GPQG+IASQ), CP1) and low (glycine-proline-glutamine-glycine+proline-alanine-glycine-glutamine (GPQG+PAGQ), CP2) cleavage activity were chosen. Fine structure was visualized using transmission electron microscopy. After 2 h of incubation, nanofiber networks showed an established fractal nature; however, nanofibers continued to bundle in all cases as incubation times increased. It was observed that despite extensive nanofiber bundling after 24 h of incubation time, the CP1 and CP2 nanoscaffolds were susceptible to MMP-2 cleavage. The properties of these engineered nanoscaffolds characterized herein illustrate that they are an excellent candidate as an enzymatically initiated peptide delivery platform.

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