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Oral peptide based nanomedicine to treat a range of diseases

The potential of peptide drugs to treat devastating systemic diseases would be vastly increased if administration was oral. The TRANS-INT project has taken us closer to this more cost-efficient and patient-friendly point through the use of nanotechnology.
Oral peptide based nanomedicine to treat a range of diseases
The pharmaceutical industry is increasingly reliant on the potency of biological molecules, including peptides, to treat complex diseases. However, a major limitation of these drugs is their dependence on injection. Oral drug administration on the other hand is the most effective delivery mechanism, with the highest rate of patient compliance: but barriers presented by the gastrointestinal ecosystem have proven difficult to surmount.

The EU-funded TRANS-INT (New Oral Nanomedicines: Transporting Therapeutic Macromolecules across the Intestinal Barrier) project set out to overcome these barriers by better understanding the underlying mechanisms involved. The team identified key properties of nanomaterials-intestinal interaction, including instability in enzyme-containing intestinal fluids, mucointeraction and trans-epithelial transport.

The resulting knowledge has generated prototype nanocarriers for oral drug delivery that overcome biological barriers, as well as formulations of peptide and protein drugs to treat diseases with high socioeconomic impact.

The nanocarrier prototypes

The gastrointestinal (GI) tract, as a whole, represents a very challenging barrier for the oral administration of peptides. Wrapping a peptide drug in a pH-sensitive formulation can ensure it passes through the stomach.

However, once the peptide molecules reach the small intestine they are very rapidly degraded into amino acids, leading to their inactivation. Even if peptide molecules could be protected from degradation, they would not be able to cross the intestinal mucosa due to their large size and hydrosolubility.

“Previously, efforts to use nanotechnology to enhance oral peptide delivery have been based on a trial and error approach,” explains project coordinator Professor Maria José Alonso. “This is because of limited information about the interaction of nanomaterials with the gastro-intestinal environment and insufficient research on peptide nano-encapsulation and controlled release. Our goal was to use this information to design oral peptide delivery nanocarriers, for local action either in the gut or through the blood-stream.”

To overcome these biological barriers TRANS-INT developed tailored nanocarriers by engineering the structural organisation of their selected components. For example, some of the customised nanocarriers contained penetration enhancers, such as cationic polymers and oligomers, surfactants and lipids. Others were protected with hydrophilic polymer coatings (e.g. polyethylene glycol) which avoided degradation of the peptide cargo by preventing interaction with enzymatic proteins, as well as facilitating muco-permeation.

Adjusting their size and composition modulated the interaction of the nanocarriers with the epithelial tissue. The team observed that the majority of the nanocarriers investigated have a low toxicity to cells, (cytotoxicity) and selected nanocarriers exhibited very low toxicity to the immune systems of mice.

Taking one set of experiments, TRANS-INT found that selected prototypes loaded with insulin exhibited good pharmacological responses in normal and diabetic rats. However, in most cases the response was variable and highly dependent on the experimental conditions (e.g. different animal models and protocols of administration). One formulation did give homogeneous and reproducible responses and is being further investigated in pigs.

These results point to the project’s central challenge of, “Conferring the nanocarriers with the desired properties that would enable them to overcome biological barriers and, at the same time, maintain a significant drug load with the necessary controlled release,” as Prof. Alonso summarises.

Getting to clinical development

The knowledge generated from the project is expected to help pharmaceutical researchers design more effective formulations for the peptide drugs in their pipelines.

As Prof. Alonso elaborates, “Chronic systemic diseases that could benefit from the technologies include diabetes, obesity and chronic pain, all three of which TRANS-INT studied. Additionally, in the near future the treatment of local diseases, such as intestinal bowel diseases, could benefit from targeted nanotechnology-based treatment.”

Taking project results to the next step, prototypes are currently undergoing preclinical development by TRANS-INT partners, in the hope that one can be selected for the clinical development of one or more oral peptide-based nanomedicines.

Related information


TRANS-INT, peptides, nanomedicine, oral, diabetes, obesity, chronic pain, diseases, epithelial tissue, prototype, gastro-intestinal, nanocarrier
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