Nanoparticulate technologies are receiving interest for their ability to enable oral peptide delivery to the brain. The pharmaceutical
industry, driven by the medical and clinical success of intravenously administered biologics, is increasingly accepting more
complex brain and peptide drug-delivery systems to enter niche treatment markets and address the growing need for brain therapeutics.
The translation of a technology for oral peptide delivery to the brain can provide an answer to a therapeutic field with unmet
For oral to brain peptide delivery, the focus has been on delivering endogenous opioid peptides and their analogs for the
treatment of neuropathic and chronic pain. The first reported strategy able to deliver peptides orally involved a leucine-enkephalin
synthetic analogue (dalargin) encapsulated in polybutylcyanoacrylate nanoparticles overcoated with polysorbate 80 (32), and
in some cases, overcoated with polysorbate 80 and polyethylene glycol (20 kDa) (33). However, the technology has not yet progressed
into Phase I studies.
On the other hand, Nanomerics has announced that its nanotechnology-enabled peptide pill (METDoloron) involving the molecular-envelope
technology (MET) will be moving into Phase I clinical trials within the next two years (34). The technology is based on an
engineered amphiphilic chitosan polymer (i.e., quaternary ammonium palmitoyl glycol chitosan) tailored to form nanoscale polymeric
aggregates that are able to package or specifically interact (covalently and noncovalently) with peptides (13).
Preclinical studies showed successful delivery of leucine-enkephalin across the BBB with significantly higher pharmaco-kinetic
amounts (i.e., a 67% increase in plasma levels [AUC0–24] and a 57% increase in brain maximum concentration [Cmax]). Moreover, significant enhancement of pharmacodynamic activity in a pain animal model was observed (13). Combining the
molecular-envelope technology with a prodrug lipidization strategy of leucine-enkephalin potentiated the oral antinociceptive
effect, leading to analgesia lasting more than eight hours after oral administration, accompanied with significant enhancements
in brain bioavailability (13).
The commercialization of peptides as oral therapies is still deemed risky by the biopharmaceutical industry. However, the
reward of niche treatment market areas will fuel the development of a peptide pill enabled by nanotechnology either alone,
or combined with chemical modification (lipidization, cyclization) or other formulation strategies (controlled-release polymer
coating, permeation enhancers, protease inhibitors).