Breakthrough in oral delivery of nanoparticles

Nanomedicine would be much more useful to treat non-life-threatening diseases if nanoparticle therapeutics could be administered in pill form, but oral delivery of nanoparticles is not yet possible because the intestine does not naturally transport particles across the epithelium and into the circulation. This major challenge has been a focus of decades of research, but so far, even the most effective strategies to promote uptake of nanoparticles by intestinal epithelia allow only small percentages of drug to reach the circulation (see this review).

One way to overcome limited alimentary uptake of nanoparticles would be to identify natural exceptions to the rule—large particles that are actively transported across intestinal epithelia—and attach the portion of the molecule that mediates uptake to nanoparticles. Omid Farokhzad’s group at Harvard has recently implemented this strategy to develop the most efficient approach yet introduced to deliver insulin orally. Not only is insulin an ideal drug to study oral delivery because of its rapid effects on blood sugar, but oral insulin capable of alleviating spikes in blood sugar would also represent a major public health breakthrough. While several pharmaceutical companies, including Oramed and Novo Nordisk, are developing oral formulations of insulin without nanoparticles (instead attaching polymers or surfactants to promote passive absorption), very small amounts are absorbed, so they are only useful as a means of slowing the onset of type 2 diabetes or as an adjunct to injected insulin.

Realizing that maternal antibodies (IgG) are actively taken up by the neonatal intestine to transfer immunity, the Harvard team attached the component of IgG that mediates this uptake (called Fc) to nanoparticles carrying insulin in their interior. This component binds to the neonatal Fc receptor, FcRn; others have used the same target to allow oral delivery of follicle-stimulating hormone (FSH, used in fertility treatments) by fusing Fc to the protein. The Farokhzad group chose instead to formulate insulin within nanoparticles to maximize the number of drug molecules transported per uptake event and to avoid genetic engineering, which could alter a therapeutic protein’s activity.

In the paper, published in Science Translational Medicine in late November, graduate student Eric Pridgen and colleagues observed a 30-45% decrease in blood glucose following oral administration of a standard insulin dose in biodegradable poly(lactic acid)–b-poly(ethylene glycol) (PLA-PEG) nanoparticles decorated with Fc. This effect is twice that of insulin delivered in non-targeted nanoparticles, which is surprising since intestinal FcRn expression decreases in adult mice. However, the group does provide evidence that uptake is mediated by FcRn: the hypoglycemic response to insulin delivered in targeted particles is half as strong in mice lacking the receptor. Since intestinal expression of FcRn in humans remains stable through adulthood, uptake of FcRn-targeted nanoparticles could be even more efficient in patients.

Since the hypoglycemic effect induced by FcRn-targeted particles is similar to that of the most widely used form of insulin, these findings seem very likely to lead to a new formulation of insulin, and possibly other protein drugs, for clinical use.