Biopharmaceutical Parameters to Consider in Order to Alter the Fate of Nanocarriers after Oral Delivery

Emilie Roger; Frederic Lagarce; Emmanuel Garcion; Jean-Pierre Benoit


Nanomedicine. 2012;5(2):287-306. 

In This Article

Conclusion & Future Perspective

There are two main challenges of drug delivery via the oral route:

  • To enhance the bioavailability of drugs;

  • To target distant pharmacological receptors after absorption.

To address the issue of bioavailability, the integrity of the nanocarriers is not requested. One of the best example was shown by Leroux et al. with Eudragit L100–55 nanoparticles, which released the drug CGP 57813 instantly at pH 5.5 and increased its relative bioavailability in comparison to Eudragit S100 particles displaying a slower dissolution rate.[196] Moreover, the formulation of bioadhesive nanoparticles help them to remain in the GI tract and locally release the encapsulated drug, thus providing a better probability for absorption. As stated by the biopharmaceutics classification system,[197] the most important parameters to consider for absorption are permeability and dissolution rate of the drug. As shown in the present paper, nanocarriers can have a significant impact on these properties. For a drug belonging to biopharmaceutics classification system class II (high permeability, low solubility) or class IV (low permeability, low solubility), the dispersion of the drug in nanosized drug delivery systems is a solution to enhance absorption, effectively and with relative simplicity. As a matter of fact, in this case the carrier has not to be functionalized using surface treatment. To increase the permeability, the positive charge and the nature of the nanocarrier seem important to consider in combination with molecular moieties that will serve for specific recognition and transport. PEG, PLGA and chitosan coatings have been used with success for enhancing permeability and uptake via enterocytes. Tomato lectins and WGA are promising ligands to facilitate the uptake by enterocytes. Further work is required to identify specific targets on the surface of the enterocytes that will increase the internalization of the carrier or the encapsulated drug in the cells.

The second challenge is to target distant pharmacological receptors via the oral route. In this case the integrity of the nanocarrier has to remain to provide specific properties such as stealthiness, controlled release of the drug, targeting of the organs. To date, no such nanoparticles have been described. Indeed, this tricky issue is to formulate a nanovector able to resist the stress of GI tract while also being capable of transcytosis and finally being able to avoid or resist the destruction by the liver during the first-pass effect. In this paper, different components able to resist the physicochemical stress have been reviewed (PEG, PLGA and chitosan). They display complementary properties and can be mixed to obtain optimal behavior. The main issue is transcytosis through enterocyte. The cellular trafficking of nanocarriers across enterocyte is poorly documented and appears to be critical in the design of new active nanovector for the oral route. For example, those carriers need to escape lysosomal degradation and avoid recycling endosomal pathways. Thus, among the described pathways, the caveolae endocytosis reaching caveosomes, appears to be the most appropriate. Unfortunately, the specific ligands to target this pathway remain to be discovered.

Even if a ligand is found, the problem remains very complex. For example, vitamin B12 recognize a glycoprotein called cubulin on the surface of enterocyte to proceed to transcytosis.[198] As this mechanism may be interesting for transcytosis targeting through nanocarrier across enterocytes it may also alter targeting within the blood due to recognition signal (initially for cubulin) used on their surface.

Thus, one of the main problems with nanocarrier design remains in the fact that intrinsic properties that may help to cross GI barrier may also significantly alter further behavior in the blood.

Until recently, oral drug delivery was mainly assessed on the basis of overall drug permeability through the GI epithelium. Bioavailability was the main issue to address. Currently, designing the 'magic bullet' for the oral route is the next milestone to reach. Using smart nanocarriers able to improve solubility of drug while conveying them to specific targets involves rationalization of their behavior within specific GI micro- or nano-environments to determine the exact relevance for each of them. Although the overall idea is not necessarily to keep full integrity of the nanocarrier used for oral drug delivery, as drug bioavailability might be improved independently, keeping properties of nanocarriers as if they were used through the blood pathway represent a great advantage.


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