Lipid-based Nanocarriers Enabled Oral Delivery of Oleanolic Acid Derivative DKS26 for Diabetes Management.

Oleanolic acid (OA, (3β)-3-hydroxy-oleanol-12-en-28-oic acid) derivative DKS26 has hypolipidemic, islet and hepatoprotective effects. However, high lipophilicity and low water solubility of DKS26 led to its extremely low oral bioavailability. Herein, lipid-based nanocarriers, including lipid nanodiscs (sND/DKS26) and liposomes (sLip/DKS26), were prepared to carry DKS26 for improved oral absorption. In comparison to free DKS26 (5.81%), the absolute oral bioavailability of both formulations was significantly increased to 29.47% (sND/DKS26) and 37.25% (sLip/DKS26) without detectable toxicity or immunogenicity even after repeated administrations. Both sND/DKS26 and sLip/DKS26 significantly reduced the feeding glucose level and the AUC of OGTT in db/db diabetic mice. Aiding by our newly developed scFv-based nanocarrier separation methods, we nearly did not detect intact nanocarriers in the blood circulation after oral administration, suggesting that both lipid-based formulations were unable to penetrate the intestinal epithelium as expected. They enhanced DKS26 absorption mainly by improving intestinal cells uptake and rapid intracellular release of the payload. Since pre-existing anti-PEG has been widely detected in human, the present oral absorption pathway of both lipid-based nanocarriers successfully avoided unfavorable immunological responses after interaction with anti-PEG antibodies. The application of lipid-based nanocarriers paves an efficient and safe avenue for the clinical translation and application of poorly soluble therapeutics derived from traditional Chinese medicine. This article is protected by copyright. All rights reserved.