Affiliation:
1. State Key Laboratory of Functions and Applications of Medicinal Plants College of Pharmacy Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D Guizhou Medical University Guiyang 550025 P. R. China
2. Department of Pharmacology School of Basic Medical Sciences & Department of Pharmacy Shanghai Pudong Hospital Fudan University Shanghai 200032 P. R. China
3. School of Pharmacy Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University) Ministry of Education Shanghai 201203 P. R. China
4. Department of Pharmacy Jing'an District Central Hospital of Shanghai Shanghai 200040 P. R. China
Abstract
AbstractOleanolic acid derivative DKS26 has hypolipidemic, islet, and hepatoprotective effects. However, high lipophilicity and low water solubility led to DKS26 extremely low oral bioavailability. Herein, lipid‐based nanocarriers, including lipid nanodiscs (sND/DKS26) and liposomes (sLip/DKS26), are prepared to improve DKS26 oral absorption. In comparison to free DKS26 (5.81%), the absolute oral bioavailabilities are 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 reduce the feeding glucose level and the AUC of OGTT in db/db diabetic mice. Aiding by the newly developed scFv‐based nanocarrier separation methods, no intact nanocarriers are detected in blood circulation after oral administration, suggesting that both formulations are unable to penetrate the intestinal epithelium. They enhance DKS26 absorption mainly by improving intestinal cell uptake and rapid intracellular release of the payload. Since pre‐existing anti‐PEG is widely detected in humans, the present oral absorption pathway of both nanocarriers successfully avoids 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.
Funder
National Natural Science Foundation of China
Subject
Pharmaceutical Science,Biomedical Engineering,Biomaterials
Cited by
3 articles.
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