{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:21:47Z","timestamp":1792758107917,"version":"4.5.0"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: The therapeutic potential of many natural products, including curcumin (CUR), betulinic acid (BA), and oleanolic acid (OA), is limited by poor oral exposure caused by low aqueous solubility, metabolic instability, and\/or first-pass metabolism. Lipid\u2013drug conjugate (LDC) strategies that mimic endogenous dietary lipid processing may provide a useful approach for improving oral absorption and lymphatic transport. Methods: A 1,3-diolein-based lipidic promoiety (IN-4) was synthesized and conjugated to curcumin, betulinic acid, and oleanolic acid to generate three representative LDCs: CUR-PRO, BA-PRO, and OA-PRO. Their oral pharmacokinetic behavior was evaluated in rats. For CUR-PRO, matched-vehicle comparisons across three oral vehicles were performed, together with mesenteric lymph duct cannulation and in vitro stability\/conversion studies in simulated gastrointestinal media, rat liver microsomes, and rat plasma. Results: All three prodrugs were successfully synthesized and showed improved systemic exposure to the corresponding parent-drug-related analytes under the tested conditions. For CUR-PRO, dose-normalized AUC0-last of released curcumin was markedly higher than direct curcumin administration across all three vehicles (increases of 15.0-, 70.9-, and 54.3-fold), and intact CUR-PRO was also detected in plasma. Mesenteric lymph sampling showed that CUR-PRO dosing, but not free-curcumin dosing, generated detectable curcumin-related signals under the present analytical conditions. In vitro, no free curcumin was detected during CUR-PRO incubation in enzyme-free simulated gastrointestinal media; CUR-PRO underwent rapid depletion in pancreatic-lipase-supplemented medium, showed greater microsomal stability than curcumin, and displayed plasma conversion that was markedly accelerated by exogenous LPL. BA-PRO and OA-PRO also increased systemic exposure of their released parent drugs, with 16.0- and 38.4-fold dose-normalized AUC0-last increases, respectively. Conclusions: These findings provide proof-of-concept evidence that 1,3-diolein-based lipidation can improve the oral exposure of selected poorly water-soluble natural products. The lymphatic transport data provide qualitative evidence supporting lymphatic access of CUR-PRO, although the quantitative contribution of this pathway to the overall exposure increase remains to be established.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070899","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T13:25:46Z","timestamp":1784726746000},"page":"899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Enhancing Oral Bioavailability of Poorly Water-Soluble Natural Products via Lipid\u2013Drug Conjugates"],"prefix":"10.3390","volume":"18","author":[{"given":"Xiaoli","family":"Zou","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Suzhou Institute of Materia Medica, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Suzhou Institute of Materia Medica, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianghe","family":"Mei","sequence":"additional","affiliation":[{"name":"Suzhou Institute of Materia Medica, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sifei","family":"Han","sequence":"additional","affiliation":[{"name":"Suzhou Institute of Materia Medica, Suzhou 215123, China"},{"name":"School of Pharmacy, China Pharmaceutical University, 24 Tongjia Lane, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixian","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Suzhou Institute of Materia Medica, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20723","DOI":"10.1021\/acs.jmedchem.4c02736","article-title":"Natural products driven medicinal chemistry","volume":"67","author":"Bharate","year":"2024","journal-title":"J. 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