ArticleJournal of controlled release : official journal of the Controlled Release Society2018
Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system.
Article in Journal of controlled release : official journal of the Controlled Release Society, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 57 citations in OpenAlex.
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- 2-Monoacylglycerol Mimetic Liposomes to Promote Intestinal Lymphatic Transport for Improving Oral Bioavailability of Dihydroartemisinin.International journal of nanomedicine · 2024Article
- Engineering of small-molecule lipidic prodrugs as novel nanomedicines for enhanced drug delivery.Journal of nanobiotechnology · 2022Review
- Lipophilic Conjugates of Drugs: A Tool to Improve Drug Pharmacokinetic and Therapeutic Profiles.Pharmaceutical research · 2021Review
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- An update on oral drug deliveryActa pharmaceutica Sinica. B · 2021Review
- Oral SMEDDS promotes lymphatic transport and mesenteric lymph nodes target of chlorogenic acid for effective T-cell antitumor immunity.Journal for immunotherapy of cancer · 2021Article
- Oral administration of tipranavir with long-chain triglyceride results in moderate intestinal lymph targeting but no efficient delivery to HIV-1 reservoir in mesenteric lymph nodes.International journal of pharmaceutics · 2021Article
- Strawberry Decreases Intraluminal and Intestinal Wall Hydrolysis of Testosterone Undecanoate.Molecules (Basel, Switzerland) · 2021Article
- The Interplay Between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and Its Implications for Cannabidiol Oral Formulations.Clinical pharmacokinetics · 2020Article
- Lymphatic Transport of Drugs after Intestinal Absorption: Impact of Drug Formulation and Physicochemical Properties.Pharmaceutical research · 2020Article
- Critical Aspects Affecting Cannabidiol Oral Bioavailability and Metabolic Elimination, and Related Clinical Implications.CNS drugs · 2020Review
- Synthesis of a long acting nanoformulated emtricitabine ProTide.Biomaterials · 2019Article
- A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin.Scientific reports · 2019Article
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Authors and funding
28 authors at 5 institutions in 5 countries.
Funding
Abstract
The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.
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