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Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity.
- Source :
-
Bioconjugate chemistry [Bioconjug Chem] 2017 Dec 20; Vol. 28 (12), pp. 2942-2953. Date of Electronic Publication: 2017 Nov 09. - Publication Year :
- 2017
-
Abstract
- Weakly basic drugs display poor solubility and tend to precipitate in the stomach's acidic environment causing reduced oral bioavailability. Tracing of these orally delivered therapeutic agents using molecular probes is challenged due to their poor absorption in the gastrointestinal tract (GIT). Therefore, we designed a gastric pH stable bile acid derived amphiphile where Tamoxifen (as a model anticancer drug) is conjugated to lithocholic acid derived phospholipid (LCA-Tam-PC). In vitro studies suggested the selective nature of LCA-Tam-PC for cancer cells over normal cells as compared to the parent drug. Fluorescent labeled version of the conjugate (LCA-Tam-NBD-PC) displayed an increased intracellular uptake compared to Tamoxifen. We then investigated the antitumor potential, toxicity, and median survival in 4T1 tumor bearing BALB/c mice upon LCA-Tam-PC treatment. Our studies confirmed a significant reduction in the tumor volume, tumor weight, and reduced hepatotoxicity with a significant increase in median survival on LCA-Tam-PC treatment as compared to the parent drug. Pharmacokinetic and biodistribution studies using LCA-Tam-NBD-PC witnessed the enhanced gut absorption, blood circulation, and tumor site accumulation of phospholipid-drug conjugate leading to improved antitumor activity. Therefore, our studies revealed that conjugation of chemotherapeutic/imaging agents to bile acid phospholipid can provide a new platform for oral delivery and tracing of chemotherapeutic drugs.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Antineoplastic Agents toxicity
Biological Availability
Humans
Hydrophobic and Hydrophilic Interactions
MCF-7 Cells
Mice
Mice, Inbred BALB C
Tamoxifen chemistry
Tamoxifen pharmacokinetics
Tamoxifen pharmacology
Tamoxifen toxicity
Tissue Distribution
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacokinetics
Diagnostic Imaging methods
Lithocholic Acid chemistry
Liver drug effects
Phospholipids chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4812
- Volume :
- 28
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Bioconjugate chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29083862
- Full Text :
- https://doi.org/10.1021/acs.bioconjchem.7b00564