Tamoxifen-Phospholipid Conjugate: A Promising Anticancer Therapeutic with Improved Antitumor Activity and Reduced Liver Toxicity.

Gynecological cancers such as breast cancer is rapidly rising in India. Surgical resection of breast tumors is the main form of therapy. To reduce the recurrence of tumors in breast cancer patients, Tamoxifen (anticancer drug) is administered daily as oral tablets up to 1-2 years. Acidic pH of stomach precipitates the Tamoxifen, thereby requiring frequent doses of Tamoxifen. Moreover, long-term treatment schedules of Tamoxifen induce hepatotoxicity.

Dr. Avinash Bajaj’s team developed phospholipid drug conjugate technology in which bio-relevant phospholipids were conjugated with anticancer drugs to improve their therapeutic efficiency and to reduce their toxicology. They used body’s own bile acid lipids and derivatized them to bile acid-phospholipids. In this work, authors conjugated Tamoxifen with lithocholic acid phospholipid with amide bond to improve its gastrointestinal pH stability based on the hypothesis that bile acid phospholipid would improve the gastro-intestinal absorption of drug. They also conjugated a fluorophore to the tamoxifen-phospholipid conjugate for tracing of the drug in blood and body tissues. Their team in collaboration with Dr. Sagar Sengupta from National Institute of Immunology showed that conjugation of Tamoxifen to phospholipid increased the drug concentration in blood plasma with two-fold increase in the drug entrapment at tumor sites. In mouse breast cancer model, Phospholipid-Tamoxifen conjugate regressed the tumor more effectively over parent drug; and improved the survivability of the mice. Interestingly, conjugation also resulted in normal levels of hepatic enzymes whereas tamoxifen caused the severe liver toxicity. Therefore, this study provides the evidence for use of bile acid derived phospholipids to engineer future cancer therapies.

For More Details: Title: Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

Bioconjugate Chem., 2017, (DOI: 10.1021/acs.bioconjchem.7b00564).