Folate Receptor-Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer.

Abstract

Triple-negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off-target effects and poor bioavailability of the FDA-approved antiobesity drug orlistat hinder its clinical translation as a repurposed new drug against TNBC. Here, we demonstrate a newly engineered drug formulation for packaging orlistat tailored to TNBC treatment. We synthesized TNBC-specific folate receptor-targeted micellar nanoparticles (NP) carrying orlistat, which improved the solubility (70-80 μg/mL) of this water-insoluble drug. The targeted NPs also improved the delivery and bioavailability of orlistat to MDA-MB-231 cells in culture and to tumor xenografts in a nude mouse model. We prepared HEA-EHA copolymer micellar NPs by copolymerization of 2-hydroxyethylacrylate (HEA) and 2-ethylhexylacrylate (EHA), and functionalized them with folic acid and an imaging dye. Fluorescence-activated cell sorting (FACS) analysis of TNBC cells indicated a dose-dependent increase in apoptotic populations in cells treated with free orlistat, orlistat NPs, and folate-receptor-targeted Fol-HEA-EHA-orlistat NPs in which Fol-HEA-EHA-orlistat NPs showed significantly higher cytotoxicity than free orlistat. In vitro analysis data demonstrated significant apoptosis at nanomolar concentrations in cells activated through caspase-3 and PARP inhibition. In vivo analysis demonstrated significant antitumor effects in living mice after targeted treatment of tumors, and confirmed by fluorescence imaging. Moreover, folate receptor-targeted Fol-DyLight747-orlistat NP-treated mice exhibited significantly higher reduction in tumor volume compared to control group. Taken together, these results indicate that orlistat packaged in HEA-b-EHA micellar NPs is a highly promising new drug formulation for TNBC therapy. Mol Cancer Ther; 15(2); 221-31. ©2015 AACR.

• Authors: Ramasamy Paulmurugan, Rohith Bhethanabotla, Kaushik Mishra, Rammohan Devulapally, Kira Foygel, Thillai V Sekar, Jeyarama S Ananta, Tarik F Massoud, Abraham Joy
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 2 Pg. 221-31 (Feb 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 26553061 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Lactones
• Micelles
• Folic Acid
• Orlistat

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Packaging
• Drug Repositioning
• Folic Acid (chemistry)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lactones (administration & dosage, chemistry, pharmacology)
• Mice
• Mice, Nude
• Micelles
• Nanoparticles (administration & dosage, chemistry)
• Orlistat
• Triple Negative Breast Neoplasms (drug therapy)