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Folate Receptor-Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer.
Folate Receptor-Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer. Molecular cancer therapeutics Paulmurugan, R., Bhethanabotla, R., Mishra, K., Devulapally, R., Foygel, K., Sekar, T. V., Ananta, J. S., Massoud, T. F., Joy, A. 2016; 15 (2): 221-231Abstract
Triple negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off target effects and poor bioavailability of the FDA approved anti-obesity 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 (NPs) 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 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 NPs 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.
View details for DOI 10.1158/1535-7163.MCT-15-0579
View details for PubMedID 26553061