title: 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.affiliation: Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California. paulmur8@stanford.edu.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Paulmurugan
authors.affiliation: Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: Rohith
authors.initials: R
authors.lastname: Bhethanabotla
authors.affiliation: Department of Polymer Science, University of Akron, Akron, Ohio.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Mishra
authors.affiliation: Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: Rammohan
authors.initials: R
authors.lastname: Devulapally
authors.affiliation: Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: Kira
authors.initials: K
authors.lastname: Foygel
authors.affiliation: Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: Thillai V
authors.initials: TV
authors.lastname: Sekar
authors.affiliation: Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: Jeyarama S
authors.initials: JS
authors.lastname: Ananta
authors.affiliation: Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: Tarik F
authors.initials: TF
authors.lastname: Massoud
authors.affiliation: Department of Polymer Science, University of Akron, Akron, Ohio.
authors.forename: Abraham
authors.initials: A
authors.lastname: Joy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004349:Drug Packaging; D058492:Drug Repositioning; D005492:Folic Acid / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D000077403:Orlistat; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D008823:Micelles; D005492:Folic Acid; D000077403:Orlistat