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 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.

Gemcitabine and Antisense-microRNA Co-encapsulated PLGA–PEG Polymer Nanoparticles for Hepatocellular Carcinoma Therapy

“…11,12 The advantages of NP-mediated drug delivery methods include their ability to modify the pharmacological effect, pharmacokinetics, bioavailability, bio-distribution, extended circulation time of drugs, and drug targeting to the site of action. 13,14 …”

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer

“…These results suggest that at 240 mg/kg, therapeutic effective dose could be achieved in plasma; however, this must be confirmed by pharmacokinetic studies. Notably, new formulations of micellar nanoparticles of orlistat for cancer treatment are in development (21), as the systemic levels of orlistat used orally for obesity are <10 ng/ml (0.02 µM) due to its poor absorption (22). For determining the dose of LND and DON used in mice, the human dose (10) was translated to a mouse dose, which is also an approximation.…”

Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines

“…However, it is difficult to make a direct comparison of drug dosage between in vitro and human studies. Recent efforts have been made to increase the bioavailability of orlistat through novel delivery methods such as micellar nanoparticles, which has been shown to increase water solubility of orlistat and increase the drug's antitumor properties in vitro and in mouse models [32,33].…”