Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer |
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| Authors: | Srinivas Ganta Amit Singh Yashesh Rawal Joseph Cacaccio Niravkumar R. Patel Praveen Kulkarni |
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| Affiliation: | 1. Nemucore Medical Innovations, Inc., Worcester, MA, USA,;2. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA,;3. Blue Ocean Biomanufacturing, Inc., Worcester, MA, USA,;4. Nemucore Medical Innovations, Inc., Worcester, MA, USA,;5. Blue Ocean Biomanufacturing, Inc., Worcester, MA, USA,;6. Center for Translational Imaging, Northeastern University, Boston, MA, USA,;7. Center for Translational Cancer Nanomedicine Northeastern University, Boston, MA, USA, and |
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| Abstract: | Objective: Ovarian cancer is a highly lethal disease in which the majority of patients eventually demonstrate multidrug resistance. Develop a novel active targeted theranostic nanomedicine designed to overcome drug efflux mechanisms, using a Generally Regarded As Safe (GRAS) grade nanoemulsion (NE) as a clinically relevant platform.Materials and methods: The NEs surface-functionalized with folate and gadolinium, were made using GRAS grade excipients and a high-shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3 and SKOV3TR. The NE accumulation in tumors was evaluated in SKOV3 tumor-bearing mice by magnetic resonance imaging (MRI).Results and discussion: The NE with particle size in vitro efficiently took up the non-targeted and folate-targeted NEs; improved cytotoxicity was observed for the folate-targeted NEs showing a 270-fold drop in the IC50 in SKOV3TR cells as compared to docetaxel alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist®. Folate-targeted NEs accumulated in tumors for prolonged period of time compared to Magnevist® and showed enhanced contrast compared to non-targeted NEs with MRI in SKOV3 tumor-bearing mice suggesting active targeting of NEs due to folate modification.Conclusions: A folate-targeted, theranostic NE delivers docetaxel by receptor mediated endocytosis that shows enhanced cytotoxicity capable of overcoming ABC transporter mediated taxane resistance. The diagnostic capability of the targeted nanomedicine showed enhanced contrast in tumors compared to clinically relevant MRI contrast agent Magnevist®. |
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| Keywords: | Docetaxel folate gadolinium MRI |
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