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ABSTRACT
Ovarian cancer ranks fifth in cancer related deaths for women in USA. The high mortality rate associated with ovarian cancer is due to diagnosis at later stages of disease and the high recurrence rate of 60–80%. Recurrent ovarian cancers are more likely to present as multidrug resistance (MDR) leading to unfavorable response from 2nd and 3rd line chemotherapy. Nanoemulsions (NEs) are emerging as an attractive drug delivery system to overcome MDR challenges. NEs can also minimize exposure of therapeutic cargo to normal tissues potentially reducing side effects. In >80% of ovarian cancers, Folate Receptor-α (FR-α) is expressed at 10- to 100-fold higher levels than on non-pathological tissues. Therefore, folate (FA) is being evaluated as an active targeting moiety for FR-α+ ovarian cancer. To improve therapeutic outcome with reduced toxicity, we developed NMI-500, a FA targeted gadolinium (Gd) annotated NE loaded with docetaxel (DTX). NMI-500 has been developed as theranostic agents as Gd will enable physician to acquire real time pharmacodynamics data on NE + DTX accumulation in target lesions. In present study, characterization for key translational metrics of NMI-500 showed size distribution in range of 120 to 150 nm and zeta potential around −45 mV. Active targeting of FA was evaluated against FR-α+ KB cells and results demonstrated significant improvement in cell association which was surface ligand density dependent. We found that NMI-500 was able to inhibit tumor growth in a spontaneous transgenic ovarian cancer model with improved safety profile and this growth inhibition could be longitudinally followed by MRI. These results indicate NMI-500 warrants advancement to clinical trials.
Acknowledgments
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Awards Number R01 CA158881, Number U54 CA151881 and Nemucore Medical Innovations, Inc. This project was funded in part by R01 CA136596 (DCC) and the Fox Chase Cancer Center Core Grant NCI P30 CA006927, and utilized FCCC Laboratory Animal, Biological Imaging/Small Animal Imaging, Histopathology, Biosample Repository and Biostatistics Facilities. We would also like to thank you to the late Dr. Susan Keyes, Nicole Stephenson, Laurie Cote, Phil Heisler, Brian Zifcak and Keri Hetherman for the valuable discussions, technical writing, and administrative assistance.