Development of EGFR-Targeted Nanoemulsion for Imaging and Novel Platinum Therapy of Ovarian Cancer

Abstract

Purpose Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian cancers, but generalized toxicity and platinum resistance limits its use. Theranostic nanoemulsion with a novel platinum prodrug, myrisplatin, and the pro-apoptotic agent, C6-ceramide, were designed to overcome these limitations. Methods The nanoemulsions, including ones with an EGFR binding peptide and gadolinium, were made using generally regarded as safe grade excipients and a high shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3, A2780 and A2780CP. Results The nanoemulsion with particle size <150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and EGFR-targeted nanoemulsions; improved cytotoxicity was observed for the these nanoemulsions with the latter showing a 50-fold drop in the IC50 in SKOV3 cells as compared to cisplatin alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist®. Conclusion The myrisplatin/C6-ceramide nanoemulsion synergistically enhanced in vitro cytotoxicity. An EGFR binding peptide addition further increased in vitro cytotoxicity in EGFR positive cancer cells. The diagnostic version showed MR imaging similar to the clinically relevant Magnevist® and may be suitable as a theranostic for ovarian cancer.

EGFR Targeted Theranostic Nanoemulsion for Image-Guided Ovarian Cancer Therapy

“…A hydrophobic platinum conjugate, myrisplatin was synthesized at the Nemucore Medical Innovations, Inc., (Worcester, MA) using published routes (14, 26). Gadolinium chelate gadolinium-diethylenetriaminepentaacetic acid-phosphatidylethanolamine (gadolinium-DTPA-PE) to incorporate into nanoemulsions for MRI functionality was synthesized as described previously (14).…”

“…We recently reported novel hydrophobic platinum-derivatives by attaching myristic acid to cisplatin (myrisplatin) which was encapsulated in the oil core of a stable nanoemulsion (14). Nanoemulsions are colloidal carriers formed by dispersion of oils in water and stabilized with an amphiphilic phospholipid monolayer (15–19).…”

“…Theranostic nanoemulsions can be engineered to have these capabilities in an all-in-one platform, which include protection and controlled release of a therapeutic payload, targeted delivery and diagnostic functionality. Our nanoemulsions formulations can be surface annotated with gadolinium, a magnetic resonance imaging (MRI) contrast agent and has been shown to have relaxation times comparable to Magnevist ® (14, 20). Folate-targeted nanoemulsions accumulated in tumors for prolonged period of time compared to Magnevist ® and showed enhanced contrast compared to non-targeted nanoemulsions with MRI in SKOV-3 tumor-bearing mice suggesting active targeting of nanoemulsions due to folate modification (20).…”

“…In our previous work we developed a novel EGFR-targeted, gadolinium-annotated-theranostic nanoemulsions that co-delivers myrisplatin and C 6 -ceramide (a proapoptotic agent) which is capable of overcoming platinum resistance in vitro and is an effective contrast agent (14). In this paper we describe the initial translational studies articulating imaging, safety, and efficacy capacity of this novel theranostic nanoemulsion.…”

Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

“…Due to their high overexpression, they have been extensively used as cancer cell selective targeting receptor. We have previously used a synthetic 12 amino acids peptide that has demonstrated efficient targeting of EGFR receptor and its targeting capability has been successfully validated in vitro as well as in vivo in various EGFR-overexpressing tumor cells such as A549 [38][39][40][41][42][43]. Most importantly, this peptide is capable of inducing nanoparticles cellular uptake without activating EGFR signaling pathway and therefore was included as targeting ligand in our formulation approach [44].…”