EGFR Targeted Theranostic Nanoemulsion for Image-Guided Ovarian Cancer Therapy

Abstract

Purpose Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose-limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro-apoptotic agent, C6-ceramide. Methods The surface of the nanoemulsion is annotated with an endothelial growth factor receptor (EGFR) binding peptide to improve targeting ability and gadolinium to provide diagnostic capability for image-guided therapy of EGFR overexpressing ovarian cancers. A high shear microfludization process was employed to produce the formulation with particle size below 150 nm. Results Pharmacokinetic study showed a prolonged blood platinum and gadolinium levels with nanoemulsions in nu/nu mice. The theranostic nanoemulsions also exhibited less toxicity and enhanced the survival time of mice as compared to an equivalent cisplatin treatment. Conclusions Magnetic resonance imaging (MRI) studies indicate the theranostic nanoemulsions were effective contrast agents and could be used to track accumulation in a tumor. The MRI study additionally indicate that significantly more EGFR-targeted theranostic nanoemulsion accumulated in a tumor than non-targeted nanoemulsuion providing the feasibility of using a targeted theranostic agent in conjunction with MRI to image disease loci and quantify the disease progression.

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

“…However, the difference was statistically significant only in the A549-DDP model. These results confirm the influence of EGFR-peptide targeted nanoparticles to target the cancer cells, which is in agreement with previous studies from our group where the same peptide was successfully used [40,65,66].…”

In Vitro and In Vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers

“…We have developed a highly flexible stable oil in water nanoemulsion (NE) platform that fits all the required attributes for the clinical development of a theranostic approach suitable for treating ovarian cancer patients. [3][4][5] Using this NE platform, we designed and created stable NMI-500, a folate (FA) targeted theranostic that has the capacity to: carry a lethal payload of docetaxel (DTX); overcome ATP-binding cassette (ABC) gene family mediated drug efflux; [6][7][8][9][10][11] specifically interact with folate receptor-a (FR-a) which is commonly expressed on ovarian tumor cells; 11,12 and act as an MRI contrast agent so DTX pharmacodynamics and disease burden can be tracked by a non-invasive, clinically relevant imaging modality (Fig. S1).…”

“…S1). 4,5,13 FR-a is one of three isoforms of the folate receptor: a, b, & g. FR-a is a 38 kD glycosyl-phosphatidylinositolanchored glycoprotein that binds FA with a K d <1 nM, »10fold more affinity than the reduced form of FA and is highly expressed in a number of human cancers including ovarian, lung, breast, renal cell carcinoma, brain, and head & neck cancers. 14 FR-a mediates FA uptake through endocytosis, showing very high affinity but low capacity.…”

“…[6][7][8][9][10][11] We also showed that receptor mediated endocytosis of targeted NE annotated with MRI contrast agents results in enhanced specificity and accumulation in subcutaneous flank tumors more effectively than non-targeted NE. 5,11 This tumor accumulation can occur by either first or second order kinetics depending upon the nature of targeting ligand and the relative expression level of the cognate receptor on target and non-target tissue. 5,11 We demonstrated that having multiple ligands on a surface, NE changes the cognate receptor interactions from one driven by affinity to one Figure 1.…”

Application of nanomedicine for crossing the blood–brain barrier: Theranostic opportunities in multiple sclerosis

“…As a drug carrier, they have several advantages such as effective encapsulation, sustained drug release and long circulatory times. It is suggested that if targeting moieties such as folate (Patlolla & Vobalaboina 2008), thiamine , endothelial growth factor receptor (EGFR) binding peptide (Ganta et al 2015), mannose (Rutishauser & Gutknecht 1976), etc., to be anchored to the nano-emulsion, they can deliver their cargo with significantly higher efficiencies and remain longer at the disease site to allow for total transfer of the drug molecules. The size of nano-emulsions is <500 nm in diameter; these can successfully incorporate poorly soluble drugs (Ganta et al 2008;Vyas et al 2008).…”