Drug-loaded, block copolymer stabilized nanoemulsions/microbubbles combine properties of drug carriers and contrast agents. They can be used for tumor-targeted, image-guided ultrasound-enhanced tumor chemotherapy.

Ultrasound-induced tumor drug delivery systems must be stable in circulation, have a suitable circulation time, and be of a size that allows extravasation when responding to ultrasound.

The proposed novel tumor treatment modality provides for ultrasound and/or 19F MRI guided, ultrasound-mediated targeted chemotherapy of solid tumors. The developed formulations are ready for trials in large animals and clinical trials.
The formulations developed are extremely stable, echogenic (ultrasound responsive), reproducible, easy to manufacture and handle, biodegradable. The nanodroplet shell forming copolymers are in phase ll-lll clinical trials in the USA; one of the shell-forming copolymers has been approved and is in clinical use in Korea as micellar drug carrier. The technique may be used with commercially available therapeutic ultrasound instruments.
The formulations comprise stable drug-loaded perfluorocarbon nanoemulsions formed from drug-loaded polymeric micelles. The core of nanoemulsion droplets is formed by perfluoro-15-crown ether-5 (RFC) while the walls are formed by biodegradable block copolymers, poly(ethylene oxide)-co-polycaprolactone (PEG-PCL) or poly(ethylene oxide)-co-polylactide (PEG-PLA). The PFC core of nanodroplets has very high oxygen solubility. Under the action of ultrasound nanodroplets convert into nano- and microbubbles. The microbubbles oscillate and cavitate under the action of tumor directed low energy therapeutic ultrasound, which induces drug release from nanodroplets and enhances the intracellular drug uptake.
In the present embodiment, drug targeting is based on the enhanced permeability and retention (EPR) effect; however active targeting by surface modification of nanodroplets with relevant tumor ligands can be added as needed. A very effective ultrasound-mediated nanotherapy with paclitaxel-loaded PFC nanoemulsion was observed for a large breast cancer tumor grown in nu/nu mouse. If needed, the chemotherapy with these drug-loaded nanoemulsions may be combined with effective radiation therapy.

Pre-Clinical Validation

• Developed nanoemulsions formulations have high thermal stability, excellent shelf life, straightforward to manufacture and handle, echogenic, and biodigradable
• Ultrasound-mediated targeted chemotherapy of solid tumors
• Ultrasound and MRI imaging by using novel nanoemulsions
• The chemotherapy treatment using these drug-loaded nanoemulsions maybe combined with radiation therapy

Rapoport N, Nam KH, Gupta R, et al. Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. J Control Release. 2011;153(1):4-15. doi:10.1016/j.jconrel.2011.01.022

Rapoport N, Payne A, Dillon C, Shea J, Scaife C, Gupta R. Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model. J Ther Ultrasound. 2013;1:11. Published 2013 Jul 1. doi:10.1186/2050-5736-1-11

Publication Number: US-2011-0177005-A1
Patent Title: Stable Nanoemulsions for Ultrasound-Mediated Drug Delivery and Imaging
Jurisdiction/Country: United States
Application Type: Non-Provisional

Aaron Duffy
(801) 585-1377
aaron.duffy@utah.edu