title: Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions.
abstract: Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or (19)F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent hard to control phenomenon of irreversible droplet-to-bubble transition upon injection. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. PFCE nanodroplets manifest both ultrasound and fluorine ((19)F) MR contrast properties, which allows using multimodal imaging and (19)F MR spectroscopy for monitoring nanodroplet pharmacokinetics and biodistribution. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. As manifested by the (19)F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation 2h after the systemic injection. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to-bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization of nanodroplets underwent stable cavitation. The nanodroplet size (200nm to 350nm depending on a type of the shell and conditions of emulsification) as well as long residence in circulation favored their passive accumulation in tumor tissue that was confirmed by ultrasonography. In the breast and pancreatic cancer animal models, ultrasound-mediated therapy with paclitaxel-loaded PFCE nanoemulsions showed excellent therapeutic properties characterized by tumor regression and suppression of metastasis. Anticipated mechanisms of the observed effects are discussed.
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA. natasha.rapoport@utah.edu
authors.forename: Natalya
authors.initials: N
authors.lastname: Rapoport
authors.forename: Kweon-Ho
authors.initials: KH
authors.lastname: Nam
authors.forename: Roohi
authors.initials: R
authors.lastname: Gupta
authors.forename: Zhongao
authors.initials: Z
authors.lastname: Gao
authors.forename: Praveena
authors.initials: P
authors.lastname: Mohan
authors.forename: Allison
authors.initials: A
authors.lastname: Payne
authors.forename: Nick
authors.initials: N
authors.lastname: Todd
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Taeho
authors.initials: T
authors.lastname: Kim
authors.forename: Jill
authors.initials: J
authors.lastname: Shea
authors.forename: Courtney
authors.initials: C
authors.lastname: Scaife
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Parker
authors.forename: Eun-Kee
authors.initials: EK
authors.lastname: Jeong
authors.forename: Anne M
authors.initials: AM
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000628:therapy; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions / Q000737:chemistry; D005260:Female; D005466:Fluorocarbons / Q000737:chemistry*; D006801:Humans; D051379:Mice; D050997:Nanomedicine / Q000379:methods; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000628:therapy; D014464:Ultrasonic Therapy / Q000379:methods*; D014463:Ultrasonography
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004655:Emulsions; D005466:Fluorocarbons; D017239:Paclitaxel