title: Sonoporation enhances liposome accumulation and penetration in tumors with low EPR.
abstract: The Enhanced Permeability and Retention (EPR) effect is a highly variable phenomenon. To enhance EPR-mediated passive drug targeting to tumors, several different pharmacological and physical strategies have been evaluated over the years, including e.g. TNFα-treatment, vascular normalization, hyperthermia and radiotherapy. Here, we systematically investigated the impact of sonoporation, i.e. the combination of ultrasound (US) and microbubbles (MB), on the tumor accumulation and penetration of liposomes. Two different MB formulations were employed, and their ability to enhance liposome accumulation and penetration was evaluated in two different tumor models, which are both characterized by relatively low levels of EPR (i.e. highly cellular A431 epidermoid xenografts and highly stromal BxPC-3 pancreatic carcinoma xenografts). The liposomes were labeled with two different fluorophores, enabling in vivo computed tomography/fluorescence molecular tomography (CT-FMT) and ex vivo two-photon laser scanning microscopy (TPLSM). In both models, in spite of relatively high inter- and intra-individual variability, a trend towards improved liposome accumulation and penetration was observed. In treated tumors, liposome concentrations were up to twice as high as in untreated tumors, and sonoporation enhanced the ability of liposomes to extravasate out of the blood vessels into the tumor interstitium. These findings indicate that sonoporation may be a useful strategy for improving drug targeting to tumors with low EPR.
authors.affiliation: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Aachen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Theek
authors.affiliation: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Aachen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Baues
authors.affiliation: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Aachen, Germany.
authors.forename: Tarun
authors.initials: T
authors.lastname: Ojha
authors.affiliation: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Aachen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Möckel
authors.affiliation: Institute for Laboratory Animal Science, University Clinic, RWTH-Aachen University, Aachen, Germany.
authors.forename: Seena Koyadan
authors.initials: SK
authors.lastname: Veettil
authors.affiliation: Institute for Laboratory Animal Science, University Clinic, RWTH-Aachen University, Aachen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Steitz
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: van Bloois
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Aachen, Germany. Electronic address: fkiessling@ukaachen.de.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Aachen, Germany; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands. Electronic address: tlammers@ukaachen.de.
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D064593:Heterografts; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D045423:Microbubbles / Q000627:therapeutic use*; D053758:Nanoparticles / Q000737:chemistry; D061848:Optical Imaging / Q000379:methods; D010539:Permeability; D011108:Polymers / Q000737:chemistry; D013499:Surface Properties; D014057:Tomography, X-Ray Computed; D000069453:Ultrasonic Waves
chemical_list: D005456:Fluorescent Dyes; D008081:Liposomes; D011108:Polymers
keywords: EPR; Liposomes; Microbubbles; Sonoporation; Ultrasound