title: Magnetic Drug Targeting: Preclinical in Vivo Studies, Mathematical Modeling, and Extrapolation to Humans.
abstract: A sound theoretical rationale for the design of a magnetic nanocarrier capable of magnetic capture in vivo after intravenous administration could help elucidate the parameters necessary for in vivo magnetic tumor targeting. In this work, we utilized our long-circulating polymeric magnetic nanocarriers, encapsulating increasing amounts of superparamagnetic iron oxide nanoparticles (SPIONs) in a biocompatible oil carrier, to study the effects of SPION loading and of applied magnetic field strength on magnetic tumor targeting in CT26 tumor-bearing mice. Under controlled conditions, the in vivo magnetic targeting was quantified and found to be directly proportional to SPION loading and magnetic field strength. Highest SPION loading, however, resulted in a reduced blood circulation time and a plateauing of the magnetic targeting. Mathematical modeling was undertaken to compute the in vivo magnetic, viscoelastic, convective, and diffusive forces acting on the nanocapsules (NCs) in accordance with the Nacev-Shapiro construct, and this was then used to extrapolate to the expected behavior in humans. The model predicted that in the latter case, the NCs and magnetic forces applied here would have been sufficient to achieve successful targeting in humans. Lastly, an in vivo murine tumor growth delay study was performed using docetaxel (DTX)-encapsulated NCs. Magnetic targeting was found to offer enhanced therapeutic efficacy and improve mice survival compared to passive targeting at drug doses of ca. 5-8 mg of DTX/kg. This is, to our knowledge, the first study that truly bridges the gap between preclinical experiments and clinical translation in the field of magnetic drug targeting.
authors.forename: Khuloud T
authors.initials: KT
authors.lastname: Al-Jamal
authors.forename: Jie
authors.initials: J
authors.lastname: Bai
authors.forename: Julie Tzu-Wen
authors.initials: JT
authors.lastname: Wang
authors.affiliation: Cardiovascular Division, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London, SE5 9NU, U.K.
authors.forename: Andrea
authors.initials: A
authors.lastname: Protti
authors.affiliation: Healthcare Biomagnetics Laboratory, University College London , 21 Albemarle Street, London W1S 4BS, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Southern
authors.affiliation: Healthcare Biomagnetics Laboratory, University College London , 21 Albemarle Street, London W1S 4BS, U.K.
authors.forename: Lara
authors.initials: L
authors.lastname: Bogart
authors.affiliation: Electron Microscopy for Materials Research (EMAT), University of Antwerp , Groenenborgerlaan 171, B-2020 Antwerp, Belgium.
authors.forename: Hamed
authors.initials: H
authors.lastname: Heidari
authors.forename: Xinjia
authors.initials: X
authors.lastname: Li
authors.forename: Andrew
authors.initials: A
authors.lastname: Cakebread
authors.forename: Dan
authors.initials: D
authors.lastname: Asker
authors.affiliation: Dr. W.T. Al-Jamal, School of Pharmacy, University of East Anglia , Norwich Research Park, Norwich NR4 7TJ, U.K.
authors.forename: Wafa T
authors.initials: WT
authors.lastname: Al-Jamal
authors.affiliation: Cardiovascular Division, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London, SE5 9NU, U.K.
authors.forename: Ajay
authors.initials: A
authors.lastname: Shah
authors.affiliation: Electron Microscopy for Materials Research (EMAT), University of Antwerp , Groenenborgerlaan 171, B-2020 Antwerp, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Bals
authors.forename: Jane
authors.initials: J
authors.lastname: Sosabowski
authors.affiliation: Healthcare Biomagnetics Laboratory, University College London , 21 Albemarle Street, London W1S 4BS, U.K.
authors.forename: Quentin A
authors.initials: QA
authors.lastname: Pankhurst
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D008279:Magnetic Resonance Imaging; D008280:Magnetics; D058185:Magnetite Nanoparticles; D051379:Mice; D008807:Mice, Inbred BALB C; D008962:Models, Theoretical; D053769:Nanocapsules; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D058185:Magnetite Nanoparticles; D053769:Nanocapsules
keywords: Polymeric nanocapsules; SPECT imaging; cancer therapy; nanomedicine; superparamagnetic iron oxide nanoparticles