title: Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound.
abstract: OBJECTIVE
  Objectives of this study were to: 1) develop iLTSL, a low temperature sensitive liposome co-loaded with an MRI contrast agent (ProHance® Gd-HP-DO3A) and doxorubicin, 2) characterise doxorubicin and Gd-HP-DO3A release from iLTSL and 3) investigate the ability of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) to induce and monitor iLTSL content release in phantoms and in vivo.
  
  
  METHODS
  iLTSL was passively loaded with Gd-HP-DO3A and actively loaded with doxorubicin. Doxorubicin and Gd-HP-DO3A release was quantified by fluorescence and spectroscopic techniques, respectively. Release with MR-HIFU was examined in tissue-mimicking phantoms containing iLTSL and in a VX2 rabbit tumour model.
  
  
  RESULTS
  iLTSL demonstrated consistent size and doxorubicin release kinetics after storage at 4°C for 7 days. Release of doxorubicin and Gd-HP-DO3A from iLTSL was minimal at 37°C but fast when heated to 41.3°C. The magnitude of release was not significantly different between doxorubicin and Gd-HP-DO3A over 10 min in HEPES buffer and plasma at 37°, 40° and 41.3°C (p > 0.05). Relaxivity of iLTSL increased significantly (p < 0.0001) from 1.95 ± 0.05 to 4.01 ± 0.1 mMs⁻¹ when heated above the transition temperature. Signal increase corresponded spatially and temporally to MR-HIFU-heated locations in phantoms. Signal increase was also observed in vivo after iLTSL injection and after each 10-min heating (41°C), with greatest increase in the heated tumour region.
  
  
  CONCLUSIONS
  An MR imageable liposome formulation co-loaded with doxorubicin and an MR contrast agent was developed. Stability, imageability, and MR-HIFU monitoring and control of content release suggest that MR-HIFU combined with iLTSL may enable real-time monitoring and spatial control of content release.
authors.affiliation: Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ayele H
authors.initials: AH
authors.lastname: Negussie
authors.forename: Pavel S
authors.initials: PS
authors.lastname: Yarmolenko
authors.forename: Ari
authors.initials: A
authors.lastname: Partanen
authors.forename: Ashish
authors.initials: A
authors.lastname: Ranjan
authors.forename: Genevieve
authors.initials: G
authors.lastname: Jacobs
authors.forename: David
authors.initials: D
authors.lastname: Woods
authors.forename: Henry
authors.initials: H
authors.lastname: Bryant
authors.forename: David
authors.initials: D
authors.lastname: Thomasson
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Wood
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dreher
mesh_terms: D000818:Animals; D003287:Contrast Media; D004317:Doxorubicin / Q000008:administration & dosage; D005682:Gadolinium; D006571:Heterocyclic Compounds; D006801:Humans; D007700:Kinetics; D008081:Liposomes / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging / Q000379:methods; D053783:Magnetic Resonance Imaging, Interventional; D009942:Organometallic Compounds; D019047:Phantoms, Imaging; D011817:Rabbits; D018084:Ultrasonography, Interventional / Q000379:methods
chemical_list: D003287:Contrast Media; D006571:Heterocyclic Compounds; D008081:Liposomes; D009942:Organometallic Compounds; C062402:gadoteridol; D004317:Doxorubicin; D005682:Gadolinium