title: Alginate Microspheres Containing Temperature Sensitive Liposomes (TSL) for MR-Guided Embolization and Triggered Release of Doxorubicin.
abstract: OBJECTIVE
  The objective of this study was to develop and characterize alginate microspheres suitable for embolization with on-demand triggered doxorubicin (DOX) release and whereby the microspheres as well as the drug releasing process can be visualized in vivo using MRI.
  
  
  RESULTS
  For this purpose, barium crosslinked alginate microspheres were loaded with temperature sensitive liposomes (TSL/TSL-Ba-ms), which release their payload upon mild hyperthermia. These TSL contained DOX and [Gd(HPDO3A)(H2O)], a T1 MRI contrast agent, for real time visualization of the release. Empty alginate microspheres crosslinked with holmium ions (T2* MRI contrast agent, Ho-ms) were mixed with TSL-Ba-ms to allow microsphere visualization. TSL-Ba-ms and Ho-ms were prepared with a homemade spray device and sized by sieving. Encapsulation of TSL in barium crosslinked microspheres changed the triggered release properties only slightly: 95% of the loaded DOX was released from free TSL vs. 86% release for TSL-Ba-ms within 30 seconds in 50% FBS at 42°C. TSL-Ba-ms (76 ± 41 μm) and Ho-ms (64 ± 29 μm) had a comparable size, which most likely will result in a similar in vivo tissue distribution after an i.v. co-injection and therefore Ho-ms can be used as tracer for the TSL-Ba-ms. MR imaging of a TSL-Ba-ms and Ho-ms mixture (ratio 95:5) before and after hyperthermia allowed in vitro and in vivo visualization of microsphere deposition (T2*-weighted images) as well as temperature-triggered release (T1-weighted images). The [Gd(HPDO3A)(H2O)] release and clusters of microspheres containing holmium ions were visualized in a VX2 tumor model in a rabbit using MRI.
  
  
  CONCLUSIONS
  In conclusion, these TSL-Ba-ms and Ho-ms are promising systems for real-time, MR-guided embolization and triggered release of drugs in vivo.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Merel
authors.initials: M
authors.lastname: van Elk
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Burcin
authors.initials: B
authors.lastname: Ozbakir
authors.affiliation: Imaging Division, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Angelique D
authors.initials: AD
authors.lastname: Barten-Rijbroek
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Nijsen
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Tina
authors.initials: T
authors.lastname: Vermonden
authors.affiliation: Imaging Division, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Deckers
mesh_terms: D000464:Alginates / Q000737:chemistry*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage*; D004621:Embolization, Therapeutic; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D008081:Liposomes; D008279:Magnetic Resonance Imaging; D008863:Microspheres; D011817:Rabbits; D013696:Temperature
chemical_list: D000464:Alginates; D000903:Antibiotics, Antineoplastic; D006603:Hexuronic Acids; D008081:Liposomes; D004317:Doxorubicin; D020723:Glucuronic Acid