Alginate microspheres containing temperature sensitive liposomes (TSL) for MR-guided embolization and triggered release of doxorubicin

M. van Elk, B. Ozbakir, A.D. Barten-Rijbroek, Gerrit Storm, F. Nijsen, W.E. Hennink, T. Vermonden, R. Deckers

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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. Methods and Findings 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.
Original languageEnglish
Article numbere141626
Pages (from-to)e0141626-
JournalPLoS ONE
Volume10
Issue number11
DOIs
Publication statusPublished - 2015

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doxorubicin
alginates
Microspheres
Liposomes
Doxorubicin
Temperature
temperature
Magnetic resonance imaging
holmium
Holmium
barium
Visualization
Barium
alginic acid
Contrast Media
fever
Fever
Ions
ions
drugs

Keywords

  • METIS-315213
  • IR-99650

Cite this

van Elk, M., Ozbakir, B., Barten-Rijbroek, A. D., Storm, G., Nijsen, F., Hennink, W. E., ... Deckers, R. (2015). Alginate microspheres containing temperature sensitive liposomes (TSL) for MR-guided embolization and triggered release of doxorubicin. PLoS ONE, 10(11), e0141626-. [e141626]. https://doi.org/10.1371/journal.pone.0141626
van Elk, M. ; Ozbakir, B. ; Barten-Rijbroek, A.D. ; Storm, Gerrit ; Nijsen, F. ; Hennink, W.E. ; Vermonden, T. ; Deckers, R. / Alginate microspheres containing temperature sensitive liposomes (TSL) for MR-guided embolization and triggered release of doxorubicin. In: PLoS ONE. 2015 ; Vol. 10, No. 11. pp. e0141626-.
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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. Methods and Findings 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.",
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van Elk, M, Ozbakir, B, Barten-Rijbroek, AD, Storm, G, Nijsen, F, Hennink, WE, Vermonden, T & Deckers, R 2015, 'Alginate microspheres containing temperature sensitive liposomes (TSL) for MR-guided embolization and triggered release of doxorubicin' PLoS ONE, vol. 10, no. 11, e141626, pp. e0141626-. https://doi.org/10.1371/journal.pone.0141626

Alginate microspheres containing temperature sensitive liposomes (TSL) for MR-guided embolization and triggered release of doxorubicin. / van Elk, M.; Ozbakir, B.; Barten-Rijbroek, A.D.; Storm, Gerrit; Nijsen, F.; Hennink, W.E.; Vermonden, T.; Deckers, R.

In: PLoS ONE, Vol. 10, No. 11, e141626, 2015, p. e0141626-.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Alginate microspheres containing temperature sensitive liposomes (TSL) for MR-guided embolization and triggered release of doxorubicin

AU - van Elk, M.

AU - Ozbakir, B.

AU - Barten-Rijbroek, A.D.

AU - Storm, Gerrit

AU - Nijsen, F.

AU - Hennink, W.E.

AU - Vermonden, T.

AU - Deckers, R.

N1 - Open access

PY - 2015

Y1 - 2015

N2 - 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. Methods and Findings 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.

AB - 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. Methods and Findings 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.

KW - METIS-315213

KW - IR-99650

U2 - 10.1371/journal.pone.0141626

DO - 10.1371/journal.pone.0141626

M3 - Article

VL - 10

SP - e0141626-

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 11

M1 - e141626

ER -