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Hijnen, Nicole, Kneepkens, Esther, de Smet, Mariska, Langereis, Sander, Heijman, Edwin and Grull, Holger (2017). Thermal combination therapies for local drug delivery by magnetic resonance-guided high-intensity focused ultrasound. Proc. Natl. Acad. Sci. U. S. A., 114 (24). S. E4802 - 10. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

Several thermal-therapy strategies such as thermal ablation, hyperthermia-triggered drug delivery from temperature-sensitive liposomes (TSLs), and combinations of the above were investigated in a rhabdomyosarcoma rat tumor model (n = 113). Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) was used as a noninvasive heating device with precise temperature control for image-guided drug delivery. For the latter, TSLs were prepared, coencapsulating doxorubicin (dox) and [Gd(HPDO3A)(H2O)], and injected in tumor-bearing rats before MR-HIFU treatment. Four treatment groups were defined: hyperthermia, ablation, hyperthermia followed by ablation, or no HIFU. The intratumoral TSL and dox distribution were analyzed by single-photon emission computed tomography (SPECT)/computed tomography (CT), autoradiography, and fluorescence microscopy. Dox biodistribution was quantified and compared with that of nonliposomal dox. Finally, the treatment efficacy of all heating strategies plus additional control groups (saline, free dox, and Caelyx) was assessed by tumor growth measurements. All HIFU heating strategies combined with TSLs resulted in cellular uptake of dox deep into the interstitial space and a significant increase of tumor drug concentrations compared with a treatment with free dox. Ablation after TSL injection showed [Gd(HPDO3A)(H2O)] and dox release along the tumor rim, mirroring the TSL distribution pattern. Hyperthermia either as standalone treatment or before ablation ensured homogeneous TSL, [Gd(HPDO3A)(H2O)], and dox delivery across the tumor. The combination of hyperthermia-triggered drug delivery followed by ablation showed the best therapeutic outcome compared with all other treatment groups due to direct induction of thermal necrosis in the tumor core and efficient drug delivery to the tumor rim.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hijnen, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Kneepkens, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED de Smet, Mariska UNSPECIFIED UNSPECIFIED UNSPECIFIED Langereis, Sander UNSPECIFIED UNSPECIFIED UNSPECIFIED Heijman, Edwin UNSPECIFIED UNSPECIFIED UNSPECIFIED Grull, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-227787
DOI:	10.1073/pnas.1700790114
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	114
Number:	24
Page Range:	S. E4802 - 10
Date:	2017
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TEMPERATURE-SENSITIVE LIPOSOMES; SOFT-TISSUE SARCOMA; THERMOSENSITIVE LIPOSOMES; RADIOFREQUENCY ABLATION; MILD HYPERTHERMIA; MEDIATED HYPERTHERMIA; PHASE-II; NANOPARTICLE EXTRAVASATION; CONVENTIONAL DOXORUBICIN; HEPATOCELLULAR-CARCINOMA Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22778