Universität zu Köln

Lokerse, Wouter J. M., Bolkestein, Michiel ORCID: 0000-0002-4215-1822, Dalm, Simone U., Eggermont, Alexander M. M., de Jong, Marion, Gruell, Holger and Koning, Gerben A. (2017). Comparing the therapeutic potential of thermosensitive liposomes and hyperthermia in two distinct subtypes of breast cancer. J. Control. Release, 258. S. 34 - 43. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1873-4995

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Abstract

Local drug delivery of Doxorubicin (Dox) with thermosensitive liposomes (TSL) and hyperthermia (HT) has shown preclinically to achieve high local drug concentrations with good therapeutic efficacy. Currently, this is clinically studied for treatment of chest wall recurrence of breast cancer, however with various outcomes. This study examines the potency of neoadjuvant TSL HT combination therapy in two orthotopic mouse models of human breast cancer, MDA-MB-231 and T-47D, which morphologically correlate to mesenchymal and epithelial phenotypes, respectively. Both cell lines showed improved in vitro chemosensitivity and Dox uptake at HT. Doxloaded TSL (TSLDox) was stable in vitro in FBS, BALB/c-nu plasma and human plasma, although release of the drug at HT was incomplete for the latter two. Combination treatment with TSLDox and HT in vivo was significantly more effective against MDA-MB-231 tumors, whereas T-47D tumors showed no significant therapeutic response. Ex vivo investigation revealed a higher mean vessel density and poorly differentiated extracellular matrix (ECM) in MDA-MB-231 tumors relative to T-47D tumors. Although in vitro results of the TSLDox and HT treatment were favorable for both cell types, the therapeutic efficacy in vivo was remarkably different. The well-differentiated and slowly-growing T-47D tumors may provide a microenvironment that limits drug delivery to the target cell and therefore renders the therapy ineffective. Mesenchymal and invasive MDAMB- 231 tumors display higher vascularization and less mature ECM, significantly enhancing tumor response to TSLDox and HT treatment. These results yield insight into the efficacy of TSL treatment within different tumor microenvironments, and further advance our understanding of factors that contribute to heterogeneous therapeutic outcomes in clinical trials.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lokerse, Wouter J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolkestein, Michiel UNSPECIFIED orcid.org/0000-0002-4215-1822 UNSPECIFIED Dalm, Simone U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Eggermont, Alexander M. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Jong, Marion UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruell, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Koning, Gerben A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-224637
DOI:	10.1016/j.jconrel.2017.05.005
Journal or Publication Title:	J. Control. Release
Volume:	258
Page Range:	S. 34 - 43
Date:	2017
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1873-4995
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TEMPERATURE-SENSITIVE LIPOSOME; TUMOR XENOGRAFT MODEL; MILD HYPERTHERMIA; DRUG-DELIVERY; CELL-LINES; DOXORUBICIN RELEASE; SOLID TUMORS; IN-VITRO; CHEMOTHERAPY; MICROENVIRONMENT Multiple languages Chemistry, Multidisciplinary; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22463