Universität zu Köln

Lokerse, Wouter J. M., Eggermont, Alexander M. M., Gruell, Holger and Koning, Gerben A. (2018). Development and evaluation of an isolated limb infusion model for investigation of drug delivery kinetics to solid tumors by thermosensitive liposomes and hyperthermia. J. Control. Release, 270. S. 282 - 290. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1873-4995

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Abstract

The combined administration of thermosensitive liposomes (TSLs) and hyperthermia (HT) has been increasingly shown to be a powerful tool for the treatment of solid tumors. At present, it is hypothesized that the circulation of TSLs through the vasculature of a heated tumor results in the rapid release of the entrapped drug, followed by its uptake and distribution within the tumor microenvironment. However, simple questions on the transport kinetics of TSLs through the heated tumor and how much drug is retained upon passage of TSLs through the tumor microcirculation have not been investigated in an experimental setting to-date. The present work describes a novel methodology for investigating these parameters by isolated limb infusion (ILI), developed in a rat model of sarcoma. This approach was used to assess the efficacy of Doxorubicin (Dox) delivery by TSL in a heated (42 degrees C) tumor following a single passage of TSL through the tumor vasculature. Analysis of the effluent post-ILI, whole-tumor histological sections, and tissue homogenates revealed that upon a single passage, Dox delivery by TSL at 42 degrees C did not exceed delivery under conventional (i.e. free Dox) or physiological (i.e. TSL at 37 degrees C, or normothermia; NT) conditions. In fact, mathematical modeling demonstrated that at least thirteen passages are required to obtain the intratumoral Dox levels typically achieved using TSL (i.e. similar to 5% ID/g). Overall, this work investigates TSL-based determinants for achieving efficacious drug delivery using a model of ILI in tumor-bearing rats and the results bear important implications for TSL disposition in vivo.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lokerse, Wouter J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Eggermont, Alexander M. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruell, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Koning, Gerben A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-198452
DOI:	10.1016/j.jconrel.2017.12.012
Journal or Publication Title:	J. Control. Release
Volume:	270
Page Range:	S. 282 - 290
Date:	2018
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 LIPOSOMES; MURINE BREAST-CANCER; MILD HYPERTHERMIA; SECRETORY PHOSPHOLIPASE-A2; NANOPARTICLE EXTRAVASATION; DOXORUBICIN RELEASE; CIRCULATION TIME; XENOGRAFT MODEL; NORMAL-TISSUES; GROUP-IIA Multiple languages Chemistry, Multidisciplinary; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19845