Cargando…

Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia

Doxorubicin (Dox) loaded thermosensitive liposomes (TSLs) have shown promising results for hyperthermia-induced local drug delivery to solid tumors. Typically, the tumor is heated to hyperthermic temperatures (41-42 °C), which induced intravascular drug release from TSLs within the tumor tissue lead...

Descripción completa

Detalles Bibliográficos
Autores principales: Lokerse, Wouter J.M., Bolkestein, Michiel, ten Hagen, Timo L.M., de Jong, Marion, Eggermont, Alexander M.M., Grüll, Holger, Koning, Gerben A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955068/
https://www.ncbi.nlm.nih.gov/pubmed/27446503
http://dx.doi.org/10.7150/thno.14960
_version_ 1782443886427242496
author Lokerse, Wouter J.M.
Bolkestein, Michiel
ten Hagen, Timo L.M.
de Jong, Marion
Eggermont, Alexander M.M.
Grüll, Holger
Koning, Gerben A.
author_facet Lokerse, Wouter J.M.
Bolkestein, Michiel
ten Hagen, Timo L.M.
de Jong, Marion
Eggermont, Alexander M.M.
Grüll, Holger
Koning, Gerben A.
author_sort Lokerse, Wouter J.M.
collection PubMed
description Doxorubicin (Dox) loaded thermosensitive liposomes (TSLs) have shown promising results for hyperthermia-induced local drug delivery to solid tumors. Typically, the tumor is heated to hyperthermic temperatures (41-42 °C), which induced intravascular drug release from TSLs within the tumor tissue leading to high local drug concentrations (1-step delivery protocol). Next to providing a trigger for drug release, hyperthermia (HT) has been shown to be cytotoxic to tumor tissue, to enhance chemosensitivity and to increase particle extravasation from the vasculature into the tumor interstitial space. The latter can be exploited for a 2-step delivery protocol, where HT is applied prior to i.v. TSL injection to enhance tumor uptake, and after 4 hours waiting time for a second time to induce drug release. In this study, we compare the 1- and 2-step delivery protocols and investigate which factors are of importance for a therapeutic response. In murine B16 melanoma and BFS-1 sarcoma cell lines, HT induced an enhanced Dox uptake in 2D and 3D models, resulting in enhanced chemosensitivity. In vivo, therapeutic efficacy studies were performed for both tumor models, showing a therapeutic response for only the 1-step delivery protocol. SPECT/CT imaging allowed quantification of the liposomal accumulation in both tumor models at physiological temperatures and after a HT treatment. A simple two compartment model was used to derive respective rates for liposomal uptake, washout and retention, showing that the B16 model has a twofold higher liposomal uptake compared to the BFS-1 tumor. HT increases uptake and retention of liposomes in both tumors models by the same factor of 1.66 maintaining the absolute differences between the two models. Histology showed that HT induced apoptosis, blood vessel integrity and interstitial structures are important factors for TSL accumulation in the investigated tumor types. However, modeling data indicated that the intraliposomal Dox fraction did not reach therapeutic relevant concentrations in the tumor tissue in a 2-step delivery protocol due to the leaking of the drug from its liposomal carrier providing an explanation for the observed lack of efficacy.
format Online
Article
Text
id pubmed-4955068
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-49550682016-07-21 Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia Lokerse, Wouter J.M. Bolkestein, Michiel ten Hagen, Timo L.M. de Jong, Marion Eggermont, Alexander M.M. Grüll, Holger Koning, Gerben A. Theranostics Research Paper Doxorubicin (Dox) loaded thermosensitive liposomes (TSLs) have shown promising results for hyperthermia-induced local drug delivery to solid tumors. Typically, the tumor is heated to hyperthermic temperatures (41-42 °C), which induced intravascular drug release from TSLs within the tumor tissue leading to high local drug concentrations (1-step delivery protocol). Next to providing a trigger for drug release, hyperthermia (HT) has been shown to be cytotoxic to tumor tissue, to enhance chemosensitivity and to increase particle extravasation from the vasculature into the tumor interstitial space. The latter can be exploited for a 2-step delivery protocol, where HT is applied prior to i.v. TSL injection to enhance tumor uptake, and after 4 hours waiting time for a second time to induce drug release. In this study, we compare the 1- and 2-step delivery protocols and investigate which factors are of importance for a therapeutic response. In murine B16 melanoma and BFS-1 sarcoma cell lines, HT induced an enhanced Dox uptake in 2D and 3D models, resulting in enhanced chemosensitivity. In vivo, therapeutic efficacy studies were performed for both tumor models, showing a therapeutic response for only the 1-step delivery protocol. SPECT/CT imaging allowed quantification of the liposomal accumulation in both tumor models at physiological temperatures and after a HT treatment. A simple two compartment model was used to derive respective rates for liposomal uptake, washout and retention, showing that the B16 model has a twofold higher liposomal uptake compared to the BFS-1 tumor. HT increases uptake and retention of liposomes in both tumors models by the same factor of 1.66 maintaining the absolute differences between the two models. Histology showed that HT induced apoptosis, blood vessel integrity and interstitial structures are important factors for TSL accumulation in the investigated tumor types. However, modeling data indicated that the intraliposomal Dox fraction did not reach therapeutic relevant concentrations in the tumor tissue in a 2-step delivery protocol due to the leaking of the drug from its liposomal carrier providing an explanation for the observed lack of efficacy. Ivyspring International Publisher 2016-06-24 /pmc/articles/PMC4955068/ /pubmed/27446503 http://dx.doi.org/10.7150/thno.14960 Text en © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.
spellingShingle Research Paper
Lokerse, Wouter J.M.
Bolkestein, Michiel
ten Hagen, Timo L.M.
de Jong, Marion
Eggermont, Alexander M.M.
Grüll, Holger
Koning, Gerben A.
Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia
title Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia
title_full Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia
title_fullStr Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia
title_full_unstemmed Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia
title_short Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia
title_sort investigation of particle accumulation, chemosensitivity and thermosensitivity for effective solid tumor therapy using thermosensitive liposomes and hyperthermia
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955068/
https://www.ncbi.nlm.nih.gov/pubmed/27446503
http://dx.doi.org/10.7150/thno.14960
work_keys_str_mv AT lokersewouterjm investigationofparticleaccumulationchemosensitivityandthermosensitivityforeffectivesolidtumortherapyusingthermosensitiveliposomesandhyperthermia
AT bolkesteinmichiel investigationofparticleaccumulationchemosensitivityandthermosensitivityforeffectivesolidtumortherapyusingthermosensitiveliposomesandhyperthermia
AT tenhagentimolm investigationofparticleaccumulationchemosensitivityandthermosensitivityforeffectivesolidtumortherapyusingthermosensitiveliposomesandhyperthermia
AT dejongmarion investigationofparticleaccumulationchemosensitivityandthermosensitivityforeffectivesolidtumortherapyusingthermosensitiveliposomesandhyperthermia
AT eggermontalexandermm investigationofparticleaccumulationchemosensitivityandthermosensitivityforeffectivesolidtumortherapyusingthermosensitiveliposomesandhyperthermia
AT grullholger investigationofparticleaccumulationchemosensitivityandthermosensitivityforeffectivesolidtumortherapyusingthermosensitiveliposomesandhyperthermia
AT koninggerbena investigationofparticleaccumulationchemosensitivityandthermosensitivityforeffectivesolidtumortherapyusingthermosensitiveliposomesandhyperthermia