Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo

Jan Kroon, Jan Kroon, J.T. Buijs, G. van der Horst, Henry Cheung, Maaike van der Mark, Louis van Bloois, L.Y. Rizzo, Twan Gerardus Gertudis Maria Lammers, Rob C. Pelger, Gerrit Storm, Gabri van der Pluijm, Josbert Maarten Metselaar

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Abstract

Background The inflammatory tumor microenvironment, and more specifically the tumor-associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which - combined with the prolonged circulation kinetics of liposomes - leads to efficient tumor localization of these drug carriers, via the so-called enhanced permeability and retention (EPR) -effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. Methods Tumor-bearing Balb-c nu/nu mice were treated intravenously with 0.2–1.0–5.0 mg/kg/week free- and liposomal DEX for 3–4 weeks and tumor growth was monitored by bioluminescent imaging. Results Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well-tolerated at clinically-relevant dosages that display potent anti-tumor efficacy. Conclusions Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation
Original languageUndefined
Pages (from-to)815-824
JournalProstate
Volume75
Issue number8
DOIs
Publication statusPublished - 2015

Keywords

  • IR-99925
  • METIS-315197

Cite this

Kroon, J., Kroon, J., Buijs, J. T., van der Horst, G., Cheung, H., van der Mark, M., ... Metselaar, J. M. (2015). Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo. Prostate, 75(8), 815-824. https://doi.org/10.1002/pros.22963
Kroon, Jan ; Kroon, Jan ; Buijs, J.T. ; van der Horst, G. ; Cheung, Henry ; van der Mark, Maaike ; van Bloois, Louis ; Rizzo, L.Y. ; Lammers, Twan Gerardus Gertudis Maria ; Pelger, Rob C. ; Storm, Gerrit ; van der Pluijm, Gabri ; Metselaar, Josbert Maarten. / Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo. In: Prostate. 2015 ; Vol. 75, No. 8. pp. 815-824.
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title = "Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo",
abstract = "Background The inflammatory tumor microenvironment, and more specifically the tumor-associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which - combined with the prolonged circulation kinetics of liposomes - leads to efficient tumor localization of these drug carriers, via the so-called enhanced permeability and retention (EPR) -effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. Methods Tumor-bearing Balb-c nu/nu mice were treated intravenously with 0.2–1.0–5.0 mg/kg/week free- and liposomal DEX for 3–4 weeks and tumor growth was monitored by bioluminescent imaging. Results Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well-tolerated at clinically-relevant dosages that display potent anti-tumor efficacy. Conclusions Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation",
keywords = "IR-99925, METIS-315197",
author = "Jan Kroon and Jan Kroon and J.T. Buijs and {van der Horst}, G. and Henry Cheung and {van der Mark}, Maaike and {van Bloois}, Louis and L.Y. Rizzo and Lammers, {Twan Gerardus Gertudis Maria} and Pelger, {Rob C.} and Gerrit Storm and {van der Pluijm}, Gabri and Metselaar, {Josbert Maarten}",
year = "2015",
doi = "10.1002/pros.22963",
language = "Undefined",
volume = "75",
pages = "815--824",
journal = "Prostate",
issn = "0270-4137",
publisher = "Wiley-Liss Inc.",
number = "8",

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Kroon, J, Kroon, J, Buijs, JT, van der Horst, G, Cheung, H, van der Mark, M, van Bloois, L, Rizzo, LY, Lammers, TGGM, Pelger, RC, Storm, G, van der Pluijm, G & Metselaar, JM 2015, 'Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo' Prostate, vol. 75, no. 8, pp. 815-824. https://doi.org/10.1002/pros.22963

Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo. / Kroon, Jan; Kroon, Jan; Buijs, J.T.; van der Horst, G.; Cheung, Henry; van der Mark, Maaike; van Bloois, Louis; Rizzo, L.Y.; Lammers, Twan Gerardus Gertudis Maria; Pelger, Rob C.; Storm, Gerrit; van der Pluijm, Gabri; Metselaar, Josbert Maarten.

In: Prostate, Vol. 75, No. 8, 2015, p. 815-824.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo

AU - Kroon, Jan

AU - Kroon, Jan

AU - Buijs, J.T.

AU - van der Horst, G.

AU - Cheung, Henry

AU - van der Mark, Maaike

AU - van Bloois, Louis

AU - Rizzo, L.Y.

AU - Lammers, Twan Gerardus Gertudis Maria

AU - Pelger, Rob C.

AU - Storm, Gerrit

AU - van der Pluijm, Gabri

AU - Metselaar, Josbert Maarten

PY - 2015

Y1 - 2015

N2 - Background The inflammatory tumor microenvironment, and more specifically the tumor-associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which - combined with the prolonged circulation kinetics of liposomes - leads to efficient tumor localization of these drug carriers, via the so-called enhanced permeability and retention (EPR) -effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. Methods Tumor-bearing Balb-c nu/nu mice were treated intravenously with 0.2–1.0–5.0 mg/kg/week free- and liposomal DEX for 3–4 weeks and tumor growth was monitored by bioluminescent imaging. Results Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well-tolerated at clinically-relevant dosages that display potent anti-tumor efficacy. Conclusions Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation

AB - Background The inflammatory tumor microenvironment, and more specifically the tumor-associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which - combined with the prolonged circulation kinetics of liposomes - leads to efficient tumor localization of these drug carriers, via the so-called enhanced permeability and retention (EPR) -effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. Methods Tumor-bearing Balb-c nu/nu mice were treated intravenously with 0.2–1.0–5.0 mg/kg/week free- and liposomal DEX for 3–4 weeks and tumor growth was monitored by bioluminescent imaging. Results Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well-tolerated at clinically-relevant dosages that display potent anti-tumor efficacy. Conclusions Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation

KW - IR-99925

KW - METIS-315197

U2 - 10.1002/pros.22963

DO - 10.1002/pros.22963

M3 - Article

VL - 75

SP - 815

EP - 824

JO - Prostate

JF - Prostate

SN - 0270-4137

IS - 8

ER -

Kroon J, Kroon J, Buijs JT, van der Horst G, Cheung H, van der Mark M et al. Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo. Prostate. 2015;75(8):815-824. https://doi.org/10.1002/pros.22963