Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme

Feng Yi Yang, Tai-Tong Wong, Ming Che Teng, Ren Shyan Liu, Maggie Lu, Hsiang Fa Liang, Ming Cheng Wei

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

The clinical application of chemotherapy to brain tumors has been severely limited because the blood-brain barrier (BBB) often prevents therapeutic levels from being achieved. Here we show that pulsed HIFU and human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (AP-1 Lipo-Dox) act synergistically in an experimental brain tumor model. We developed an intracranial brain-tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells. Pulsed HIFU was used to transcranially disrupt the BBB in these mouse brains by delivering ultrasound waves in the presence of microbubbles. Prior to each sonication, AP-1 Lipo-Dox or unconjugated Lipo-Dox was administered intravenously, and the concentration in the brains was quantified by fluorometer. Compared to control animals treated with injections of AP-1 Lipo-Dox or unconjugated Lipo-Dox, animals receiving the drug followed by pulsed HIFU exhibited enhanced accumulation of the drug in tumor cells. Drug injection with sonication increased the tumor-to-normal brain doxorubicin ratio of the target tumors by about twofold compared with the control tumors. Moreover, the tumor-to-normal brain ratio was highest after the injection of AP-1 Lipo-Dox with sonication. Combining sonication with AP-1 Lipo-Dox also significantly inhibited tumor growth compared with chemotherapy alone. There was a modest but significant increase in the median survival time in mice treated with AP-1 Lipo-Dox followed by pulsed HIFU, compared to those treated with AP-1 Lipo-Dox without sonication. The use of AP-1-conjugated liposomes carrying cytotoxic agents followed by pulsed HIFU represents a feasible approach for enhanced targeted drug delivery in brain tumor therapies. Crown

Original languageEnglish
Pages (from-to)652-658
Number of pages7
JournalJournal of Controlled Release
Volume160
Issue number3
DOIs
Publication statusPublished - Jun 28 2012
Externally publishedYes

Fingerprint

Interleukin-4 Receptors
Transcription Factor AP-1
Glioblastoma
Antineoplastic Agents
Sonication
Brain Neoplasms
Brain
Neoplasms
Blood-Brain Barrier
Liposomes
Pharmaceutical Preparations
Doxorubicin
Injections
liposomal doxorubicin
Drug Therapy
Microbubbles
Inbred NOD Mouse
Cytotoxins
Atherosclerotic Plaques
Crowns

Keywords

  • AP-1
  • Blood-brain barrier
  • Brain tumor
  • Focused ultrasound
  • Targeted drug delivery

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme. / Yang, Feng Yi; Wong, Tai-Tong; Teng, Ming Che; Liu, Ren Shyan; Lu, Maggie; Liang, Hsiang Fa; Wei, Ming Cheng.

In: Journal of Controlled Release, Vol. 160, No. 3, 28.06.2012, p. 652-658.

Research output: Contribution to journalArticle

Yang, Feng Yi ; Wong, Tai-Tong ; Teng, Ming Che ; Liu, Ren Shyan ; Lu, Maggie ; Liang, Hsiang Fa ; Wei, Ming Cheng. / Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme. In: Journal of Controlled Release. 2012 ; Vol. 160, No. 3. pp. 652-658.
@article{4954a1f427674fa38f93ca976309e69d,
title = "Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme",
abstract = "The clinical application of chemotherapy to brain tumors has been severely limited because the blood-brain barrier (BBB) often prevents therapeutic levels from being achieved. Here we show that pulsed HIFU and human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (AP-1 Lipo-Dox) act synergistically in an experimental brain tumor model. We developed an intracranial brain-tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells. Pulsed HIFU was used to transcranially disrupt the BBB in these mouse brains by delivering ultrasound waves in the presence of microbubbles. Prior to each sonication, AP-1 Lipo-Dox or unconjugated Lipo-Dox was administered intravenously, and the concentration in the brains was quantified by fluorometer. Compared to control animals treated with injections of AP-1 Lipo-Dox or unconjugated Lipo-Dox, animals receiving the drug followed by pulsed HIFU exhibited enhanced accumulation of the drug in tumor cells. Drug injection with sonication increased the tumor-to-normal brain doxorubicin ratio of the target tumors by about twofold compared with the control tumors. Moreover, the tumor-to-normal brain ratio was highest after the injection of AP-1 Lipo-Dox with sonication. Combining sonication with AP-1 Lipo-Dox also significantly inhibited tumor growth compared with chemotherapy alone. There was a modest but significant increase in the median survival time in mice treated with AP-1 Lipo-Dox followed by pulsed HIFU, compared to those treated with AP-1 Lipo-Dox without sonication. The use of AP-1-conjugated liposomes carrying cytotoxic agents followed by pulsed HIFU represents a feasible approach for enhanced targeted drug delivery in brain tumor therapies. Crown",
keywords = "AP-1, Blood-brain barrier, Brain tumor, Focused ultrasound, Targeted drug delivery",
author = "Yang, {Feng Yi} and Tai-Tong Wong and Teng, {Ming Che} and Liu, {Ren Shyan} and Maggie Lu and Liang, {Hsiang Fa} and Wei, {Ming Cheng}",
year = "2012",
month = "6",
day = "28",
doi = "10.1016/j.jconrel.2012.02.023",
language = "English",
volume = "160",
pages = "652--658",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",
number = "3",

}

TY - JOUR

T1 - Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme

AU - Yang, Feng Yi

AU - Wong, Tai-Tong

AU - Teng, Ming Che

AU - Liu, Ren Shyan

AU - Lu, Maggie

AU - Liang, Hsiang Fa

AU - Wei, Ming Cheng

PY - 2012/6/28

Y1 - 2012/6/28

N2 - The clinical application of chemotherapy to brain tumors has been severely limited because the blood-brain barrier (BBB) often prevents therapeutic levels from being achieved. Here we show that pulsed HIFU and human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (AP-1 Lipo-Dox) act synergistically in an experimental brain tumor model. We developed an intracranial brain-tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells. Pulsed HIFU was used to transcranially disrupt the BBB in these mouse brains by delivering ultrasound waves in the presence of microbubbles. Prior to each sonication, AP-1 Lipo-Dox or unconjugated Lipo-Dox was administered intravenously, and the concentration in the brains was quantified by fluorometer. Compared to control animals treated with injections of AP-1 Lipo-Dox or unconjugated Lipo-Dox, animals receiving the drug followed by pulsed HIFU exhibited enhanced accumulation of the drug in tumor cells. Drug injection with sonication increased the tumor-to-normal brain doxorubicin ratio of the target tumors by about twofold compared with the control tumors. Moreover, the tumor-to-normal brain ratio was highest after the injection of AP-1 Lipo-Dox with sonication. Combining sonication with AP-1 Lipo-Dox also significantly inhibited tumor growth compared with chemotherapy alone. There was a modest but significant increase in the median survival time in mice treated with AP-1 Lipo-Dox followed by pulsed HIFU, compared to those treated with AP-1 Lipo-Dox without sonication. The use of AP-1-conjugated liposomes carrying cytotoxic agents followed by pulsed HIFU represents a feasible approach for enhanced targeted drug delivery in brain tumor therapies. Crown

AB - The clinical application of chemotherapy to brain tumors has been severely limited because the blood-brain barrier (BBB) often prevents therapeutic levels from being achieved. Here we show that pulsed HIFU and human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (AP-1 Lipo-Dox) act synergistically in an experimental brain tumor model. We developed an intracranial brain-tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells. Pulsed HIFU was used to transcranially disrupt the BBB in these mouse brains by delivering ultrasound waves in the presence of microbubbles. Prior to each sonication, AP-1 Lipo-Dox or unconjugated Lipo-Dox was administered intravenously, and the concentration in the brains was quantified by fluorometer. Compared to control animals treated with injections of AP-1 Lipo-Dox or unconjugated Lipo-Dox, animals receiving the drug followed by pulsed HIFU exhibited enhanced accumulation of the drug in tumor cells. Drug injection with sonication increased the tumor-to-normal brain doxorubicin ratio of the target tumors by about twofold compared with the control tumors. Moreover, the tumor-to-normal brain ratio was highest after the injection of AP-1 Lipo-Dox with sonication. Combining sonication with AP-1 Lipo-Dox also significantly inhibited tumor growth compared with chemotherapy alone. There was a modest but significant increase in the median survival time in mice treated with AP-1 Lipo-Dox followed by pulsed HIFU, compared to those treated with AP-1 Lipo-Dox without sonication. The use of AP-1-conjugated liposomes carrying cytotoxic agents followed by pulsed HIFU represents a feasible approach for enhanced targeted drug delivery in brain tumor therapies. Crown

KW - AP-1

KW - Blood-brain barrier

KW - Brain tumor

KW - Focused ultrasound

KW - Targeted drug delivery

UR - http://www.scopus.com/inward/record.url?scp=84861985598&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861985598&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2012.02.023

DO - 10.1016/j.jconrel.2012.02.023

M3 - Article

VL - 160

SP - 652

EP - 658

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

IS - 3

ER -