Inducing a Transient Increase in Blood-Brain Barrier Permeability for Improved Liposomal Drug Therapy of Glioblastoma Multiforme

David J. Lundy, Keng Jung Lee, I. Chia Peng, Chia Hsin Hsu, Jen Hao Lin, Kun Hung Chen, Yu Wen Tien, Patrick C.H. Hsieh

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The blood-brain barrier (BBB) selectively controls the passage of endogenous and exogenous molecules between systemic circulation and the brain parenchyma. Nanocarrier-based drugs such as liposomes and nanoparticles are an attractive prospect for cancer therapy since they can carry a drug payload and be modified to improve targeting and retention at the desired site. However, the BBB prevents most therapeutic drugs from entering the brain, including physically restricting the passage of liposomes and nanoparticles. In this paper, we show that a low dose of systemically injected recombinant human vascular endothelial growth factor induces a short period of increased BBB permeability. We have shown increased delivery of a range of nanomedicines to the brain including contrast agents for imaging, varying sizes of nanoparticles, small molecule chemotherapeutics, tracer dyes, and liposomal chemotherapeutics. However, this effect was not uniform across all brain regions, and permeability varied depending on the drug or molecule measured. We have found that this window of BBB permeability effect is transient, with normal BBB integrity restored within 4 h. This strategy, combined with liposomal doxorubicin, was able to significantly extend survival in a mouse model of human glioblastoma. We have found no evidence of systemic toxicity, and the technique was replicated in pigs, demonstrating that this technique could be scaled up and potentially be translated to the clinic, thus allowing the use of nanocarrier-based therapies for brain disorders.

Original languageEnglish
JournalACS Nano
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

blood-brain barrier
Drug therapy
chemotherapy
brain
Brain
permeability
drugs
Liposomes
Nanoparticles
Pharmaceutical Preparations
nanoparticles
Molecules
therapy
Medical nanotechnology
molecules
swine
payloads
toxicity
integrity
Contrast Media

Keywords

  • doxorubicin
  • drug delivery
  • glioblastoma
  • nanomedicine
  • xenograft model

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

Cite this

Inducing a Transient Increase in Blood-Brain Barrier Permeability for Improved Liposomal Drug Therapy of Glioblastoma Multiforme. / Lundy, David J.; Lee, Keng Jung; Peng, I. Chia; Hsu, Chia Hsin; Lin, Jen Hao; Chen, Kun Hung; Tien, Yu Wen; Hsieh, Patrick C.H.

In: ACS Nano, 01.01.2018.

Research output: Contribution to journalArticle

Lundy, David J. ; Lee, Keng Jung ; Peng, I. Chia ; Hsu, Chia Hsin ; Lin, Jen Hao ; Chen, Kun Hung ; Tien, Yu Wen ; Hsieh, Patrick C.H. / Inducing a Transient Increase in Blood-Brain Barrier Permeability for Improved Liposomal Drug Therapy of Glioblastoma Multiforme. In: ACS Nano. 2018.
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