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Inducing a Transient Increase in Blood–Brain Barrier Permeability for Improved Liposomal Drug Therapy of Glioblastoma Multiforme
journal contribution
posted on 2018-12-11, 00:00 authored by David
J. Lundy, Keng-Jung Lee, I-Chia Peng, Chia-Hsin Hsu, Jen-Hao Lin, Kun-Hung Chen, Yu-Wen Tien, Patrick C. H. HsiehThe
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.
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tracer dyesbrain disordersnanoparticlecontrast agentstechniquepassageNanocarrier-based drugs4 hdrug payloadliposomesexogenous moleculesnanocarrier-based therapiesbrain regionsLiposomal Drug Therapybrain parenchymaBBB permeabilityBBB permeability effectgrowth factorGlioblastoma Multiformeliposomal doxorubicinmouse modelBBB integritymolecule chemotherapeuticscancer therapyliposomal chemotherapeutics
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