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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,§ and Patrick C. H. Hsieh*,†,§,∥,⊥ Downloaded via YORK UNIV on December 21, 2018 at 12:38:11 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
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Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, Taipei 110, Taiwan § Department of Surgery, National Taiwan University and Hospital, Taipei 100, Taiwan ∥ Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100, Taiwan ⊥ Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan ‡
S Supporting Information *
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 nanocarrierbased therapies for brain disorders. KEYWORDS: glioblastoma, doxorubicin, nanomedicine, drug delivery, xenograft model
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and cytokines. Much of the physical barrier property results from tight junctions between the endothelial cells of the brain vasculature, but it is known that cells (astrocytes, microglia, pericytes, neurones) and an enormous array of selective transporters and efflux pumps all contribute toward a biochemical barrier.9 As a result, the BBB prevents the majority of therapeutic drugs from passing into the brain following intravenous or oral administration.10 In particular, larger substances such as nanoparticles or liposomes are generally unable to enter the brain parenchyma.
lioblastoma multiforme (GBM) is an aggressive primary cancer of the brain with a life expectancy of
