期刊
ONCOTARGET
卷 4, 期 1, 页码 64-79出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.777
关键词
glioblastoma multiforme; nanocarrier; radiation therapy; brain tumors; chemotherapy
资金
- National Institutes of Health [RC1 CA145075, R01 EB007049, K08 NS076548-01]
- University of Pennsylvania Nano/Bio Interface Center (NBIC)
- Radiation Biology Training Grant [C5T32CA009677]
- National Institutes of Health
- Burroughs Wellcome Career Award for Medical Scientists [1006792]
- NATIONAL CANCER INSTITUTE [P30CA016520, T32CA009677] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [K08NS076548] Funding Source: NIH RePORTER
Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only similar to 15 months. It has proven resistant in clinical trials to chemotherapeutic agents such as paclitaxel that are highly effective in vitro, presumably because of impaired drug delivery across the tumor's blood-brain barrier (BBB). In an effort to increase paclitaxel delivery across the tumor BBB, we linked the drug to a novel filomicelle nanocarrier made with biodegradable poly(ethylene-glycol)-block-poly(epsilon-caprolactone-r-D, L-lactide) and used precisely collimated radiation therapy (RT) to disrupt the tumor BBB's permeability in an orthotopic mouse model of GBM. Using a non-invasive bioluminescent imaging technique to assess tumor burden and response to therapy in our model, we demonstrated that the drug-loaded nanocarrier (DLN) alone was ineffective against stereotactically implanted intracranial tumors yet was highly effective against GBM cells in culture and in tumors implanted into the flanks of mice. When targeted cranial RT was used to modulate the tumor BBB, the paclitaxel-loaded nanocarriers became effective against the intracranial tumors. Focused cranial RT improved DLN delivery into the intracranial tumors, significantly improving therapeutic outcomes. Tumor growth was delayed or halted, and survival was extended by >50% (p<0.05) compared to the results obtained with either RT or the DLN alone. Combinations of RT and chemotherapeutic agents linked to nanocarriers would appear to be an area for future investigations that could enhance outcomes in the treatment of human GBM.
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