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Enhancing the efficacy of drug-loaded nanocarriers against brain tumors by targeted radiation therapy.

ABSTRACT: Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only ~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(?-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 less than 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.

SUBMITTER: Baumann BC

PROVIDER: S-EPMC3702208 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Enhancing the efficacy of drug-loaded nanocarriers against brain tumors by targeted radiation therapy.

Baumann Brian C BC Kao Gary D GD Mahmud Abdullah A Harada Takamasa T Swift Joe J Chapman Christina C Xu Xiangsheng X Discher Dennis E DE Dorsey Jay F JF

Oncotarget 20130101 1

Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only ~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-po ...[more]

PMID: 23296073

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Project description:The present studies noninvasively investigate the passive tumor distribution potential of a series of poly(ethylene glycol) (PEG) nanocarriers using a SkinSkan spectrofluorometer and an In Vivo Imaging System (IVIS) 100. Fluorescein conjugated PEG nanocarriers of varying molecular weights (10, 20, 30, 40, and 60 kDa) were prepared and characterized. The nanocarriers were administered intravenously to female balb/c mice bearing subcutaneous 4T1 tumors. Passive distribution was measured in vivo (λ(exc), 480 nm; λ(em), 515-520 nm) from the tumor and a contralateral skin site (i.e., control site). The signal intensity from the tumor was always significantly higher than that from the contralateral site. Trends in results between the two methods were consistent with tumor distribution increasing in a molecular weight-dependent manner (10 < 20 < 30 ≪ 40 ≪ 60 kDa). The 10 kDa nanocarrier was not detected in tumors at 24 h, whereas 40-60 kDa nanocarriers were detected in tumors for up to 96 h. The 30, 40, and 60 kDa nanocarriers showed 2.1, 5.3, and 4.1 times higher passive distribution in tumors at 24 h, respectively, as compared to the 20 kDa nanocarrier. The 60 kDa nanocarrier exhibited 1.5 times higher tumor distribution than 40 kDa nanocarrier at 96 h. Thus, PEG nanocarriers (40 and 60 kDa) with molecular weights close to or above the renal exclusion limit, which for globular proteins is ≥45 kDa, showed significantly higher tumor distribution than those below it. The hydrodynamic radii of PEG polymers, measured using dynamic light scattering (DLS), showed that nanocarriers obtained from polymers with hydrodynamic radii ≥8 nm exhibited higher tumor distribution. Ex vivo mass balance studies revealed that nanocarrier tissue distribution followed the rank order tumor > lung > spleen > liver > kidney > muscle > heart, thus validating the in vivo studies. The results of the current studies suggest that noninvasive dermal imaging of tumors provides a reliable and rapid method for the initial screening of nanocarrier tumor distribution pharmacokinetics.

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Enhancing the efficacy of drug-loaded nanocarriers against brain tumors by targeted radiation therapy.

Publications

Enhancing the efficacy of drug-loaded nanocarriers against brain tumors by targeted radiation therapy.

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