Abstract
Brain cancer is a devastating disease affecting many people worldwide. Effective treatment with chemotherapeutics is limited due to the presence of the blood-brain barrier (BBB) that tightly regulates the diffusion of endogenous molecules but also xenobiotics. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is based on already marketed pegylated liposomal doxorubicin (Doxil®/Caelyx®), with an additional glutathione coating that safely enhances drug delivery across the BBB.Uptake of 2B3-101 by human brain capillary endothelial cells in vitro was time-, concentration- and temperature-dependent, while pegylated liposomal doxorubicin mainly remained bound to the cells. In vivo, 2B3-101 and pegylated liposomal doxorubicin had a comparable plasma exposure in mice, yet brain retention 4 days after administration was higher for 2B3-101. 2B3-101 was overall well tolerated by athymic FVB mice with experimental human glioblastoma (luciferase transfected U87MG). In 2 independent experiments a strong inhibition of brain tumor growth was observed for 2B3-101 as measured by bioluminescence intensity. The effect of weekly administration of 5 mg/kg 2B3-101 was more pronounced compared to pegylated liposomal doxorubicin (p<0.05) and saline (p<0.01). Two out of 9 animals receiving 2B3-101 showed a complete tumor regression. Twice-weekly injections of 5 mg/kg 2B3-101 again had a significant effect in inhibiting brain tumor growth (p<0.001) compared to pegylated liposomal doxorubicin and saline, and a complete regression was observed in 1 animal treated with 2B3-101. In addition, twice-weekly dosing of 2B3-101 significantly increased the median survival time by 38.5% (p<0.001) and 16.1% (p<0.05) compared to saline and pegylated liposomal doxorubicin, respectively.Overall, these data demonstrate that glutathione pegylated liposomal doxorubicin enhances the effective delivery of doxorubicin to brain tumors and could become a promising new therapeutic option for the treatment of brain malignancies.
Highlights
Brain cancer is a devastating disease affecting many people worldwide
The fluorescence of cells exposed to 2B3-101 was followed in a timedependent manner and was higher compared to that of cells incubated with pegylated liposomal doxorubicin
While the signal from 2B3-101-treated cells did not reach a plateau within 5.5 h, the level of pegylated liposomal doxorubicin signal already plateaued after 2–4 h (Figure 2A)
Summary
In the US, the incidence of primary brain tumors is 7– 8 per 100,000, and it is expected that well over 23,000 new cases will be diagnosed in 2013 (http://www.cancer.gov/cancertopics/ types/brain). The median survival after starting treatment, including surgery, radiation, chemotherapy, and combinations thereof, is less than a year [1,2]. The standard treatment for primary brain tumors involves maximal surgical resection followed by chemoradiation therapy [3]. The treatment of patients with metastases from peripheral tumors depends on the number of metastases: patients with multiple metastases are usually treated with whole-brain radiation therapy (WBRT), while patients with 3 or fewer metastases can benefit from aggressive local treatment with surgery or stereotactic radiosurgery (SRS) combined with WBRT [4]
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