Abstract
Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof.
Highlights
Malignant brain tumors consist of high-grade primary brain tumors such as malignant gliomas[1], and metastatic lesions to the brain from peripheral cancers such as lung, breast, renal, gastrointestinal tract, and melanoma[2,3]
Even though malignant gliomas are generally treated with a combination of surgery, radiotherapy and systemic chemotherapy[7,8], and metastatic brain tumors with a combination of surgery and radiotherapy [9,10,11], the overall long-term prognosis of patients with these tumors, whether primary or metastatic, remains poor
In the treatment of both malignant gliomas and metastatic brain tumors, surgery and radiotherapy are more effective when used in combination[7,8,9,10,11,18,19,20]
Summary
Malignant brain tumors consist of high-grade primary brain tumors such as malignant gliomas[1], and metastatic lesions to the brain from peripheral cancers such as lung, breast, renal, gastrointestinal tract, and melanoma[2,3]. Due to the prolonged residence time of particles within the extravascular compartment of tumor tissue, there is significant endocytosis of particles into individual RG-2 glioma cells, which is evident on fluorescence microscopy of tumor tissue harvested 2 hours following the intravenous administration of rhodamine B dye conjugated Gd-G5 dendrimers (Figure 4, panel D)[73] This finding indicates that spherical nanoparticles ranging between 7 nm and 10 nm in diameter can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the BBTB and into individual malignant glioma cells. Nanoparticles bearing chemotherapy that are within this 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the BBTB into individual brain tumor cells
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