The physiologic upper limit of pore size in the blood-tumor barrier of cancer microvasculature is
approximately 12 nanometers, independent of whether cancer location is in the brain and the central nervous
system, or outside, in peripheral tissues. Chemotherapy drugs in clinical use are less than 1 to 2 nanometers
in diameter and can readily extravasate across the blood-tumor barrier to enter the extravascular
compartment of cancer tissue. However, these small molecule chemotherapy drugs maintain peak blood
concentrations for only a few minutes, and therefore, do not accumulate to high concentrations within
individual cancer cells in the extravascular compartment. Spherical nanoparticles in the 7 to 10 nanometer
size range maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm
physiologic upper limit of pore size within the blood-tumor barrier to accumulate to high concentrations
within individual cancer cells. The Gd-G5-doxorubicin dendrimer is an imageable nanoparticle bearing
chemotherapy within the 7 to 10 nanometer size range. Doxorubicin attachment to the Gd-G5-doxorubicn
dendrimer via the pH-sensitive covalent hydrazone bond facilitates efficient intracellular release of
doxorubicin and doxorubicin accumulation in cancer cell nuclei. One dose of the Gd-G5-doxorubicin
dendrimer is significantly more effective than one dose of free doxorubicin at inhibiting the growth of RG-2
rodent brain cancers for 24 hours. The therapeutic efficacy of the Gd-G5-doxorubicin dendrimer in vivo
stems from the effective transvascular delivery of doxorubicin across the blood-tumor barrier into individual
brain cancer cells and doxorubicin accumulation to high concentrations within brain cancer cell nuclei. It is
foreseeable that such imageable nanoparticles bearing chemotherapy, which are within the 7 to 10
nanometer size range, will also demonstrate therapeutic efficacy in the treatment of cancers located outside
the brain and central nervous system.
Keywords: Blood brain barrier; cancer; chemotherapy; nanoparticles; doxorubicin; dendrimer; magnetic
resonance imaging; tumour cells, microvascular; gadolinium.
