Figure 2
Dynamic contrast-enhanced MRI-based Gd concentration maps of Gd-dendrimer distribution within large and small RG-2 rodent gliomas over time. A) Large RG-2 gliomas. Gd-G1 thorough Gd-G7 dendrimers extravasate across the BBTB of the microvasculature of large RG-2 gliomas. After extravasating across the BBTB, Gd-G1 through Gd-G4 dendrimers only remain temporarily within the extravascular compartment of tumor tissue, as these lower Gd-dendrimer generations maintain peak blood concentrations for only a few minutes. The Gd-G5 through Gd-G7 dendrimers accumulate over time within the extravascular compartment of tumor tissue, as these generations maintain peak blood concentrations for several hours. The Gd-G8 dendrimers remain intravascular, since Gd-G8 dendrimers are larger than the physiologic upper limit of pore size in the BBTB of large RG-2 gliomas. RG-2 glioma volumes (mm3): Gd-G1, 104; Gd-G2, 94; Gd-G3, 94; lowly conjugated (LC) Gd-G4, 162; Gd-G4, 200; Gd-G5, 230; Gd-G6, 201; Gd-G7, 170; Gd-G8, 289. B) Small RG-2 gliomas. Gd-G1 thorough Gd-G6 dendrimers extravasate across the BBTB of the microvasculature of small RG-2 gliomas. Since small RG-2 gliomas are less vascular than large RG-2 gliomas, there is a relative lack of accumulation of the lower Gd-dendrimer generations in the extravascular compartment of small RG-2 gliomas as compared to large RG-2 gliomas (panel A). This is especially evident in the case of Gd-G1 dendrimers, which maintain peak blood concentrations for the shortest time period of all the Gd-dendrimer generations. Gd-G5 and Gd-G6 dendrimers accumulate over time within the extravascular compartment of even the small RG-2 gliomas, since these generations maintain peak blood concentrations fro several hours and are smaller than the physiologic upper limit of pore size in the BBTB. Both Gd-G7 and Gd-G8 dendrimers remain intravascular in small RG-2 gliomas, since both Gd-G7 and Gd-G8 dendrimers are larger than the physiologic upper limit of pore size in the BBTB of small RG-2 gliomas. RG-2 glioma volumes (mm3): Gd-G1, 27; Gd-G2, 28; Gd-G3, 19; LC Gd-G4, 24; Gd-G4, 17; Gd-G5, 18; Gd-G6, 22; Gd-G7, 24; Gd-G8, 107. Respective Gd-dendrimer generations administered intravenously over 1 minute at a Gd dose of 0.09 mmol Gd/kg animal body weight. Scale ranges from 0 mM [Gd] to 0.1 mM [Gd]. Adapted from reference[73].