The Role of Blood-Brain Barrier Permeability in Brain Tumor Imaging and Therapeutics

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The Role of Blood-Brain Barrier Permeability in Brain Tumor Imaging and Therapeutics

James M. Provenzale¹, Srinivasan Mukundan¹ and Mark Dewhirst²

¹ Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710.
² Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710.

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Fig. 1A —Effect of hyperthermia on extravasation of 100-nm liposomes in mouse window chamber model of human tumor (SKOV-3) xenograft, which is highly impermeable under normothermic conditions (34° C). In this model, xenograft is grown in dorsal skin fold (i.e., on back of mouse) inside window chamber. Skin along back of mouse is incised and tumor xenograft is placed on exposed subcutaneous tissue. Then, glass window is placed over exposed area to allow tumor growth to be monitored using fluorescent microscopy. Glass-covered tissue window allows for direct observation of tumor and its associated microvessels. Fluorescent (rhodamine)-labeled pegylated (stealth) liposomes are infused into tail vein and circulation of liposomes through tumor microcirculation is monitored with microscope while animal is lying in lateral recumbent position with window under microscope objective. (Reprinted with permission from [28]) Under normothermic conditions, imaging at 1 min shows tumor vasculature, but no extravasation of fluorescent liposomes. Similarly, at 30 min (B) and 60 min (C), no extravasation is seen.

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Fig. 1B —Effect of hyperthermia on extravasation of 100-nm liposomes in mouse window chamber model of human tumor (SKOV-3) xenograft, which is highly impermeable under normothermic conditions (34° C). In this model, xenograft is grown in dorsal skin fold (i.e., on back of mouse) inside window chamber. Skin along back of mouse is incised and tumor xenograft is placed on exposed subcutaneous tissue. Then, glass window is placed over exposed area to allow tumor growth to be monitored using fluorescent microscopy. Glass-covered tissue window allows for direct observation of tumor and its associated microvessels. Fluorescent (rhodamine)-labeled pegylated (stealth) liposomes are infused into tail vein and circulation of liposomes through tumor microcirculation is monitored with microscope while animal is lying in lateral recumbent position with window under microscope objective. (Reprinted with permission from [28]) Under normothermic conditions, imaging at 1 min shows tumor vasculature, but no extravasation of fluorescent liposomes. Similarly, at 30 min (B) and 60 min (C), no extravasation is seen.

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Fig. 1C —Effect of hyperthermia on extravasation of 100-nm liposomes in mouse window chamber model of human tumor (SKOV-3) xenograft, which is highly impermeable under normothermic conditions (34° C). In this model, xenograft is grown in dorsal skin fold (i.e., on back of mouse) inside window chamber. Skin along back of mouse is incised and tumor xenograft is placed on exposed subcutaneous tissue. Then, glass window is placed over exposed area to allow tumor growth to be monitored using fluorescent microscopy. Glass-covered tissue window allows for direct observation of tumor and its associated microvessels. Fluorescent (rhodamine)-labeled pegylated (stealth) liposomes are infused into tail vein and circulation of liposomes through tumor microcirculation is monitored with microscope while animal is lying in lateral recumbent position with window under microscope objective. (Reprinted with permission from [28]) Under normothermic conditions, imaging at 1 min shows tumor vasculature, but no extravasation of fluorescent liposomes. Similarly, at 30 min (B) and 60 min (C), no extravasation is seen.

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Fig. 1D —Effect of hyperthermia on extravasation of 100-nm liposomes in mouse window chamber model of human tumor (SKOV-3) xenograft, which is highly impermeable under normothermic conditions (34° C). In this model, xenograft is grown in dorsal skin fold (i.e., on back of mouse) inside window chamber. Skin along back of mouse is incised and tumor xenograft is placed on exposed subcutaneous tissue. Then, glass window is placed over exposed area to allow tumor growth to be monitored using fluorescent microscopy. Glass-covered tissue window allows for direct observation of tumor and its associated microvessels. Fluorescent (rhodamine)-labeled pegylated (stealth) liposomes are infused into tail vein and circulation of liposomes through tumor microcirculation is monitored with microscope while animal is lying in lateral recumbent position with window under microscope objective. (Reprinted with permission from [28]) On application of hyperthermia by heating tumor to 42° C, imaging at 1 min shows very small amount of extravasation of liposome as bright focus.

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Fig. 1E —Effect of hyperthermia on extravasation of 100-nm liposomes in mouse window chamber model of human tumor (SKOV-3) xenograft, which is highly impermeable under normothermic conditions (34° C). In this model, xenograft is grown in dorsal skin fold (i.e., on back of mouse) inside window chamber. Skin along back of mouse is incised and tumor xenograft is placed on exposed subcutaneous tissue. Then, glass window is placed over exposed area to allow tumor growth to be monitored using fluorescent microscopy. Glass-covered tissue window allows for direct observation of tumor and its associated microvessels. Fluorescent (rhodamine)-labeled pegylated (stealth) liposomes are infused into tail vein and circulation of liposomes through tumor microcirculation is monitored with microscope while animal is lying in lateral recumbent position with window under microscope objective. (Reprinted with permission from [28]) Imaging of hyperthermic tumor at 30 min shows more marked extravasation of liposomes (bright foci).

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Fig. 1F —Effect of hyperthermia on extravasation of 100-nm liposomes in mouse window chamber model of human tumor (SKOV-3) xenograft, which is highly impermeable under normothermic conditions (34° C). In this model, xenograft is grown in dorsal skin fold (i.e., on back of mouse) inside window chamber. Skin along back of mouse is incised and tumor xenograft is placed on exposed subcutaneous tissue. Then, glass window is placed over exposed area to allow tumor growth to be monitored using fluorescent microscopy. Glass-covered tissue window allows for direct observation of tumor and its associated microvessels. Fluorescent (rhodamine)-labeled pegylated (stealth) liposomes are infused into tail vein and circulation of liposomes through tumor microcirculation is monitored with microscope while animal is lying in lateral recumbent position with window under microscope objective. (Reprinted with permission from [28]) At 60 min, marked extravasation of liposomes (bright foci) is seen.

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Fig. 2A —Use of T1-weighted dynamic contrast-enhanced technique to evaluate permeability in patient with residual high-grade glioma after previous resection. Technique uses dynamic contrast-enhanced 3D spoiled gradient imaging sequence obtained every 6.45 sec for 58 sec after IV infusion of 0.1 mmol/kg of gadopentetate dimeglumine. Before contrast material infusion, five unenhanced T1-weighted spoiled gradient images are obtained, each using different flip angle to derive T1 values of tissue needed for analysis of permeability. Anatomic image obtained using contrast-enhanced T1-weighted spoiled gradient sequence through tumor shows lesion to have inhomogeneous contrast enhancement, with periphery of tumor having more marked contrast enhancement than central portion.

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Fig. 2B —Use of T1-weighted dynamic contrast-enhanced technique to evaluate permeability in patient with residual high-grade glioma after previous resection. Technique uses dynamic contrast-enhanced 3D spoiled gradient imaging sequence obtained every 6.45 sec for 58 sec after IV infusion of 0.1 mmol/kg of gadopentetate dimeglumine. Before contrast material infusion, five unenhanced T1-weighted spoiled gradient images are obtained, each using different flip angle to derive T1 values of tissue needed for analysis of permeability. Quantitative color-coded K_trans (volume transfer constant between blood plasma and extravascular extracellular space, min^-1) map obtained at same location as A showing range of K_trans values from 0.0 min^-1 (dark end of scale) to 0.1 min^-1 (bright end of scale) shows marked increase in permeability within much of periphery of tumor. (Map of K_trans generated using TOPPCAT software) [29]. (Image provided courtesy of Daniel Barboriak, MD)

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Fig. 2C —Use of T1-weighted dynamic contrast-enhanced technique to evaluate permeability in patient with residual high-grade glioma after previous resection. Technique uses dynamic contrast-enhanced 3D spoiled gradient imaging sequence obtained every 6.45 sec for 58 sec after IV infusion of 0.1 mmol/kg of gadopentetate dimeglumine. Before contrast material infusion, five unenhanced T1-weighted spoiled gradient images are obtained, each using different flip angle to derive T1 values of tissue needed for analysis of permeability. Color-coded quantitative map of degree of contrast enhancement, an indirect measure of permeability, superimposed on image in A depicts pixels that have peak signal intensity values between 120% and 139% of mode signal intensity value of contralateral hemisphere in blue, those between 140% and 159% in yellow, and those greater than 160% in red. Most of tumor has marked degree of contrast enhancement due to disruption of blood-brain barrier, and central portion has lower degree of enhancement, reflecting relatively well appearance of K_trans map in B.

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