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

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.

Received January 5, 2005; accepted after revision February 22, 2005.

 
Address correspondence to J. M. Provenzale.

Abstract

Top Abstract Introduction Relationship of Permeability and... Methods for Studying... Methods for Altering Rate... References

 
OBJECTIVE. Our purpose is to describe methods of assessing leakiness of the blood-brain barrier and explain mechanisms for exploiting the blood-brain barrier for therapeutic purposes.

CONCLUSION. Knowledge of the workings of the blood-brain barrier is important for an understanding of the ways in which blood-brain barrier permeability may be used as a surrogate marker for drug therapeutic response. Manipulation of the blood-brain barrier may provide a means for selectively targeting tumors for drug delivery.

Introduction

Top Abstract Introduction Relationship of Permeability and... Methods for Studying... Methods for Altering Rate... References

 
Blood-brain barrier permeability, or leakage of various substances across the blood-brain barrier, has long played an important role in brain imaging. The blood-brain barrier consists of a complex of capillary endothelial cells, pericytes, and astroglial and perivascular macrophages and serves as an effective physical barrier to the entry of lipophobic substances into the brain [1]. The permeability of the blood-brain barrier to most molecules is governed by their octanol/water partition coefficients [2]. In general, substances with high octanol/water partition coefficients easily cross the blood-brain barrier. However, exceptions to this general rule exist. For instance, some substances with low octanol/water partition coefficients can easily penetrate the blood-brain barrier due to active or facilitated transport, while other substances with high octanol/water partition coefficients poorly penetrate the blood-brain barrier due to active transport back into the blood [2]. A number of articles cover these factors comprehensively [2, 3].

It is well recognized that the blood-brain barrier is interrupted in the setting of high-grade tumors (and in other disease processes), which produces contrast enhancement on CT and MRI. However, the concept of permeability across the blood-brain barrier in brain tumor patients has recently gained renewed emphasis for a number of reasons. First, changes in permeability may serve as a surrogate marker for other important physiologic processes in brain tumors, such as angiogenesis. Second, an understanding of permeability can elucidate the mechanisms by which therapeutic agents enter brain parenchyma. Third, an understanding of methods for increasing permeability can help in the development of methods to selectively alter the blood-brain barrier to enhance drug delivery. This review will provide an understanding of current means to assess leakiness of the blood-brain barrier using human and animal tumor models and explain mechanisms for exploiting the interrupted blood-brain barrier for therapeutic purposes.

Relationship of Permeability and Angiogenesis

Top Abstract Introduction Relationship of Permeability and... Methods for Studying... Methods for Altering Rate... References

 
The importance of permeability has been underscored by the fact that substances that direct tumor growth also affect permeability. In the last few decades, the role of angiogenesis promoters in the growth of neoplasms has been increasingly recognized. It is now well-established that a tumor must develop its own vascular network to grow beyond a few millimeters in size [4]. The most dominant angiogenesis factor, vascular endothelial growth factor (VEGF), is a potent promoter of vascular permeability [5]. The neovasculature within tumors consists of vessels with increased permeability to macromolecules due to the presence of large endothelial cell gaps compared with normal vessels. One major method for assessment of permeability in a rodent model is fluorescence microscopy using a skin-fold window chamber. In such a model, the superstructure of a window with a metallic frame is placed on the animal's back and, after pulling the skin from the back, a circular window is cut from one surface, exposing underlying fascia. Tumor cells are transplanted onto the fascial surface and then the tissue is covered by a glass coverslip that fits into the metal chamber. The animal is then monitored while tumor growth occurs, allowing visualization of blood vessel formation. Using fluorescent microscopy, the extravasation of fluorescent-labeled particles from vessels can be used to measure permeability in a quantitative manner [6] (Figs. 1A, 1B, 1C, 1D, 1E, and 1F).

View larger version (94K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (77K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (60K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (101K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (134K): [in this window] [in a new window] [as a PowerPoint slide]   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).

View larger version (143K): [in this window] [in a new window] [as a PowerPoint slide]   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.

Examination of surgical resection specimens from human brain tumors has shown significant correlation of VEGF messenger RNA levels with capillary permeability and vascular volume [7]. Preclinical data have shown that antiangiogenesis agents that target VEGF produce decreases in vascular permeability [8]. Recent human clinical data also support this conjecture. A small series of patients with rectal cancer who were treated with a monoclonal VEGF antibody underwent measurement of tumor interstitial fluid pressure using a 23-gauge needle inserted through the working channel of a flexible sigmoidoscope into the tumor. The needle had a 2-3 mm side hole located 4-5 mm from the tip and was connected to tubing that allowed pressure measurements. That study showed decreases in interstitial fluid pressure after several days of therapy, which is consistent with a decrease in vascular permeability [9]. Therefore, measuring permeability in intracranial tumors may prove to be a valuable surrogate marker for assessing effectiveness of such agents. Evidence supporting this hypothesis can be seen in a number of animal models. For instance, MRI of breast tumor models in mice has shown alteration in permeability characteristics caused by treatment with VEGF antibody [10, 11]. In another study, investigators found a significant decrease in permeability after treating rats harboring a tumor raised from human glioblastoma multiforme cell lines with a monoclonal antibody raised against VEGF [12].

Methods for Studying Permeability in Human Brain Tumors

Top Abstract Introduction Relationship of Permeability and... Methods for Studying... Methods for Altering Rate... References

 
Most studies for assessing leakiness of the blood-brain barrier in human brain tumors have used T1-weighted techniques. The most commonly used technique is T1-weighted dynamic contrast-enhanced imaging [13]. Many investigators perform this technique using a 3D spoiled gradient acquisition steady-state technique that monitors contrast material accumulation over a few minutes rather than observing the first-pass phenomenon, as in T2^*-weighted imaging methods (Figs. 1A, 1B, 1C, 1D, 1E, and 1F). The advantages of this technique are a relatively short imaging time, a need for only a single dose of contrast material, and availability of a large number of user-friendly analysis programs. Although the anatomic resolution and spatial coverage are good using this technique, temporal resolution is relatively low [14]. One method for analyzing these data uses changes in signal intensity as an approximation of gadolinium tracer concentration and using a bidirectional two-compartment model to determine microvascular permeability, which is expressed as the transendothelial transfer constant k^PS (having units of mL/100 cm³/min). The mathematics of the bidirectional model have been well outlined [15]. Briefly, this model, as explained by Tofts et al. [16], measures the influx volume transfer constant (min^-1) between plasma and the extravascular, extracellular space, also known as the permeability surface area product per unit volume of tissue; and the volume of extravascular, extracellular space per unit volume of tissue. The efflux rate constant (min^-1) is the ratio of the first term (i.e., influx volume transfer constant) divided by the second term (i.e., volume of extravascular, extracellular space). This analysis technique does not depend on calculation of T1 values before infusion of contrast material, unlike other computational models that use change in T1 of tissue as an indicator of tissue concentration. In one study using this form of analysis, investigators using a dynamic contrast-enhanced technique to study microvascular permeability in human brain tumors found very good correlation between microvascular permeability and tumor grade [14].

In another study, which used first-pass data from solely the first minute of imaging after contrast material infusion and a first-pass pharmacokinetic model, investigators assessed endothelial permeability using an iterative estimation that decomposes tissue residue function into intravascular and extravascular components [17]. They reported that the technique provided a robust, reproducible method of measuring endothelial permeability that may be useful for therapeutic trials. In yet another study, investigators assessed a measurement of permeability termed the volume transfer constant (K^trans) in typical meningiomas and atypical meningiomas using dynamic contrast-enhanced perfusion MRI and found that the two tumor types could be distinguished using this method [18]. The volume transfer constant is a term used to describe the rate of passage of contrast agent from the intravascular space to the extracellular, extravascular space [19]. A voxel containing enhancing tissue can be thought of as having three compartments: intravascular plasma space; extracellular, extravascular space; and intravascular space. Because gadolinium-based contrast agents do not pass across the cell membrane, only the first two compartments mentioned need to be considered. The concentration of contrast material within any single voxel (C_t) is then a function of the proportion of the voxel that is composed of intravascular plasma space (v_p) and the proportion that is composed of the extracellular, extravascular space (v_e) and the concentration of contrast material in the intravascular plasma space (C_p) and that in the extracellular, extravascular space (C_e). The transfer of contrast material from the intravascular plasma space to the extracellular, extravascular space over time (t) is described by the equation:

Methods for Altering Rate of Transit of Agents Across the Blood-Brain Barrier

Top Abstract Introduction Relationship of Permeability and... Methods for Studying... Methods for Altering Rate... References

 
One of the major issues encountered in the development of novel methods of tumor therapy is the fact that many tumoricidal agents that are highly effective in vitro are ineffective in vivo [20]. A number of strategies have been used to increase the dose of therapeutic agent that could be provided to a tumor, such as increasing drug plasma concentration (e.g., intraarterial infusion), chemical modification to increase drug permeability, design of inactive drug precursors (so-called prodrugs) that could more easily cross the blood-brain barrier before conversion to a drug with active formulation, and osmotic disruption of the blood-brain barrier using mannitol [21]. A disadvantage of these methods is nonselective opening of the blood-brain barrier that also allows other substances to cross into normal brain tissue. One alternative is a receptor-mediated agent such as bradykinin and its synthetic analogue, receptor-mediated permeabilizer-7, which has the advantage of preferentially increasing the permeability of the blood-brain barrier solely at the tumor site [22].

One novel method that has a high degree of potential for selective delivery of chemotherapy across the blood-brain barrier is sequestration of a drug within a vehicle or carrier that could preferentially cross solely at the blood-tumor barrier. Liposomes, which are microscopic spherical vesicles constructed of phospholipid bilayers that can be designed to encapsulate contrast agents and drugs, may suit this purpose (Figs. 2A, 2B, and 2C). Considerable interest has been generated in understanding the mechanisms by which liposomes cross the blood-brain barrier under various physiologic conditions and developing methods for preferential delivery of liposomes at the tumor site. Liposomes passively target tumors in which there is disorganized vasculature [23]. This feature is more related to higher permeability than to disorganization per se [24-26]. However, specific features, such as vesicle size, chemical affinity, and thermal (or pH) sensitivities can be engineered, which provide the means for targeting liposomes for specific delivery to tumors.

View larger version (171K): [in this window] [in a new window] [as a PowerPoint slide]   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.

View larger version (120K): [in this window] [in a new window] [as a PowerPoint slide]   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 Ktrans (volume transfer constant between blood plasma and extravascular extracellular space, min-1) map obtained at same location as A showing range of Ktrans 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 Ktrans generated using TOPPCAT software) [29]. (Image provided courtesy of Daniel Barboriak, MD)

View larger version (119K): [in this window] [in a new window] [as a PowerPoint slide]   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 Ktrans map in B.

In conclusion, knowledge of the workings of the blood-brain barrier is important to comprehend the imaging features of brain tumors and understand the ways in which blood-brain barrier permeability may be used as a surrogate marker for drug therapeutic response. In addition, it appears likely that manipulation of the blood-brain barrier will provide a means for selectively targeting tumors for drug delivery.

References

Top Abstract Introduction Relationship of Permeability and... Methods for Studying... Methods for Altering Rate... References

 

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