Download Characterization of tumor angiogenesis with dynamic contrast

Magnetic Resonance in Medicine 60:1347–1352 (2008)
Characterization of Tumor Angiogenesis With Dynamic
Contrast-Enhanced MRI and Biodegradable
Macromolecular Contrast Agents in Mice
Yi Feng,1,2 Eun-Kee Jeong,3 Aaron M. Mohs,1 Lyska Emerson,4 and Zheng-Rong Lu1*
The efficacy of polydisulfide-based biodegradable macromolecular contrast agents for characterizing tumor angiogenesis
was investigated in a mouse model using dynamic contrastenhanced MRI (DCE-MRI). Biodegradable macromolecular MRI
contrast agents, gadopentetate dimeglumine (Gd-DTPA) cystamine copolymers (GDCC), and Gd-DTPA cystine copolymers
(GDCP), with molecular weights of 20 and 70 kDa were used in
the study. Gadodiamide (Gd [DTPA-BMA]) and albumin labeled
with Gd-DTPA [albumin-(Gd-DTPA)] were used as the controls.
The DCE-MRI studies were performed in nude mice bearing
prostate tumor xenografts from the MDA-PCa-2b cell line. Tumor angiogenic kinetic parameters, including endothelial transfer coefficient (KPS), fractional tumor plasma volume (fPV), and
permeability surface area product (PS), were estimated from
the DCE-MRI data using a two-compartment model. The KPS
and fPV values estimated by the biodegradable macromolecular
contrast agents were between those estimated by Gd(DTPABMA) and albumin-(Gd-DTPA). The parameters estimated by
the agent with a slow degradation rate and high molecular
weight, GDCP-70 (KPS ⴝ 2.09 ⴞ 0.50 ml/min/100 cc and fPV ⴝ
0.075 ⴞ 0.021), were closer to those by albumin-(Gd-DTPA)
(KPS ⴝ 1.43 ⴞ 0.64 ml/min/100 cc and fPV ⴝ 0.044 ⴞ 0.007) than
by other agents with relatively low molecular weight or rapid
degradation rate. The polydisulfide-based biodegradable macromolecular contrast agents are promising for characterizing
tumor vascularity and angiogenesis with DCE-MRI. Magn Reson Med 60:1347–1352, 2008. © 2008 Wiley-Liss, Inc.
Key words: DCE-MRI; tumor angiogenesis; biodegradable macromolecular contrast agent; Gd-DTPA cystamine copolymers;
GDCC; Gd-DTPA cystine copolymers; GDCP
Tumor angiogenesis is essential for tumor growth and
metastasis and the angiogenic tumor blood vessels are
chaotic with high vascular permeability (1). Accurate assessment of tumor angiogenesis based on tumor vascular
permeability or vascularity is crucial for tumor diagnosis
and prognosis, assessment of tumor treatment efficacy, and
cancer patient management (2–5). Dynamic contrast-enhanced MRI (DCE-MRI) can provide quantitative assess-
1Department of Pharmaceutics and Pharmaceutical Chemistry, University of
Utah, Salt Lake City, Utah, USA.
2Department of Materials Science and Engineering, University of Utah, Salt
Lake City, Utah, USA.
3Department of Radiology, University of Utah, Salt Lake City, Utah, USA.
4Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
Grant sponsor: National Institutes of Health (NIH); Grant numbers: R33
CA095873, R01 EB00489.
Current address for Aaron M. Mohs: Department of Biomedical Engineering,
Emory University and Georgia Institute of Technology, Atlanta, GA.
*Correspondence to: Zheng-Rong Lu, 421 Wakara Way, Suite 318, Salt Lake
City, UT 84108. E-mail: [email protected]
Received 29 January 2008; revised 17 June 2008; accepted 28 July 2008.
DOI 10.1002/mrm.21791
Published online in Wiley InterScience (www.interscience.wiley.com).
© 2008 Wiley-Liss, Inc.
ment of tumor vascular parameters such as the endothelial
transfer coefficient (KPS), fractional tumor plasma volume
(fPV), and permeability surface area product (PS) or related
parameters (6,7). It has been shown that these quantitative
parameters can be correlated to histological microvessel
density and tumor angiogenesis (3). DCE-MRI can also be
used to assess efficacy of tumor response to various therapies, including antiangiogenesis therapy (4).
Currently, DCE-MRI has been mostly performed by using low molecular weight Gd(III) chelates, e.g., gadopentetate dimeglumine (Gd-DTPA), as contrast agents to
characterize tumor vascularity. These agents can be used
to measure abnormal uptake of contrast agents in tumor
tissue in comparison with the uptake in the surrounding
normal tissue. However, they rapidly extravasate from the
blood to the extracellular space in tumor tissue. Consequently, DCE-MRI with these low molecular contrast
agents often gives overestimated results on tumor blood
volume and vascular permeability (8). Therefore, it is difficult to accurately assess tumor angiogenesis with these
agents (9,10). It has been reported that macromolecular
MRI contrast agents are effective in assessment of tumor
vascularity and characterization of individual tumor malignancy with DCE-MRI (3). DCE-MRI with macromolecular contrast agents of high molecular weight provides more
accurate assessment of tumor angiogenesis than the agents
with low molecular weights (11–14). Good correlation has
also been reported between the histological analysis and
tumor vascular permeability estimated by DCE-MRI and
macromolecular contrast agent, but not for low molecular
weight agents (5). Unfortunately, no macromolecular MRI
contrast agents are available for clinical applications because of the safety concerns related to their slow excretion
and high tissue accumulation of toxic Gd(III) ions.
We recently developed polydisulfide Gd(III) chelates as
biodegradable macromolecular MRI contrast agents to facilitate the excretion of Gd(III) chelates after MRI examinations (15–18). These agents initially behave as macromolecular agents and result in contrast enhancement superior to low molecular weight contrast agents in the
vasculature and tumor tissues, suggesting that they can be
used for the characterization of tumor angiogenesis with
DCE-MRI. They can be readily degraded in vivo into oligomeric and low molecular weight Gd(III) chelates, which
rapidly excrete from the body via renal filtration, resulting
in minimal tissue accumulation, similar to that of low
molecular weight contrast agents (16,19,20). The half-life
of the plasma distribution phase (␣) of Gd-DTPA cystamine copolymers (GDCC) (60 kDa) and Gd-DTPA cystine
copolymers (GDCP) (35 kDa) are 1.74 ⫾ 0.57 and 3.15 ⫾
1.26 min, respectively (19,20), longer than that of Gadodia-
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mide (Gd [DTPA-BMA]) (0.48 ⫾ 0.16 min) and shorter
than a nondegradable macromolecular agent, Gd-DTPA
hexanediamine copolymers (35 kDa, 5.92 ⫾ 2.02 min). The
long-term Gd tissue accumulation of the biodegradable
macromolecular agents is comparable to that of Gd(DTPABMA) (19,20). These agents have shown a great promise
for further clinical development.
The purpose of this study was to evaluate the potential
of the polydisulfide Gd(III) complexes in the characterization of tumor angiogenesis with DCE-MRI in an animal
tumor model. A two-compartment model was used for
calculating the tumor vascular parameters such as KPS, fPV,
and PS from the DCE-MRI data (6,8,21). The effect of the
size and biodegradability of the agents on the vascular
kinetic parameters was analyzed and compared to those
obtained with Gd (DTPA-BMA) and albumin labeled with
Gd-DTPA [albumin-(Gd-DTPA)].
MATERIALS AND METHODS
Contrast Agents
GDCC and GDCP were prepared as previously described
(16,22). They were fractionated using a preparative Superose 6 column on an AKTAPrime™plus (GE Biosciences,
Piscataway, NJ, USA) to prepare the agents with narrow
molecular weight distributions. The average molecular
weights of the fractions were determined by size exclusion
chromatography using linear poly[N-(2-hydroxypropyl)methacrylamide] as a standard with a analytic Superose 6
column on an AKTA fast protein liquid chromatography
(FPLC) system (GE Biosciences). Albumin-(Gd-DTPA) (92
kDa) is a nondegradable macromolecular contrast agent
and was prepared according to a published method (23).
The Gd(III) content in the agents was determined by inductively-coupled plasma optical emission spectroscopy
(ICP-OES) ( Optima 3100XL; Perkin Elmer).
Tumor Model and Animal Model
MDA-PCa-2b, a slow-growing prostate adenocarcinoma
cell line derived from bone metastasis, was obtained from
American Type Culture Collection (ATCC number: CRL2422). MDA-PCa-2b cells were cultured according to the
protocol provided by the ATCC. Athymic male nu/nu
nude mice (5 weeks old) were purchased from the National
Cancer Institute (Frederick, MD, USA). MDA-PCa-2b cell
suspensions in the complete medium (F12K medium with
2 mM L-glutamine, modified by ATCC) were mixed with
Matrigel matrix (BD Biosciences, San Jose, CA, USA) in a
1:1 ratio. Approximately 5 ⫻ 106 cells in 120 ␮l mixture
were inoculated subcutaneously in both hips of the mice.
DCE-MRI study was performed when the tumors reached
about 1 cm in diameter 2 months later.
DCE-MRI
All images were acquired on a Siemens Trio 3T scanner
using the system body coil for RF excitation and a human
wrist coil for RF reception. A group of three mice were
used for each agent. Mice were anesthetized by intraperitoneal injection of a mixture of ketamine (Bedford, OH,
USA; 90 mg/kg) and xylazine (St. Joseph, MO, USA;
Feng et al.
10 mg/kg). They were then placed prone with the tumors
located at the center of a human wrist coil. A tail vein of
the mouse was catheterized using a 30-gauge needle connected to a 2-m-long thin tubing filled with heparinized
saline. Contrast agent solution (120 ␮l) was injected via the
tubing and 200 ␮l saline was used to flush the tubing after
the injection of contrast agents. The dose for all contrast
agents was 0.1 mmol Gd/kg except that the dose for albumin-(Gd-DTPA) was 0.03 mmol Gd/kg as reported in the
literature.
Three-dimensional (3D) images of mice were acquired
using a 3D fast low angle shot (FLASH) sequence (TR/TE ⫽
7.75/2.56 ms, ␣ ⫽ 25°, coronal slice thickness ⫽ 0.5 mm,
averages ⫽ 4, fat saturation, and scan time ⫽ 1:21 min:s)
before contrast administration. The heart and tumor were
located at 3D FLASH images. Two-dimensional axial images of the heart and tumor were then acquired using a
T1-weighted 2D spin echo (SE) sequence (TR/TE ⫽ 400/
10 ms, ␣ ⫽ 90°, axial slice thickness ⫽ 2 mm, averages ⫽
2, fat saturation, slices ⫽ 8, and scan time ⫽ 1:01 min:s).
Dynamic MRI scans were performed with a 2D FLASH
sequence (TR/TE ⫽ 58/4.03 ms, ␣ ⫽ 30°, axial slice thickness ⫽ 2 mm, acquisitions ⫽ 1, acquisition size ⫽ 1 ⫻ 1 ⫻
2 mm, axial slices ⫽ 6, and scan time ⫽ 6 s). The first slice
was selected to cover the heart and the rest slices were
selected to cover the majority of the tumor tissues. After a
30-s delay, the contrast agent was administered by bolus
injection via the catheter. The duration of data acquisition
was 45 min for the mice injected with albumin-(Gd-DTPA)
and 30 min for the mice injected with all other contrast
agents.
Image Analysis
The 3D FLASH and 2D SE images were reconstructed and
analyzed using Osirix (http://homepage.mac.com/rossetantoine/osirix). A package of programs based on MATLAB
(The MathWorks, Inc., Natick, MA, USA) was developed
to process dynamic 2D FLASH data in the digital imaging
and communications in medicine (DICOM) format. Regions of interest (ROIs) were placed in the whole tumor
and in the right ventricle of the heart to obtain signal
intensity (SI) of the blood. The average MR SI (SIpre) of ROI
before the contrast agent injection was used as the baseline
and was subtracted from the SI after contrast agent injection (SIpost) to calculate the increase in SI (⌬SI). It is assumed that ⌬SI is proportional to the change of the contrast agent concentration, which is a reasonable approximation at low contrast agent concentration (21). A twocompartment model (Fig. 1) consisting of the tumor
plasma compartment and the extravascular and extracellular space (EES) was used for analyzing DCE-MRI data
(21). The tumor KPS, fPV, and PS were similarly calculated
by the methods as described in the literature (21). Since a
high temporal resolution of 6 s per acquisition was used in
this study, the maximum blood ⌬SI was used directly to
calculate the fPV. The extrapolation method in case of
1 min per acquisition in the literature (21) is no longer
needed.
Statistical Analysis
Statistical analysis was performed using a Student’s t-test
(GraphPad Prism; GraphPad Software, San Diego, CA,
Biodegradable Macromolecular Contrast Agents
1349
FIG. 1. Diagram of a two-compartment model describing kinetics of
exchange of contrast agent between fPV and EES in tumor tissue.
USA). P-values were two-tailed with a confidence interval
of 95%.
RESULTS
Contrast Agents
The polydisulfide Gd(III) complexes, GDCC and GDCP, of
different molecular weights and narrow molecular weight
distribution, were prepared by the fractionation of the
polymeric agents using size-exclusion chromatography.
GDCP is a modified polydisulfide Gd(III) complex of GDCC
with a slower degradation rate (15). Table 1 lists the physicochemical parameters of the contrast agents, including
the number average molecular weight (Mn), weight average
molecular weight (Mw), polydispersion index (PDI), and T1
relaxivity per complexed Gd(III) ion at 3T. The agents with
molecular weights of 20 and 70 kDa, GDCC-20, GDCC-70,
GDCP-20, and GDCP-70, were chosen to represent biodegradable macromolecular MRI contrast agents of relatively
low and high molecular weights for studying the size
effect. The apparent molecular weights of albumin-(GdDTPA) were smaller than its true molecular weight because they were measured as the hydrodynamic volume
relative to the linear poly[N-(2-hydroxypropyl)methacrylamide] standards in order to better compare to the linear
biodegradable macromolecular contrast agents.
Table 1
Mn, Mw, PDI, and Relaxivity (r1 at 3T) of the Contrast Agents
Contrast agent
Mn
(kDa)
Mw
(kDa)
PDI
Relaxivity (r1)
(mM⫺1s⫺1)
Gd (DTPA-BMA)
GDCC-20
GDCC-20
GDCP-70
GDCP-70
Albumin-(Gd-DTPA)
0.574
19
19
68
68
44
0.574
21
21
73
73
45
N/A
1.10
1.07
1.10
1.07
1.02
4.62
5.45
6.04
5.35
6.44
7.05
FIG. 2. Representative SI time curve of the heart (a) and the whole
tumor (b) after contrast agent injection.
DCE-MRI
Figure 2a depicts representative kinetics of the MR SI of
the blood in the heart before and after injection of the
contrast agents. Strong and prolonged enhancement was
observed in the blood with the agents of high molecular
weights and low degradability. Gd (DTPA-BMA) cleared
more rapidly from the blood than the macromolecular
contrast agents. GDCC-20 and GDCP-20 reached peak SI
about 2 min after injection and started to clear quickly as
compared to the corresponding high molecular weight
agents. The blood enhancement by GDCC-70 after the peak
enhancement decayed more rapidly than that with
GDCP-70 because of the high biodegradability of GDCC.
The nondegradable control agent, albumin-(Gd-DTPA),
maintained a high blood enhancement during the period
of data acquisition.
Figure 2b shows the representative kinetics of the MR SI
in the tumor tissue. The peak time of SI delayed as the
molecular weight of the agents increased and their degradability decreased. The peak enhancement by GDCP-70 was
reached about 30 min after injection, while the enhancement of tumor by albumin-(Gd-DTPA) was still increasing
at 30 min after injection. The infusion of contrast agents
into the tumor EES is controlled by their size and concentration in the blood, and the permeability of the tumor
microvasculature. The initial signal rise indicated the
plasma volume or EES measured by the contrast agents
based on their size-dependent infusion into tumor tissue.
With the increasing concentration of the contrast agents in
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Feng et al.
Table 2
Estimated Values of fPV, KPS, and PS Estimated by DCE-MRI Using Gd (DTPA-BMA), GDCC-20, GDCP-20, GDCC-70, GDCP-70, and
Albumin-(Gd-DTPA)*
Gd DTPA-BMA
GDCC-20
GDCP-20
GDCC-70
GDCP-70
Albumin-(Gd-DTPA)
fPV
KPS (ml/min/100 cc)
PS (ml/min/100 cc)
0.161 ⫾ 0.018
0.117 ⫾ 0.010
0.112 ⫾ 0.029a
0.087 ⫾ 0.005
0.075 ⫾ 0.021
0.044 ⫾ 0.007
29.08 ⫾ 10.95
9.98 ⫾ 1.75
11.08 ⫾ 5.63a
6.75 ⫾ 0.16
2.09 ⫾ 0.50b
1.43 ⫾ 0.64
4.809 ⫾ 2.385
1.170 ⫾ 0.209a
1.343 ⫾ 1.001a
0.586 ⫾ 0.047
0.161 ⫾ 0.070
0.064 ⫾ 0.029
*The difference is significant when the parameters estimated by the biodegradable macromolecular contrast agents are compared to those
by albumin-(Gd-DTPA) and Gd DTPA-BMA, unless indicated otherwise.
aStatistically not significantly different when compared to Gd (DTPA-BMA).
bStatistically not significantly different when compared to albumin-(Gd-DTPA).
the tumor and the decreasing concentration in the blood
due to excretion, the SI in tumor would reach a plateau
and then decrease. The larger the contrast agent of the
same degradability, the later the plateau was reached.
The kinetic parameters of the tumor vascularity (fPV, KPS,
and PS) estimated by DCE-MRI using the biodegradable
macromolecular contrast agents and control agents are
listed in Table 2. The comparison of the vascular parameters estimated by different contrast agents is shown in
Fig. 3. Gd (DTPA-BMA) had the highest fPV, KPS, and PS
values, while albumin-(Gd-DTPA) had the lowest fPV, KPS,
and PS values. The values estimated by GDCC-20, GDCP20, GDCC-70, and GDCP-70 were between those by Gd
(DTPA-BMA) and albumin-(Gd-DTPA). GDCC and GDCP
of 70 kDa had lower values of fPV, KPS, and PS than the
corresponding agents of 20 kDa. At the same molecular
weight, GDCP had smaller values of fPV, KPS, and PS than
GDCC. The fPV of MDA-PCa-2b prostate adenocarcinoma
xenografts estimated using albumin-(Gd-DTPA) was
0.044 ⫾ 0.007, which was in the same range of reported
FIG. 3. Tumor vascular parameters, fPV (a), KPS (b), and PS (c),
estimated by DCE-MRI using albumin-(Gd-DTPA), GDCP-70,
GDCC-70, GDCP-20, GDCC-20, and Gd (DTPA-BMA), respectively.
data (0.034 ⫾ 0.02 and 0.064 ⫾ 0.055) of other tumor
models (3,6). The reported KPS with albumin-(Gd-DTPA)
varied from tumor models (3,6,24), which was also different from the data in this study, possibly because different
tumor models had different vascular permeability.
DISCUSSION
This study is the first attempt of using biodegradable macromolecular MRI contrast agents for characterizing tumor
angiogenesis with DCE-MRI. Angiogenic tumor vasculature is hyperpermeable to macromolecules. The vascular
parameters KPS and PS measured by macromolecular MRI
contrast agents with DCE-MRI can represent the tumor
vascular permeability and can also be used for quantitative
assessment of tumor angiogenesis (8,24). Polydisulfide
Gd(III) complexes are promising biodegradable macromolecular MRI contrast agents for further clinical development. The results in this study have shown that the tumor
vascular kinetic parameters (fPV, KPS, and PS) measured by
DCE-MRI depend on the size and degradability of the
agents.
The fractional plasma volume (fPV) determined by
GDCC-20 and GDCP-20 was relatively high, which may be
attributed to the relatively rapid diffusion of the agents
into tumor extracellular space, similar to the low molecular weight agent Gd (DTPA-BMA). It is hypothesized that
the high values of fPV obtained with low molecular weight
contrast agents are due to their relatively rapid extravasation into the tumor EES (8,24). The rapid uptake of the low
molecular weight contrast agents was evidenced by the
tumor contrast uptake kinetics (Fig. 2b). The values from
GDCC-20 and GDCP-20 may overestimate the tumor fractional plasma volume due to diffusion. This may also be
the reason why GDCC-20 and GDCP-20 had similar tumor
uptake kinetics, while GDCC-70 and GDCP-70 had different uptake kinetics due to their difference in degradability.
The fPV measured by the GDCC-70 and GDCP-70 was relatively low because of limited diffusion due to their large
size. The fPV from GDCC-70 and GDCP-70 was slightly
higher than that estimated by albumin-(Gd-DTPA) because
the low molecular weight degradation products of
GDCC-70 and GDCP-70 could diffuse into tumor extracellular space, even though GDCC-70 and GDCP-70 initially
had a larger hydrodynamic volume.
The KPS and PS measured by the biodegradable macromolecular contrast agents are significantly smaller than
Biodegradable Macromolecular Contrast Agents
1351
Table 3
Ratios of the Parameters Estimated by GDCP-70, GDCC-70,
GDCP-20, GDC-20, and Gd DTPA-BMA to those Estimated by
Albumin-(Gd-DTPA)
Ratio GDCP-70 GDCC-70 GDCP-20 GDCC-20 Gd DTPA-BMA
R(fPV)
R(KPS)
R(PS)
1.7
1.5
2.5
2.0
4.7
9.2
2.5
7.7
21.0
2.7
6.9
18.3
3.7
20.3
75.2
those determined by Gd (DTPA-BMA), possibly due to
their limited diffusion (8,24). The difference in biodegradability between GDCC and GDCP did not affect the KPS and
PS measured by GDCC-20 and GDCP-20, possibly because
of their relatively high diffusion rate from the blood to
tumor extracellular space. For the agents with higher molecular weights, GDCC-70 with high degradability gave
higher values for KPS and PS than GDCP-70. Based on the
tumor kinetic uptake in Fig. 2b, it is plausible to assume
that the rapid degradation of GDCC in the blood plasma
resulted in higher uptake rate for GDCC-70 than GDCP-70
due to diffusion of the low molecular weight degradation
products into tumor extracellular space. Nevertheless, the
parameters measured by the degradable macromolecular
MRI contrast agents with high molecular weights were
closer to those estimated by albumin-(Gd-DTPA).
The difference of the tumor vascular parameters of the
different contract agents can also be expressed as the ratios
of the parameters to those measured by albumin-(GdDTPA) (Table 3). The ratios might be an indictor of the
deviation of these vascular parameters caused by the diffusion of the contrast agents. Gd (DTPA-BMA) had the
highest deviation, possibly because of its highest diffusion
rate from blood to tumor among the tested agents. The
deviation of the biodegradable macromolecular contrast
agents with high molecular weight was much smaller than
other tested agents. Although it is difficult to know the
exact kinetic vascular parameters of tumor tissue, it is
reasonable to deduce that GDCP-70 and GDCC-70 can be
effective to evaluate tumor angiogenesis with DCE-MRI
based on the tumor vascular kinetic parameters.
Noninvasive and accurate evaluation of tumor angiogenesis is critical for tumor characterization and assessment of
tumor response to anticancer treatment, particularly antiangiogenesis therapies. Although it has been demonstrated
that DCE-MRI with macromolecular MRI contrast agents is
more accurate to evaluate tumor angiogenesis than that
with small molecular contrast agents, clinical development of macromolecular contrast agents are limited by
their slow excretion and prolonged tissue accumulation.
This study has shown that polydisulfide-based biodegradable macromolecular MRI contrast agents are effective for
evaluation of tumor angiogenesis with DCE-MRI. One concern for the biodegradable macromolecular contrast agents
is the change of the relaxivities of Gd(III) chelates after the
degradation of the macromolecules. As shown in this
study and our previous studies, the relaxivities of macromolecular contrast agents generally decrease as their molecular weights decrease, but the change of the relaxivities
of GDCC and GDCP is not dramatic among the agents of
different molecular weights (16). Since DCE-MRI is not a
perfectly quantitative method, a slight change in relaxivities due to the degradation of the macromolecules may not
be a great concern for assessing tumor angiogenesis. Another concern is the change of pharmacokinetics of lower
molecular weight degradation products, which may complicate the kinetic analysis of the DCE-MRI data. As we
have shown in this study, although the degradability and
size of the biodegradable macromolecular contrast agent
affect the vascular kinetic parameters, the parameters estimated by the biodegradable macromolecular contrast
agents, particularly those with relatively large sizes, are
comparable to those estimated by albumin-(Gd-DTPA).
The two-compartment model used here is commonly used
for DCE-MRI with macromolecular contrast agents, which
is focused on the initial permeation of the contrast agents
in the tumor tissue. However, the method used for analyzing the DCE-MRI data is empirical and does not include
curve-fitting of the kinetic data. In order to more accurately
investigate the effectiveness of the biodegradable macromolecular MRI contrast agents on assessing tumor angiogenesis with DCE-MRI, further study is ongoing to analyze
the DCE-MRI data with the biodegradable macromolecular
MRI contrast agents using other reported kinetic models.
CONCLUSIONS
Polydisulfide-based biodegradable macromolecular contrast agents are effective for evaluation of tumor angiogenesis with DCE-MRI in an animal tumor model. The size of
biodegradable macromolecular contrast agents has a significant effect on the vascular kinetic parameters. The
degradability only has a significant impact on the agents of
the high molecular weights. The biodegradable macromolecular agents with high molecular weights may provide
more accurate assessment on tumor vascularity and angiogenesis with DCE-MRI than the low molecular weight
agents.
ACKNOWLEDGEMENTS
We thank Dr. Yong-En Sun for the animal handling, Melody Johnson for the operation of MRI scanner.
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