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Radiation dosimetry estimates of 18F-alfatide II based on whole-body PET imaging of mice
Applied Radiation and Isotopes 105 (2015) 1–5
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Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Radiochemistry and radionuclide applications - A
Radiation dosimetry estimates of PET imaging of mice
18
F-alfatide II based on whole-body
Si-yang Wang a,b,c,d, Xiao Bao a,b,c,d, Ming-wei Wang a,b,c,d, Yong-ping Zhang a,b,c,d, Ying-jian Zhang a,b,c,d, Jian-ping Zhang a,b,c,d,n a
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China c Center for Biomedical Imaging, Fudan University, Shanghai, China d Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai, China b
H I G H L I G H T S
G R A P H I C A L
A B S T R A C T
We demonstrated a proper mice model to estimate human radiation dosimetry. This is the first paper to estimate human radiation dosimetry of 18 F-alfatide II. Estimated effective dose are in the range of routine nuclear medicine studies.
art ic l e i nf o
a b s t r a c t
Article history: Received 16 December 2014 Received in revised form 7 July 2015 Accepted 11 July 2015 Available online 13 July 2015
We estimated the dosimetry of 18F-alfatide II with the method established by MIRD based on biodistribution data of mice. Six mice (three females and three males) were scanned for 160 min on an Inveon MicroPET/CT scanner after injection of 18F-alfatide II via tail vein. Eight source organs were delineated on the CT images and their residence times calculated. The data was then converted to human using scaling factors based on organ and body weight. The absorbed doses for human and the resulting effective dose were computed by OLINDA 1.1 software. The highest absorbed doses was observed in urinary bladder wall (male 0.102 mGy/MBq, female 0.147 mGy/MBq); and the lowest one was detected in brain (male 0.0030 mGy/MBq, female 0.0036). The total effective doses were 0.0127 mSv/MBq for male and 0.0166 mSv/MBq for female, respectively. A 370-MBq injection of 18F-alfatide II led to an estimated effective dose of 4.70 mSv for male and 6.14 mSv for female. The potential radiation burden associated with 18F-alfatide II/PET imaging therefore is comparable to other PET examinations. & 2015 Elsevier Ltd. All rights reserved.
Keywords: 18 F-alfatide II Biodistribution Radiation dosimetry
1. Introduction Positron-emission tomography (PET) is a diagnostic imaging technique based on the use of a positron-emitting radionuclide. 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET/CT outperformed FDG-PET by 10% in sensitivity, 20% in specificity, and 16% in n
Corresponding author at: No. 270, Dong'an Road, Xuhui District, Shanghai, China. E-mail address: [email protected] (J.-p. Zhang).
http://dx.doi.org/10.1016/j.apradiso.2015.07.013 0969-8043/& 2015 Elsevier Ltd. All rights reserved.
accuracy, showing the higher diagnostic accuracy of PET/CT (Kitajima et al., 2009). 18F-FDG is currently the most widely used PET probe for many kinds of cancers. However, it still has drawbacks because a high uptake is not necessarily associated with a tumor. The false-positive results could be caused by various factors, including different infection forms, inflammation, granulomatous
2
S.-y. Wang et al. / Applied Radiation and Isotopes 105 (2015) 1–5
disease, and even many other physiological or pathological conditions (Culverwell et al., 2011); meanwhile, the false-negative was frequently observed in tumors with lower glucose metabolism. In recent years, the peptide ligand of integrin αvβ3 with the sequence of arginine–glycine–aspartic acid (RGD) has been modified and labeled with various radionuclides for either singlephoton emission computed tomography or PET imaging of tumor angiogenesis (Ahmadi et al., 2008; Chen et al., 2004; Jeong et al., 2008; Jacobson et al., 2011). It is widely accepted that imaging of tumor angiogenesis with RGD could be used not only for early detection of cancers, but also for monitoring treatment outcomes (Beer et al., 2011). In previous studies, (Guo et al., 2014) the newly synthesized 18F-AlF-NOTA-E[PEG4-c(RGDfk)] 2 (denoted as 18 F-alfatide II) conjugates could withstand treatments during heating, solvent evaporation, pH adjustment, serum incubation, and in vivo circulation without detectable hydrolysis. More importantly, 18F-alfatide II appeared to be superior to 18F-alfatide I due to the lower liver uptake and higher tumor accumulation, which had been proved by in vivo imaging data (tumor uptake and tumor/non-tumor ratios). However, internal dosimetry data for 18F-alfatide II in human has not been available in the literature yet. The aim of this study was to assess the biodistribution of 18F-alfatide II in mice and extrapolate it to humans as well as establish the radiation dose estimates.
2. Experimental procedures 2.1. Radiopharmaceutical preparation The 18F-alfatide II was obtained from PET Center, Fudan University Shanghai Cancer Center. The synthesis of the 18F-alfatide II was based on the technique described in previous published papers (Guo et al., 2014; Kiesewetter et al., 2012). After comparison of three dimeric 18F-AlF-NOTA-RGD Tracers (Guo et al., 2014), we used NOTA-PEG4-E[c(RGDfk)2] as precursor. The radiochemical purity of the 18F-alfatide II syntheses was above 98%, assessed by an analytical high performance liquid chromatography system equipped with an ultraviolet and radioactivity detector, and the radiochemical yield was more than 40% (decay corrected), with specific activity of 21 MBq/mmol.
correction of PET images and to provide anatomical identification of mouse organs of interest in the study. 2.3. Image analysis Analysis of reconstructed images was performed with Inveon Research Workplace software. For each MicroPET/CT scans, 3D volumes of interest (VOIs) were drawn manually on the following “source” organs: brain, lung, liver, heart wall, kidney, small intestine and large intestine. All of the source organs were identified, and the VOIs were drawn as irregular contours on the high-resolution CT images. The size of each VOI was smaller than the actual size of each organ in order to reduce the PET effects of spill in and spill over from adjacent organs. We chose these organs because they were the main parenchymatous organs in body and secondly, were defined as source organs in the software OLINDAEXM 1.1. All VOIs were transferred to dynamic PET images and the decay-corrected mean time activity curves (TACs) were extracted for each source organ. 2.4. Residence times and absorbed dose calculations Not decay-corrected TACs were traced and the area under the curve for each organ was calculated using trapezoidal method up to the last time point at 160 min. For the sake of a conservative dose estimate, we calculated the area under the curve from the last time point to infinity assuming that only physical decay of 18F occurred (i.e., there was no biologic clearance after the last time point 160 min). The area under the curve between the time of 18 F-alfatide II injection and start of the scan was computed assuming linearity. The area under the TAC of source organ from zero to infinity was regarded as the residence times (Van Laere et al., 2008). Further, we used the method of Kirschner to extrapolate the animal data obtained from normal mice after injection of 18 F-alfatide II to obtain the residence times of human Blau (1975). The extrapolation formula was given by
⎧ ⎪
(ROrgan )Human = n1 ⎨⎪
⎩ i = 1,2, … , n
⎧ ⎪ ⎨ ROrgan ⎪ ⎩
(
⎛ mOrgan ⎞ ⎟⎟ × ⎜⎜ ⎝ MTB weight ⎠Human
2.2. PET and CT scanning All the animal studies were conducted in compliance with Institutional Animal Care and Use Committee (IACUC) guidelines. MicroPET/CT scans and image analysis were performed using an Inveon MicroPET/CT (Siemens Medical Solution). Each mouse was injected with 9.77 71.63 MBq of 18F-alfatide II via tail vein, and then immediately put on the scanner bed in an imaging chamber. 160 min PET dynamic acquisitions were performed by the Inveondedicated PET scanner. The average delay between the time of injection and start of the PET acquisition was 4 min. After the PET acquisition, each mouse received a 20 min high-resolution CT scan with the Inveon MM CT scanner. The animals were maintained under 2% isoflurane anesthesia throughout the scanning period. The PET raw data were dynamically sorted into 27 frames (8 1, 8 2, 6 6 and 5 20 min) and were reconstructed using three-dimensional ordered-subset expectation maximization/ maximum algorithm (OSEM3D/MAP). All dynamic images were automatically corrected for radioactive decay according to manufacturer software settings. Following the reconstruction, the CT images were spatially aligned to match the PET images using a fixed, predetermined transformation matrix. The CT scan served two purposes: to acquire an attenuation map for attenuation
∑
( )
where ROrgan
(
gan, ROrgan
)
Mice (i )
Human
⎫⎫ ⎛ MTB weight ⎞ ⎪⎪ ⎟⎟ ⎬⎬ mOrgan ⎠ ⎪⎪ Mice (i) ⎭ ⎭
)Mice (i) × ⎜⎜⎝
(1)
denoted the residence times of human or-
represent the residence times of the mice (n ¼3),
⎛ MTB weight ⎞ ⎜ ⎟ was the ratio between the weights of the i-th mice ⎝ mOrgan ⎠Mice (i)
⎛ mOrgan ⎞ ⎜ ⎟ was the ratio be⎝ MTB weight ⎠Human tween the weights of human organ and human body. The residence times of the “remainder of body” of human was calculated for each formulated time point, which was the difference between the decayed value of all residence times in the whole body of human and the residence times in the animals’ source organs. When performing the extrapolation, the residence times of animal organs ROrgan , the whole body weight of the animal, the organ and the mice body, and
(
)
Mice
weight of human organs and whole body must be given. The human total body weight (MTB weight )Human and the human organ masses (morgan )Human were taken from OLINDA/EXM 1.1 for adult female and adult male phantoms, respectively. The volume of animals' source organ was delineated manually on every section of the high-resolution CT images, and then multiplied by a default density of 1 g/ml to obtain the weight of source organs besides
S.-y. Wang et al. / Applied Radiation and Isotopes 105 (2015) 1–5
that of lung. A density of 0.3 g/ml was used to calculate the weight of lung. The absorbed doses in healthy human bodies were estimated using the organ residence times data above by OLINDA/EXM 1.1 program (Vanderbilt University, Nashville, TN, USA). The effective dose (ED) then was calculated according to its definition in ICRP 103.
3
shown in Fig.1, where rapid accumulation of the radioactivity into the kidneys was observed, reaching the highest uptake value at 10 min after injection. There was a relatively low level of uptake in brain and large intestine. 18F-alfatide II showed predominant renal clearance and minimal hepatobiliary excretion. 3.2. Residence times and absorbed dose calculations
3. Results 3.1. Biodistribution The decay-corrected time-activity curves for the brain, liver, heart, lung, kidney, small intestine wall, upper large intestine and lower large intestine of mice after injection of 18F-alfatide II were
Fig. 1. Time activity curves for major organ uptake of LLI ¼ lower large intestine.
18
Table 1 shows the residence times of 18F-alfatide II for mice of the 8 selected organs. It was demonstrated that the reminder had the largest residence times (male: 9.28E 01 71.93E 01 MBq h/ MBq; female: 7.92E 017 1.23E 01 MBq h/MBq), followed by the urinary bladder wall (male: 7.06E 017 1.50E 01 MBq h/MBq; female: 8.88E 017 1.08E 01 MBq h/MBq) and the liver (male: 5.84E 02 71.10E 02 MBq h/MBq female: 3.63E 027 9.65E
F-alfatide II for male mice (A, B and C) and female mice (D, E and F). SI¼ small intestine, ULI ¼upper large intestine,
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S.-y. Wang et al. / Applied Radiation and Isotopes 105 (2015) 1–5
Table 1 Residence times (MBq h/MBq) of
18
F-alfatide II in mouse organs.
Organ
Male average ( 7 SD)
Female average ( 7SD)
Brain Lungs Heart Wall Liver Kidneys UB Contenta Small intestine ULIa LLIa Remainder
3.34E 037 6.68E 04 6.21E 037 2.03E 03 6.35E 037 2.45E 03 5.84E 027 1.10E 02 2.58E 027 1.27E 02 7.06E 017 1.50E 01 5.87E 027 1.32E 02 7.86E 037 2.00E 03 4.96E 037 1.04E 03 9.28E 017 1.93E 01
2.67E 037 1.54E 04 8.49E 037 2.66E 03 3.74E 037 1.08E 03 3.63E 027 9.65E 03 1.67E 027 8.36E 03 8.88E 017 1.09E 01 2.94E 027 1.20E 02 4.89E 037 1.00E 03 2.03E 037 1.15E 03 7.92E 017 1.23E 01
a
UB ¼urinary bladder, ULI ¼ upper large intestine, LLI ¼ lower large intestine.
Table 2 Human residence times (MBq h/MBq) estimates of residence times and real organ mass.
18
F-alfatide II based on mouse
Organ
Male average
Female average
Brain Lungs Heart Wall Liver Kidneys UB Contenta Small Intestine ULIa LLIa Remainder
4.73E 037 9.45E 04 2.49E 027 8.16E 03 2.95E 037 1.14E 03 2.05E 027 3.87E 03 1.02E 027 5.04E 03 1.95E 017 4.17E 02 7.57E 037 1.70E 03 1.96E 037 4.97E 04 9.36E 04 7 1.96E 04 1.92E 007 6.52E 02
3.68E 037 3.76E 04 1.38E 027 3.07E 03 1.70E 037 4.92E 04 1.21E 027 3.22E 03 8.69E 037 4.22E 03 2.05E 017 5.75E 02 4.36E 037 1.78E 03 1.43E 037 2.93E 04 4.75E 04 7 2.69E 04 1.97E 007 9.98E 02
a
UB ¼urinary bladder, ULI ¼ upper large intestine, LLI ¼ lower large intestine.
03 MBq h/MBq). Other organs had shorter residence times. Table 2 lists the mean residence times for both adult female and male phantoms. The largest values were found in the reminder, and then in urinary bladder wall and lung for both male and female phantoms. As shown in Table 3, the ED of 18F-alfatide II organ dosimetry for the adult phantom were 1.27E 02 7 3.69E 04 mSv/MBq for male and 1.66E 02 71.13E 03 mSv/ MBq for female, respectively. For the male adult, the organ of the highest absorbed dose was the urinary bladder wall (1.02E 01 71.92E 02 mGy/MBq); followed by the osteogenic cell (1.47E 0274.51E 04 mGy/MBq) and lower large intestine wall (1.38E 02 72.65E 04 mGy/MBq). The brain showed the lowest absorbed doses (2.91E 03 72.22E 04 mGy/MBq). As for female adult, urinary bladder wall (1.47E 01 73.74E 02 mGy/ MBq) was also the organ of the highest absorbed dose while the brain was the lowest one (3.57E 03 71.88E 04 mGy/MBq).
4. Discussion In this paper, we studied the biodistribution of 18F-alfatide II in mice to estimate radiation absorbed dose of 18F-alfatide II in healthy human. PET imaging technique provided an optimal noninvasive method, which could quantitatively measure the in vivo tissue biodistribution of radiopharmaceuticals on human or animal (Ding and Wu, 2012). The availability of preclinical PET and CT scanners and the existence of physical models for internal dose assessment in small animals allowed preliminary evaluation of tracer biodistribution in mice or rats and extrapolation it to humans. Although this method might potentially lead to errors when applying in large animals and inter-species, and that metabolic variation could introduce errors when extrapolating the data of animals to human (Moerlein et al., 1997; Zhang et al., 2012), it was relatively simple, time saving and economic. Thus, this method has
Table 3 Estimates of human absorbed dose (mGy/MBq) and effective dose (mSv/MBq) of 18 F-alfatide II with Hermaphroditic Adult Phantom from mice's biodistribution. Target organ
Male
Female
Adrenals Brain Breasts Gallbladder wall LLI wall SI Stomach wall ULI wall Heart wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red marrow Osteogenic Cells Skin Spleen Testes Thymus Thyroid Urinary Bladder wall Uterus Total body Effective dose (mSv/MBq)
1.05E 027 5.09E 04 2.91E 037 2.22E 04 7.77E 037 3.20E 04 1.08E 027 4.58E 04 1.38E 027 2.65E 04 1.32E 027 4.62E 04 1.06E 027 4.04E 04 1.18E 027 4.58E 04 7.40E 037 9.03E 04 1.16E 027 3.26E 03 6.61E 037 6.67E 04 8.97E 037 1.59E 03 9.84E 037 2.42E 04 NA 1.11E 027 4.51E 04 9.16E 037 2.65E 04 1.47E 027 4.51E 04 7.54E 037 2.25E 04 1.04E 027 4.51E 04 1.10E 027 1.00E 04 9.61E 037 4.00E 04 9.63E 037 3.50E 04 1.02E 017 1.92E 02 NA 9.80E 037 2.90E 04 1.27E 02 73.69E 04
1.34E 027 6.66E 04 3.57E 037 1.88E 04 1.00E 027 4.94E 04 1.29E 027 6.08E 04 1.74E 027 1.53E 04 1.46E 027 5.51E 04 1.35E 027 6.35E 04 1.46E 027 5.20E 04 8.47E 037 6.80E 04 1.23E 027 2.69E 03 7.24E 037 6.95E 04 9.57E 037 9.12E 04 1.24E 027 2.69E 03 1.72E 027 2.08E 04 1.41E 027 6.93E 04 1.16E 02 73.79E 04 1.96E 027 8.66E 04 9.56E 037 3.78E 04 1.32E 027 6.43E 04 NA 1.25E 027 6.66E 04 1.15E 02 75.77E 04 1.47E 017 3.74E 02 2.09E 027 1.29E 03 1.24E 027 3.79E 04 1.66E 02 71.13E 03
been frequently used to estimate radiation absorbed dose for PET radiopharmaceuticals from small animal biodistribution data (Constantinescu et al., 2013a, b). Therefore, we assumed that, firstly, the injected activity was uniformly distributed throughout the body immediately following the injection; secondly, all unmeasured activity was assigned to the remainder of the body. Another hypothesis of homogeneous distribution of the radioactivity throughout the organ was proposed when we observed the absorbed dose. No voiding urinary bladder model was used in calculation of the residence times. This could lead to a dose overestimation of the bladder and adjacent organs, like ovaries. The biodistribution data of 18F-alfatide II in mice showed that there was a rapid uptake of this tracer to most source organs (Table 1). Accumulation of 18F-alfatide II was much higher in the urinary tract than in the digestive system (e.g., stomach and LLI), indicating a renal excretion of 18F-alfatide II. This pattern of biodistribution and clearance of 18F-alfatide II in mice was similar to that reported in other study (Guo et al., 2014). In particular, the radioactivity accumulation in these organs and the renal clearance were fairly fast. The uptake level was relatively low in liver, muscle, and heart throughout the 160 min. To assess human radiation exposure due to the administration of 18F-alfatide II, the radiation absorbed dose of organs were estimated by the software OLINDA/EXM 1.1. These doses were expressed in millisieverts per megabecquerel. The mean absorbed dose of various organs and tissues and the effective dose calculated by mice data were shown in Table 3. We could see that the EDs for the female and male model were 1.66E 02 71.13E 03 mSv/MBq and 1.27E 02 7 3.69E 04 mSv/MBq, respectively. For 370 MBq (10 mCi) administered activity of 18F-alfatide II, the ED observed in this study would be about 6.14 mSv for female and 4.70 mSv for the male, which all fell into class II-b defined by ICRP/World Health Organization (ICRP, 1992). Other organs had mean absorbed doses in the range of 0.003–0.147 mGy/MBq, which was acceptable and favorable for research and clinical applications. If administered at 185 MBq (5 mCi) per study, these limits should allow multiple studies per year for each subject. It
S.-y. Wang et al. / Applied Radiation and Isotopes 105 (2015) 1–5
appeared that our estimated limit for administered activity in a single human study was higher than expected. One possible explanation is the omission of a voiding urinary bladder model and the resulting higher dose to bladder and its adjacent organs. For instance, ovaries are adjacent to kidneys and bladder in female mouse, causing relatively high dose to ovaries. Although it did not imply to be a substitute for a complete dose assessment in humans, the current study was a useful preliminary data set as 18 F-alfatide II being translated to humans. In future research, we plan to study 18F-alfatide II dosimetry in human subjects and it will assist to verify and validate the accuracy of the animal model results presented in this study. When deriving human doses from mouse data, two important factors are to be considered, the tracer metabolic rates between this two different species and the extrapolation method. For this study we assumed that the metabolic rates were similar in mice and human. Studies with translocation protein tracers, which used the same mass extrapolation method, showed that the ED calculated from mice data were overestimated compared to those measured in nonhuman primates (Verschuer et al., 2012). For more accurate estimation of the absorbed dose, dynamic bladder model should be used.
5. Conclusion In summary, the total body absorbed doses were 9.80E 03 72.90E 04 mGy/MBq for male and 1.24E 02 73.79E 04 mGy/MBq for female, respectively; and the effective doses were 1.27E 0273.69E 04 mSv/MBq (male) and 1.66E 027 1.13E 03 mSv/MBq (female). The results showed that the small animal biodistribuation data could be used in preclinical evaluation of radiopharmaceutical dosimetry. The effective doses for male and female observed in this study were about 4.70 mSv and 6.14 mSv for 370 MBq administered activity. The organ and totalbody doses were lower than the maximum suggested individual organ study dose (50 mGy).
Conflicts of interest None.
Acknowledgments The authors thank the PET radiopharmacy team of Shanghai Cancer Center for tracer preparations.
5
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Contents lists available at ScienceDirect
Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Radiochemistry and radionuclide applications - A
Radiation dosimetry estimates of PET imaging of mice
18
F-alfatide II based on whole-body
Si-yang Wang a,b,c,d, Xiao Bao a,b,c,d, Ming-wei Wang a,b,c,d, Yong-ping Zhang a,b,c,d, Ying-jian Zhang a,b,c,d, Jian-ping Zhang a,b,c,d,n a
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China c Center for Biomedical Imaging, Fudan University, Shanghai, China d Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai, China b
H I G H L I G H T S
G R A P H I C A L
A B S T R A C T
We demonstrated a proper mice model to estimate human radiation dosimetry. This is the first paper to estimate human radiation dosimetry of 18 F-alfatide II. Estimated effective dose are in the range of routine nuclear medicine studies.
art ic l e i nf o
a b s t r a c t
Article history: Received 16 December 2014 Received in revised form 7 July 2015 Accepted 11 July 2015 Available online 13 July 2015
We estimated the dosimetry of 18F-alfatide II with the method established by MIRD based on biodistribution data of mice. Six mice (three females and three males) were scanned for 160 min on an Inveon MicroPET/CT scanner after injection of 18F-alfatide II via tail vein. Eight source organs were delineated on the CT images and their residence times calculated. The data was then converted to human using scaling factors based on organ and body weight. The absorbed doses for human and the resulting effective dose were computed by OLINDA 1.1 software. The highest absorbed doses was observed in urinary bladder wall (male 0.102 mGy/MBq, female 0.147 mGy/MBq); and the lowest one was detected in brain (male 0.0030 mGy/MBq, female 0.0036). The total effective doses were 0.0127 mSv/MBq for male and 0.0166 mSv/MBq for female, respectively. A 370-MBq injection of 18F-alfatide II led to an estimated effective dose of 4.70 mSv for male and 6.14 mSv for female. The potential radiation burden associated with 18F-alfatide II/PET imaging therefore is comparable to other PET examinations. & 2015 Elsevier Ltd. All rights reserved.
Keywords: 18 F-alfatide II Biodistribution Radiation dosimetry
1. Introduction Positron-emission tomography (PET) is a diagnostic imaging technique based on the use of a positron-emitting radionuclide. 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET/CT outperformed FDG-PET by 10% in sensitivity, 20% in specificity, and 16% in n
Corresponding author at: No. 270, Dong'an Road, Xuhui District, Shanghai, China. E-mail address: [email protected] (J.-p. Zhang).
http://dx.doi.org/10.1016/j.apradiso.2015.07.013 0969-8043/& 2015 Elsevier Ltd. All rights reserved.
accuracy, showing the higher diagnostic accuracy of PET/CT (Kitajima et al., 2009). 18F-FDG is currently the most widely used PET probe for many kinds of cancers. However, it still has drawbacks because a high uptake is not necessarily associated with a tumor. The false-positive results could be caused by various factors, including different infection forms, inflammation, granulomatous
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disease, and even many other physiological or pathological conditions (Culverwell et al., 2011); meanwhile, the false-negative was frequently observed in tumors with lower glucose metabolism. In recent years, the peptide ligand of integrin αvβ3 with the sequence of arginine–glycine–aspartic acid (RGD) has been modified and labeled with various radionuclides for either singlephoton emission computed tomography or PET imaging of tumor angiogenesis (Ahmadi et al., 2008; Chen et al., 2004; Jeong et al., 2008; Jacobson et al., 2011). It is widely accepted that imaging of tumor angiogenesis with RGD could be used not only for early detection of cancers, but also for monitoring treatment outcomes (Beer et al., 2011). In previous studies, (Guo et al., 2014) the newly synthesized 18F-AlF-NOTA-E[PEG4-c(RGDfk)] 2 (denoted as 18 F-alfatide II) conjugates could withstand treatments during heating, solvent evaporation, pH adjustment, serum incubation, and in vivo circulation without detectable hydrolysis. More importantly, 18F-alfatide II appeared to be superior to 18F-alfatide I due to the lower liver uptake and higher tumor accumulation, which had been proved by in vivo imaging data (tumor uptake and tumor/non-tumor ratios). However, internal dosimetry data for 18F-alfatide II in human has not been available in the literature yet. The aim of this study was to assess the biodistribution of 18F-alfatide II in mice and extrapolate it to humans as well as establish the radiation dose estimates.
2. Experimental procedures 2.1. Radiopharmaceutical preparation The 18F-alfatide II was obtained from PET Center, Fudan University Shanghai Cancer Center. The synthesis of the 18F-alfatide II was based on the technique described in previous published papers (Guo et al., 2014; Kiesewetter et al., 2012). After comparison of three dimeric 18F-AlF-NOTA-RGD Tracers (Guo et al., 2014), we used NOTA-PEG4-E[c(RGDfk)2] as precursor. The radiochemical purity of the 18F-alfatide II syntheses was above 98%, assessed by an analytical high performance liquid chromatography system equipped with an ultraviolet and radioactivity detector, and the radiochemical yield was more than 40% (decay corrected), with specific activity of 21 MBq/mmol.
correction of PET images and to provide anatomical identification of mouse organs of interest in the study. 2.3. Image analysis Analysis of reconstructed images was performed with Inveon Research Workplace software. For each MicroPET/CT scans, 3D volumes of interest (VOIs) were drawn manually on the following “source” organs: brain, lung, liver, heart wall, kidney, small intestine and large intestine. All of the source organs were identified, and the VOIs were drawn as irregular contours on the high-resolution CT images. The size of each VOI was smaller than the actual size of each organ in order to reduce the PET effects of spill in and spill over from adjacent organs. We chose these organs because they were the main parenchymatous organs in body and secondly, were defined as source organs in the software OLINDAEXM 1.1. All VOIs were transferred to dynamic PET images and the decay-corrected mean time activity curves (TACs) were extracted for each source organ. 2.4. Residence times and absorbed dose calculations Not decay-corrected TACs were traced and the area under the curve for each organ was calculated using trapezoidal method up to the last time point at 160 min. For the sake of a conservative dose estimate, we calculated the area under the curve from the last time point to infinity assuming that only physical decay of 18F occurred (i.e., there was no biologic clearance after the last time point 160 min). The area under the curve between the time of 18 F-alfatide II injection and start of the scan was computed assuming linearity. The area under the TAC of source organ from zero to infinity was regarded as the residence times (Van Laere et al., 2008). Further, we used the method of Kirschner to extrapolate the animal data obtained from normal mice after injection of 18 F-alfatide II to obtain the residence times of human Blau (1975). The extrapolation formula was given by
⎧ ⎪
(ROrgan )Human = n1 ⎨⎪
⎩ i = 1,2, … , n
⎧ ⎪ ⎨ ROrgan ⎪ ⎩
(
⎛ mOrgan ⎞ ⎟⎟ × ⎜⎜ ⎝ MTB weight ⎠Human
2.2. PET and CT scanning All the animal studies were conducted in compliance with Institutional Animal Care and Use Committee (IACUC) guidelines. MicroPET/CT scans and image analysis were performed using an Inveon MicroPET/CT (Siemens Medical Solution). Each mouse was injected with 9.77 71.63 MBq of 18F-alfatide II via tail vein, and then immediately put on the scanner bed in an imaging chamber. 160 min PET dynamic acquisitions were performed by the Inveondedicated PET scanner. The average delay between the time of injection and start of the PET acquisition was 4 min. After the PET acquisition, each mouse received a 20 min high-resolution CT scan with the Inveon MM CT scanner. The animals were maintained under 2% isoflurane anesthesia throughout the scanning period. The PET raw data were dynamically sorted into 27 frames (8 1, 8 2, 6 6 and 5 20 min) and were reconstructed using three-dimensional ordered-subset expectation maximization/ maximum algorithm (OSEM3D/MAP). All dynamic images were automatically corrected for radioactive decay according to manufacturer software settings. Following the reconstruction, the CT images were spatially aligned to match the PET images using a fixed, predetermined transformation matrix. The CT scan served two purposes: to acquire an attenuation map for attenuation
∑
( )
where ROrgan
(
gan, ROrgan
)
Mice (i )
Human
⎫⎫ ⎛ MTB weight ⎞ ⎪⎪ ⎟⎟ ⎬⎬ mOrgan ⎠ ⎪⎪ Mice (i) ⎭ ⎭
)Mice (i) × ⎜⎜⎝
(1)
denoted the residence times of human or-
represent the residence times of the mice (n ¼3),
⎛ MTB weight ⎞ ⎜ ⎟ was the ratio between the weights of the i-th mice ⎝ mOrgan ⎠Mice (i)
⎛ mOrgan ⎞ ⎜ ⎟ was the ratio be⎝ MTB weight ⎠Human tween the weights of human organ and human body. The residence times of the “remainder of body” of human was calculated for each formulated time point, which was the difference between the decayed value of all residence times in the whole body of human and the residence times in the animals’ source organs. When performing the extrapolation, the residence times of animal organs ROrgan , the whole body weight of the animal, the organ and the mice body, and
(
)
Mice
weight of human organs and whole body must be given. The human total body weight (MTB weight )Human and the human organ masses (morgan )Human were taken from OLINDA/EXM 1.1 for adult female and adult male phantoms, respectively. The volume of animals' source organ was delineated manually on every section of the high-resolution CT images, and then multiplied by a default density of 1 g/ml to obtain the weight of source organs besides
S.-y. Wang et al. / Applied Radiation and Isotopes 105 (2015) 1–5
that of lung. A density of 0.3 g/ml was used to calculate the weight of lung. The absorbed doses in healthy human bodies were estimated using the organ residence times data above by OLINDA/EXM 1.1 program (Vanderbilt University, Nashville, TN, USA). The effective dose (ED) then was calculated according to its definition in ICRP 103.
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shown in Fig.1, where rapid accumulation of the radioactivity into the kidneys was observed, reaching the highest uptake value at 10 min after injection. There was a relatively low level of uptake in brain and large intestine. 18F-alfatide II showed predominant renal clearance and minimal hepatobiliary excretion. 3.2. Residence times and absorbed dose calculations
3. Results 3.1. Biodistribution The decay-corrected time-activity curves for the brain, liver, heart, lung, kidney, small intestine wall, upper large intestine and lower large intestine of mice after injection of 18F-alfatide II were
Fig. 1. Time activity curves for major organ uptake of LLI ¼ lower large intestine.
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Table 1 shows the residence times of 18F-alfatide II for mice of the 8 selected organs. It was demonstrated that the reminder had the largest residence times (male: 9.28E 01 71.93E 01 MBq h/ MBq; female: 7.92E 017 1.23E 01 MBq h/MBq), followed by the urinary bladder wall (male: 7.06E 017 1.50E 01 MBq h/MBq; female: 8.88E 017 1.08E 01 MBq h/MBq) and the liver (male: 5.84E 02 71.10E 02 MBq h/MBq female: 3.63E 027 9.65E
F-alfatide II for male mice (A, B and C) and female mice (D, E and F). SI¼ small intestine, ULI ¼upper large intestine,
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Table 1 Residence times (MBq h/MBq) of
18
F-alfatide II in mouse organs.
Organ
Male average ( 7 SD)
Female average ( 7SD)
Brain Lungs Heart Wall Liver Kidneys UB Contenta Small intestine ULIa LLIa Remainder
3.34E 037 6.68E 04 6.21E 037 2.03E 03 6.35E 037 2.45E 03 5.84E 027 1.10E 02 2.58E 027 1.27E 02 7.06E 017 1.50E 01 5.87E 027 1.32E 02 7.86E 037 2.00E 03 4.96E 037 1.04E 03 9.28E 017 1.93E 01
2.67E 037 1.54E 04 8.49E 037 2.66E 03 3.74E 037 1.08E 03 3.63E 027 9.65E 03 1.67E 027 8.36E 03 8.88E 017 1.09E 01 2.94E 027 1.20E 02 4.89E 037 1.00E 03 2.03E 037 1.15E 03 7.92E 017 1.23E 01
a
UB ¼urinary bladder, ULI ¼ upper large intestine, LLI ¼ lower large intestine.
Table 2 Human residence times (MBq h/MBq) estimates of residence times and real organ mass.
18
F-alfatide II based on mouse
Organ
Male average
Female average
Brain Lungs Heart Wall Liver Kidneys UB Contenta Small Intestine ULIa LLIa Remainder
4.73E 037 9.45E 04 2.49E 027 8.16E 03 2.95E 037 1.14E 03 2.05E 027 3.87E 03 1.02E 027 5.04E 03 1.95E 017 4.17E 02 7.57E 037 1.70E 03 1.96E 037 4.97E 04 9.36E 04 7 1.96E 04 1.92E 007 6.52E 02
3.68E 037 3.76E 04 1.38E 027 3.07E 03 1.70E 037 4.92E 04 1.21E 027 3.22E 03 8.69E 037 4.22E 03 2.05E 017 5.75E 02 4.36E 037 1.78E 03 1.43E 037 2.93E 04 4.75E 04 7 2.69E 04 1.97E 007 9.98E 02
a
UB ¼urinary bladder, ULI ¼ upper large intestine, LLI ¼ lower large intestine.
03 MBq h/MBq). Other organs had shorter residence times. Table 2 lists the mean residence times for both adult female and male phantoms. The largest values were found in the reminder, and then in urinary bladder wall and lung for both male and female phantoms. As shown in Table 3, the ED of 18F-alfatide II organ dosimetry for the adult phantom were 1.27E 02 7 3.69E 04 mSv/MBq for male and 1.66E 02 71.13E 03 mSv/ MBq for female, respectively. For the male adult, the organ of the highest absorbed dose was the urinary bladder wall (1.02E 01 71.92E 02 mGy/MBq); followed by the osteogenic cell (1.47E 0274.51E 04 mGy/MBq) and lower large intestine wall (1.38E 02 72.65E 04 mGy/MBq). The brain showed the lowest absorbed doses (2.91E 03 72.22E 04 mGy/MBq). As for female adult, urinary bladder wall (1.47E 01 73.74E 02 mGy/ MBq) was also the organ of the highest absorbed dose while the brain was the lowest one (3.57E 03 71.88E 04 mGy/MBq).
4. Discussion In this paper, we studied the biodistribution of 18F-alfatide II in mice to estimate radiation absorbed dose of 18F-alfatide II in healthy human. PET imaging technique provided an optimal noninvasive method, which could quantitatively measure the in vivo tissue biodistribution of radiopharmaceuticals on human or animal (Ding and Wu, 2012). The availability of preclinical PET and CT scanners and the existence of physical models for internal dose assessment in small animals allowed preliminary evaluation of tracer biodistribution in mice or rats and extrapolation it to humans. Although this method might potentially lead to errors when applying in large animals and inter-species, and that metabolic variation could introduce errors when extrapolating the data of animals to human (Moerlein et al., 1997; Zhang et al., 2012), it was relatively simple, time saving and economic. Thus, this method has
Table 3 Estimates of human absorbed dose (mGy/MBq) and effective dose (mSv/MBq) of 18 F-alfatide II with Hermaphroditic Adult Phantom from mice's biodistribution. Target organ
Male
Female
Adrenals Brain Breasts Gallbladder wall LLI wall SI Stomach wall ULI wall Heart wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red marrow Osteogenic Cells Skin Spleen Testes Thymus Thyroid Urinary Bladder wall Uterus Total body Effective dose (mSv/MBq)
1.05E 027 5.09E 04 2.91E 037 2.22E 04 7.77E 037 3.20E 04 1.08E 027 4.58E 04 1.38E 027 2.65E 04 1.32E 027 4.62E 04 1.06E 027 4.04E 04 1.18E 027 4.58E 04 7.40E 037 9.03E 04 1.16E 027 3.26E 03 6.61E 037 6.67E 04 8.97E 037 1.59E 03 9.84E 037 2.42E 04 NA 1.11E 027 4.51E 04 9.16E 037 2.65E 04 1.47E 027 4.51E 04 7.54E 037 2.25E 04 1.04E 027 4.51E 04 1.10E 027 1.00E 04 9.61E 037 4.00E 04 9.63E 037 3.50E 04 1.02E 017 1.92E 02 NA 9.80E 037 2.90E 04 1.27E 02 73.69E 04
1.34E 027 6.66E 04 3.57E 037 1.88E 04 1.00E 027 4.94E 04 1.29E 027 6.08E 04 1.74E 027 1.53E 04 1.46E 027 5.51E 04 1.35E 027 6.35E 04 1.46E 027 5.20E 04 8.47E 037 6.80E 04 1.23E 027 2.69E 03 7.24E 037 6.95E 04 9.57E 037 9.12E 04 1.24E 027 2.69E 03 1.72E 027 2.08E 04 1.41E 027 6.93E 04 1.16E 02 73.79E 04 1.96E 027 8.66E 04 9.56E 037 3.78E 04 1.32E 027 6.43E 04 NA 1.25E 027 6.66E 04 1.15E 02 75.77E 04 1.47E 017 3.74E 02 2.09E 027 1.29E 03 1.24E 027 3.79E 04 1.66E 02 71.13E 03
been frequently used to estimate radiation absorbed dose for PET radiopharmaceuticals from small animal biodistribution data (Constantinescu et al., 2013a, b). Therefore, we assumed that, firstly, the injected activity was uniformly distributed throughout the body immediately following the injection; secondly, all unmeasured activity was assigned to the remainder of the body. Another hypothesis of homogeneous distribution of the radioactivity throughout the organ was proposed when we observed the absorbed dose. No voiding urinary bladder model was used in calculation of the residence times. This could lead to a dose overestimation of the bladder and adjacent organs, like ovaries. The biodistribution data of 18F-alfatide II in mice showed that there was a rapid uptake of this tracer to most source organs (Table 1). Accumulation of 18F-alfatide II was much higher in the urinary tract than in the digestive system (e.g., stomach and LLI), indicating a renal excretion of 18F-alfatide II. This pattern of biodistribution and clearance of 18F-alfatide II in mice was similar to that reported in other study (Guo et al., 2014). In particular, the radioactivity accumulation in these organs and the renal clearance were fairly fast. The uptake level was relatively low in liver, muscle, and heart throughout the 160 min. To assess human radiation exposure due to the administration of 18F-alfatide II, the radiation absorbed dose of organs were estimated by the software OLINDA/EXM 1.1. These doses were expressed in millisieverts per megabecquerel. The mean absorbed dose of various organs and tissues and the effective dose calculated by mice data were shown in Table 3. We could see that the EDs for the female and male model were 1.66E 02 71.13E 03 mSv/MBq and 1.27E 02 7 3.69E 04 mSv/MBq, respectively. For 370 MBq (10 mCi) administered activity of 18F-alfatide II, the ED observed in this study would be about 6.14 mSv for female and 4.70 mSv for the male, which all fell into class II-b defined by ICRP/World Health Organization (ICRP, 1992). Other organs had mean absorbed doses in the range of 0.003–0.147 mGy/MBq, which was acceptable and favorable for research and clinical applications. If administered at 185 MBq (5 mCi) per study, these limits should allow multiple studies per year for each subject. It
S.-y. Wang et al. / Applied Radiation and Isotopes 105 (2015) 1–5
appeared that our estimated limit for administered activity in a single human study was higher than expected. One possible explanation is the omission of a voiding urinary bladder model and the resulting higher dose to bladder and its adjacent organs. For instance, ovaries are adjacent to kidneys and bladder in female mouse, causing relatively high dose to ovaries. Although it did not imply to be a substitute for a complete dose assessment in humans, the current study was a useful preliminary data set as 18 F-alfatide II being translated to humans. In future research, we plan to study 18F-alfatide II dosimetry in human subjects and it will assist to verify and validate the accuracy of the animal model results presented in this study. When deriving human doses from mouse data, two important factors are to be considered, the tracer metabolic rates between this two different species and the extrapolation method. For this study we assumed that the metabolic rates were similar in mice and human. Studies with translocation protein tracers, which used the same mass extrapolation method, showed that the ED calculated from mice data were overestimated compared to those measured in nonhuman primates (Verschuer et al., 2012). For more accurate estimation of the absorbed dose, dynamic bladder model should be used.
5. Conclusion In summary, the total body absorbed doses were 9.80E 03 72.90E 04 mGy/MBq for male and 1.24E 02 73.79E 04 mGy/MBq for female, respectively; and the effective doses were 1.27E 0273.69E 04 mSv/MBq (male) and 1.66E 027 1.13E 03 mSv/MBq (female). The results showed that the small animal biodistribuation data could be used in preclinical evaluation of radiopharmaceutical dosimetry. The effective doses for male and female observed in this study were about 4.70 mSv and 6.14 mSv for 370 MBq administered activity. The organ and totalbody doses were lower than the maximum suggested individual organ study dose (50 mGy).
Conflicts of interest None.
Acknowledgments The authors thank the PET radiopharmacy team of Shanghai Cancer Center for tracer preparations.
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