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Edited by
Massimo Broggini
Mario Negri Institute for Pharmacological Research (IRCCS), Italy
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Francoise Degoul
Institut National de la Santé et de la Recherche Médicale (INSERM), France
Nan Li
Beijing Cancer Hospital, China
Table of contents

 * Abstract
 * 1. Introduction
 * 2. Materials and methods
 * 3. Results
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ORIGINAL RESEARCH ARTICLE

Front. Oncol., 14 December 2022
Sec. Cancer Molecular Targets and Therapeutics
Volume 12 - 2022 | https://i646f69o6f7267z.oszar.com/10.3389/fonc.2022.1027792


PREPARATION, BIOLOGICAL CHARACTERIZATION AND PRELIMINARY HUMAN IMAGING STUDIES
OF 68GA-DOTA-IBA

Yingwei Wang1,2,3†Qixin Wang1,2,3†Zan Chen4†Jian Yang1,2,3†Hanxiang
Liu1,2,3Dengsai Peng1,2,3Lei Lei1,2,3Lin Liu1,2,3Li Wang1,2,3Naiguo Xing1,2,3Lin
Qiu1,2,3*Yue Feng1,2,3*Yue Chen1,2,3*
 * 1Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical
   University, Luzhou, Sichuan, China
 * 2Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province,
   Luzhou, Sichuan, China
 * 3Nuclear Medicine Institute of Southwest Medical University, Luzhou, Sichuan,
   China
 * 4Department of Orthopaedics, The Affiliated Hospital of Southwest Medical
   University, Luzhou, Sichuan, China

Purpose: In this study, DOTA-IBA was radiolabeled with 68Ga and we determined
the optimum labelling conditions and assessed the biological properties of
68Ga-DOTA-IBA. We investigated the biodistribution of 68Ga-DOTA-IBA in normal
animals and undertook PET/CT imaging in humans. Finally, we explored the
feasibility 68Ga-DOTA-IBA as a bone imaging agent and demonstrated its potential
for the therapeutic release of 177Lu/225Ac-DOTA-IBA.

Methods: The controlled variables method was used to assess the impact of
variables on the radiochemical purity of 68Ga-DOTA-IBA. The biological
properties of 68Ga-DOTA-IBA were investigated.68Ga-DOTA-IBA micro-PET/CT imaging
was performed on animals. Volunteers were recruited for 68Ga-DOTA-IBA imaging
and data were compared to 99mTc-MDP imaging studies to calculate the target to
non-target ratio (T/NT) of the lesions.

Results: The prepared 68Ga-DOTA-IBA had a radiochemical purity of >97% and
demonstrated good biological properties with a good safety profile in normal
mice. PET/CT imaging of the animals showed rapid blood clearance with high
contrast between the bone and stroma. Human imaging showed that 68Ga-DOTA-IBA
could detect more lesions compared to 99mTc-MDP and had a higher targeted to
untargeted ratio.

Conclusions: 68Ga-DOTA-IBA is an osteophilic radiopharmaceutical that can be
synthesized using a simple labelling method. 68Ga-DOTA-IBA has high
radiochemical purity and is stable in vitro stability. It is rapidly cleared
from the blood, has low toxicity and has strong targeting to the bone with long
retention times. We also found that it is rapidly cleared in non-target tissues
and has high contrast on whole-body bone imaging. 68Ga-DOTA-IBA PET/CT has
potential as a novel bone imaging bone modality in patients with metastatic
disease.




1. INTRODUCTION

Cancer remains a significant threat to human health, particularly advanced
diseases that have metastasized to the bones. Prostate, breast, lung, liver and
thyroid cancers have a high propensity to metastasize to the bones (1–3).
Nuclear imaging techniques are widely used in the diagnosis of bone metastases
using agents such as [18F] 18F-NaF and [99mTc] 99mTc-methylene diphosphonate
(MDP). [18F] 18F-NaF requires an accelerator for generation limiting its use in
the clinic. Also, [99mTc] 99mTc-MDP often shows false negatives for lesions with
no obvious osteogenic response. The value of bisphosphonates in the diagnosis
and treatment of skeletal disorders is well established as they have a strong
affinity for bone (4). Gallium-68 [68Ga] is used clinically as a positron
imaging agent and has several advantages. Specifically, [68Ga] can be obtained
using a germanium gallium generator (68Ge/68Ga), it is a β-emitter and has a
half-life of 67.71 minutes. 68Ga/177Lu [Lutetium] is a diagnostic and
therapeutic nuclide (5).

Ibandronic (IBA) acid is a third generation bisphosphonate. Studies have
reported the labelling of metal ions with IBA acid using complex methods
requiring larger amounts of precursors and products that have toxic side effects
(6, 7). Previous studies have shown that the bifunctional chelate DOTA can be
used for the complexation of metal compounds (5). In this study, we combined
DOTA with bisphosphate to form a new compound, DOTA-IBA that was then combined
with 68Ga to form the novel probe, 68Ga-DOTA-IBA. In this paper, we describe the
preparation conditions and characterize the biological and imaging properties of
68Ga-DOTA-IBA.


2. MATERIALS AND METHODS


2.1. MATERIALS

68Ga solution (0.4 M HCL) was eluted from a 68Ge/68Ga generator (ITG 101,
EckertZiegler, Germany). The molecular design of DOTA-IBA was provided by our
laboratory and the drug synthesis was provided by the Shanghai New Drug
Development Company. Sodium acetate, thin-layer chromatography silica plates and
other reagents were purchased from the Shanghai Maclean Biochemical Company.
Animal micro positron emission computed tomography (micro-PET/CT; SIEMENS Inveon
TM Siemens, Germany), PET/CT (United Imaging 780 Shanghai United Imaging Medical
Technology Co., Ltd.). Other equipment, chemicals and animals used in the
experiments were provided by the Sichuan Provincial Key Laboratory of Nuclear
Medicine and Molecular Imaging. All studies were approved by the Ethics
Committee of Southwest Medical University.


2.2. RADIOLABELING AND QUALITY CONTROL

A controlled variables approach was used to investigate the effect of the
various factors on the radiochemical purity of the markers. The solution was
prepared by mixing a certain amount of DOTA-IBA solution (1mg/1ml), sodium
acetate solution and 68GaCl3 solution in sequence. The pH of the solution was
adjusted with 0.1 M hydrochloric acid and 0.25 M sodium acetate. The reaction
was performed at a specific temperature for a specific time. The solution was
cooled and the pH was adjusted to 4-5 before being sterilized and filtered.

Thin layer chromatography silica plates were used as a support and 0.1 M sodium
citrate solution was used as a solvent to unfold the system. Quality control
images of 68Ga-DOTA-IBA: 68Ga-DOTA-IBA at the origin (Rf=0.3-0.4); while free
68GaCl3 moved ahead of the strip with the solvent (Rf=0.9-1.0).

The optimum reaction parameters were 10 μg (10 μL) of DOTA-IBA, 1 ml of sodium
acetate and 4 ml of 68GaCl3. The radiochemical purity of the prepared
68Ga-DOTA-IBA was >97%. The pH was 4-5, the reaction temperature was 95°C and
the reaction time was 15 min.


2.3. IN VITRO STABILITY

The radiochemical purity of 68Ga-DOTA-IBA under optimal labelling conditions was
determined by incubation in 0.9% NaCl and fresh human serum at 37°C. Paper
chromatography was performed at 15 min, 30 min, 1 h, 2 h and 4 h. The
experiments were repeated three times and the results are expressed as mean ±
standard deviation.

2.3.1. PLASMA PROTEIN BINDING RATE

Fresh human plasma (0.1 ml) and freshly prepared 0.5 mCi 68Ga-DOTA-IBA were
added to the test tubes and incubated at 37°C for 2 hours. A 25% trichloroacetic
acid solution (1.0 mL) was then added to the tubes and centrifuged for 5 min.
The supernatants were collected and the process was repeated three times. The
CPM of the supernatant and the precipitate were measured separately using a
gamma counter and the plasma protein binding rate (PPB) of 68Ga-DOTA-IBA was
calculated according to the formula; PPB= [(A-background radioactive
count)/(A+B-background radioactive count×2)] × 100%. All results are expressed
as the mean ± standard deviation.

2.3.2. LIPID AND WATER DISTRIBUTION

Freshly prepared 0.5 mCi 68Ga-DOTA-IBA was added to the tubes before shaking in
a vortex mixer for 20 minutes followed by centrifugation for 5 minutes. The
upper liquid (organic phase) and the lower liquid (aqueous phase) were collected
separately in test tubes. The radioactivity counts of the organic and aqueous
phases were measured separately using a gamma counter. The formula lipid-water
distribution coefficients (logP) were calculated according to the formula;
LogP=log [(B-background radioactive count)/(C-background radioactive count)].
The results were expressed as mean ± standard deviation.


2.4. MOUSE TOXICITY TESTS

24 mice were randomly divided into four experimental groups consisting of a
control group and 68Ga-DOTA-IBA groups at low, medium and high doses. Each group
had equal numbers of male and female animals. The control group was injected
with 0.2 ml of 0.9% NaCl and the experimental groups were injected with 0.1 mCi,
0.5 mCi and 1.0 mCi of 68Ga-DOTA-IBA solution, respectively. The body weights
and general conditions of the mice were observed for 4 weeks. Routine blood
tests and liver and kidney function were performed after 2 and 4 weeks in each
group. After the 4th week of observation, tissues and organs were harvested from
the mice for pathological examination (Ethics committee approval No: KY2022114).

2.4.1. MOUSE BIODISTRIBUTION STUDIES

30 healthy mice were divided into 5 groups. All mice were injected with
68Ga-DOTA-IBA 0.1 mCi (approximately 0.2ml) via the tail vein. Mice were
executed under anesthesia at 15 min, 30 min, 1 h, 2 h and 4 h after dosing.
Blood, heart, liver, spleen, lung, kidney, stomach, small intestine, brain,
femur and muscle tissues were sampled and the radioactivity counts of the
different tissues were measured using a gamma counter. The counts were corrected
for attenuation and the %ID/g was calculated for each time point. The results
were expressed as the mean ± standard deviation.


2.5. 68GA-DOTA-IBA IMAGING ANALYSIS IN A NEW ZEALAND RABBIT MODEL

Anesthetized normal New Zealand rabbits were injected with 1.0-2.0 mCi (0.5-0.6
ml) of 68Ga-DOTA-IBA under optimal labelling conditions from a marginal ear
vein. Whole-body static imaging was performed at 1 h and 3 h after injection
using a United Imaging 780 PET/CT instrument. PET images were acquired with a
time window of 3.48 ns, an energy range of 350-650 KeV, a 128×128 matrix and a
10 min acquisition time. CT scans were obtained using a tube voltage of 80 Kv, a
tube current of 500 Ua and a scan time of 10 min.


2.6. 68GA-DOTA-IBA IMAGING STUDY IN NORMAL MICE

Whole-body bone imaging using micro-PET/CT was performed at 30 mins, 1.5 h and 3
h after tail vein injection of 68Ga-DOTA-IBA 0.2 mCi in anaesthetized mice. The
PET imaging parameters were as follows; a time window of 3.48 ns, energy range
350-650 KeV, matrix 128×128, acquisition 10 min. CT scans were obtained at a
tube voltage of 80 Kv, and a tube current of 500 As with a scan time of 10 mins.


2.7. ESTABLISHMENT OF A BONE METASTASIS MODEL AND IMAGING STUDIES

A bone metastasis model was established in nude mice by intertibial bone marrow
injection. 25 μL of PC-3 prostate cancer cell culture medium was injected into
the left tibia of healthy nude mice. 3-4 weeks after inoculation, the mice were
scanned by micro-CT (SIEMENS InveonTM, Munich, Germany) to determine the
condition of the bone. The appearance of bone destruction (osteolytic,
osteogenic or mixed) in the left tibia indicated that the model was successful.
The mouse was anaesthetized with gas anaesthesia (isoflurane) and 68Ga-DOTA-IBA
0.1 mCi (50 μl) was injected into the tail vein with an insulin needle under
optimal labelling conditions. Whole-body bone imaging was performed 1 h after
the injection. Micro-PET/CT and PET acquisitions were performed as described
above for normal mice.


2.8. 68GA-DOTA-IBA IMAGING IN PATIENTS

2.8.1. PATIENT SELECTION

68Ga-DOTA-IBA and 99mTc-MDP whole-body bone imaging were performed in 5 patients
and the imaging agents were compared. The patients included 2 males and 3
females who had a mean age of 54.2 years (34-66 years). The interval between the
two examinations was > 3 days < 7 days.

The inclusion criteria were patients who had already undergone 99mTc-MDP
imaging, had no previous bisphosphonate treatment 1 month before the examination
and were able to cooperate well during the examination. The exclusion criteria
were patients who has used bisphosphonates within the past month, inability to
cooperate during the test and patients who were breastfeeding or pregnant.

All of the above patients were recruited under written consent. This study was
approved by the hospital ethics committee and was conducted in compliance with
the Helsinki Declaration. Before the 68Ga-DOTA-IBA PET/CT examination, patients
had routine laboratory blood tests including routine blood counts, and liver and
kidney function tests at 7 and 15 days to determine the impact of 68Ga-DOTA-IBA
on biochemical parameters (Clinical Ethics Registration Number:
ChiCTR2200064487).

2.8.2. 68GA-DOTA-IBA PET/CT IMAGING

The patients were weighed before the examination. An intravenous injection of
68Ga-DOTA-IBA with a radiochemical purity of >97% at 0.1 mCi per kg body weight
was given. Prior to injection, patients were advised to drink plenty of water
and instructed to empty their bladder before imaging. Images were acquired at a
tube voltage of 120 Kv, a tube current of 100 mAs and a layer thickness of 5.0
mm. The scanning ranged from the top of the head to the palms of both feet
(whole body scan) and was acquired with the patients in a supine position. The
foot advanced scanning mode involved a total acquisition of 10-11 beds at 120
s/bed with a subset number 33, an iteration number 3 and a 512×512 matrix. When
the reconstruction was complete, the images were processed using PET/CT
post-processing software.

2.8.3. ANALYSIS OF 68GA-DOTA-IBA AND 99MTC-MDP IMAGES

68Ga-DOTA-IBA and 99mTc-MDP images were analyzed independently in a double-blind
manner by two nuclear medicine physicians with > 5 years of experience in
diagnostic imaging. Based on the results of the 68Ga-DOTA-IBA and 99mTc-MDP
imaging agents, the lesions were classified as osteolytic, osteogenic, mixed and
normal bone. A lesion was defined as a region of abnormal radioactivity when the
uptake value was > the surrounding normal bone background.


2.9. STATISTICAL ANALYSIS

Statistical analysis was performed using SPSS 26.0. All quantitative information
was expressed as the mean ± standard deviation. In the toxicity test, changes in
the body weights of each group of mice were compared using repeated measures
ANOVA. A P-value threshold of 0.05 was set to indicate statistical significance.


3. RESULTS


3.1. RADIOLABELING AND QUALITY CONTROL

68Ga-DOTA-IBA is a third generation bisphosphonate derivative that targets bone
metastases. The structure of the 68Ga-DOTA-IBA is shown in Figure 1. The optimum
preparation conditions were 10 μg (10 μL) of DOTA-IBA, 1 ml of sodium acetate
solution and 4 ml of 68GaCl3 drench solution. The radiochemical purity of the
prepared 68Ga-DOTA-IBA was >97%. The pH of the reaction was 4-5, the reaction
temperature was 95°C and the reaction time was 15 min. Thin layer chromatography
silica plates were used as a support and 0.1 M sodium citrate solution was used
as a solvent to unfold the system. Quality control images of 68Ga-DOTA-IBA,
68Ga-DOTA-IBA at the origin (Rf=0.3-0.4), while the free 68GaCl3 moved in front
of the strip with the solvent (Rf=0.9-1.0).


FIGURE 1

Figure 1 The chemical structure of the DOTA-IBA.




3.2. IN VITRO STABILITY OF 68GA-DOTA-IBA

The in vitro stability data for 68Ga-DOTA-IBA under different conditions are
summarized in Table 1. 68Ga-DOTA-IBA had good in vitro stability at room
temperature (26 ± 2°C).


TABLE 1

Table 1 In vitro stability of 68Ga-DOTA-IBA under different conditions.




3.3. PLASMA PROTEIN BINDING OF 68GA-DOTA-IBA

The PPB of freshly prepared 68Ga-DOTA-IBA under optimal labelling conditions was
80.8 ± 0.61% after 1 h incubation in plasma.


3.4. 68GA-DOTA-IBA LIPID WATER DISTRIBUTION COEFFICIENT

The logP of the lipid-water distribution coefficient of freshly prepared
68Ga-DOTA-IBA using the optimal labelling conditions was -2.26 ± 0.03. These
data indicated that 68Ga-DOTA-IBA has a higher level of water solubility and is
less lipid soluble.


3.5. 68GA-DOTA-IBA ANIMAL TOXICITY TEST STUDY

All groups of mice in the toxicity test groups showed no abnormalities in the
basic health condition at 4 weeks after injection of 68Ga-DOTA-IBA. No
significant differences in mouse weights were observed between the four
experimental groups (P>0.05). At the end of the observation period, samples were
isolated from the mice for pathological analysis. The data were discussed with a
pathologist and no significant differences in the number, size, morphology and
proportion of cells in the tissues of the mice in the high, medium and low dose
groups were observed compared to the saline control (Figure 2 and Supplement
Figure 1–3 HE).


FIGURE 2

Figure 2 Tissue and organ pathology of mice injected with 1.0 mCi of
68Ga-DOTA-IBA (high dose group) for 4 weeks at different magnifications [(A):
heart; (B): liver; (C): spleen; (D): lung; (E): kidney; (F): stomach; (G):
intestine; (H): brain; (I): bone marrow; (J): muscle)].




3.6. IN VIVO DISTRIBUTION OF 68GA-DOTA-IBA IN MICE

The results of the in vivo distribution of 68Ga-DOTA-IBA studies in mice are
summarized in Table 2. From Table 2, the blood clearance of 68Ga-DOTA-IBA was
rapid with only 0.325 ± 0.103% ID/g blood retention at 4 h. Bone had a higher
uptake of 68Ga-DOTA-IBA that reached a maximum after 2 h (8.365 ± 1.849% ID/g).
Uptake was also high in the kidney as 68Ga-DOTA-IBA is mainly excreted through
the urinary tract.


TABLE 2

Table 2 In vivo distribution of 68Ga-DOTA-IBA in mice from 15 min – 4 h (n = 4).




3.7. IMAGING ANALYSIS OF 68GA-DOTA-IBA IN NEW ZEALAND RABBITS

Whole-body static bone imaging was performed in New Zealand rabbits at 1 and 3h
after intravenous injection of freshly prepared 68Ga-DOTA-IBA 2.0 mCi under
optimal labelling conditions via the ear margins as shown in Figure 3. 1 h after
injection of 68Ga-DOTA-IBA, the rabbit’s urinary tract was clearly visualized
and the whole body bone could be seen clearly with the whole spine and limb
joints being the most visible. At 3 h after injection, the whole body bone
remained clearly visible. In summary, 68Ga-DOTA-IBA is a radiopharmaceutical
that is excreted through the kidney, and has rapid soft tissue clearance and
high skeletal uptake with a long retention time in bone lesions.


FIGURE 3

Figure 3 New Zealand rabbits were injected with 68Ga-DOTA-IBA 2.0 mCi at 1 h (A)
and 3 h (B) after whole body bone visualization.




3.8. IMAGING STUDY OF 68GA-DOTA-IBA IN MICE

Whole-body bone images acquired at 30 min, 1.5 h and 3 h after tail vein
injection of 68Ga-DOTA-IBA 0.2 mCi in mice are shown in Figure 4.


FIGURE 4

Figure 4 PET/CT images of 68Ga-DOTA-IBA in normal mice at different time points
[(A): 30 min; (B):1.5 h; (C):3 h].




3.8. IMAGING ANALYSIS OF 68GA-DOTA-IBA IN A BALB/C NUDE MOUSE MODEL

A whole-body bone image of a BALB/c nude mouse (PC-3) injected with
68Ga-DOTA-IBA 0.2 mCi from the tail vein at 1.5 h is shown in Figure 5. The
model rat showed significant bone destruction in the left tibia with high
developer uptake (the arrow) and a SUVmax of 10.3. The T/NT ratio was 6.3 for
the lesion.


FIGURE 5

Figure 5 BALB/c nude mice (PC-3) after injection of 0.2 mCi 68Ga- DOTA-IBA
PET/CT imaging (1.5h).




3.10. PRELIMINARY IMAGING STUDY OF 68GA-DOTA-IBA

A total of 5 patients were recruited to the study that consisted of two males
and three females who were 34-66 years old with a mean age of 54.2 years. The
patient information is summarized in Table 3.


TABLE 3

Table 3 Summary of the basic patient information and clinical diagnosis for
99mTc-MDP imaging results with 68Ga-DOTA-IBA.



From the presented images, 68Ga-DOTA-IBA was comparable to 99mTc-MDP in the
display of skeletal lesions. 68Ga-DOTA-IBA was more sensitive at showing small
lesions compared to 99mTc-MDP. The targeted to non-targeted ratio (T/NT) was
calculated for 99mTc-MDP SPETCT/CT as 3.2-5.3 and 5.8-9.1 for 68Ga-DOTA-IBA
PET/CT indicating that 68Ga-DOTA-IBA PET/CT lesions had a high targeted to
non-targeted (T/NT) ratio (Figures 6–9).


FIGURE 6

Figure 6 A 34-year-old male patient who underwent resection of a left lung tumor
that was discovered 6 months previously. The patient underwent 99mTc-MDP (A)
and68Ga-DOTA-IBA (B) imaging. It was observed from the MIP image that the
patient’s whole body bones are clear with no abnormal concentrations of
developer in the whole body bones.


FIGURE 7

Figure 7 A 58-year-old male patient who underwent surgery for prostate cancer 2
months previously. The patient underwent 99mTc-MDP (A) and 68Ga-DOTA-IBA (B)
imaging. From the MIP image, multiple foci of abnormal developer concentrations
are visible in the thoracic spine and rib cage. The SUVmax of the lesion shown
is approximately 7.8, T/NT 5.8 (arrow).


FIGURE 8

Figure 8 A 60-year-old female patient, who underwent surgery for left breast
cancer 3 years previously who had recent generalized skeletal pain. The patient
underwent 99mTc-MDP (A) and 68Ga-DOTA-IBA (B) imaging. From the MIP image
multiple bone lesions were detected throughout the body with multiple foci of
abnormal developer concentrations and a SUVmax of approximately 10.2 for the
lesion, T/NT 9.1 (arrow).


FIGURE 9

Figure 9 A 66-year-old female patient who underwent surgery for left breast
cancer one year ago and now has generalized skeletal pain. The patient underwent
99mTc-MDP (A) and 68Ga-DOTA-IBA (B) imaging. From the MIP image, multiple foci
of abnormal developer concentrations can be seen throughout the mesial bones and
pelvic bones with a SUVmax of approximately 6.8 for the lesion, T/NT 5.2
(arrow).




4. DISCUSSION

The clinical use of radiopharmaceuticals has led to improvements in the
diagnosis and treatment of cancer and cardiovascular and cerebrovascular
diseases (8–12). The continued development of novel radionuclides and molecular
probes has led to their increased use in therapeutic radiology applications
(13–17). Radionuclide bone imaging is currently the most commonly used method to
evaluate abnormalities in bone metabolism. 99mTc-MDP and 18F-NaF are the most
commonly used bone imaging agents in the diagnosis of bone metastases (8,
18–20). The amount of precursors used in the synthesis of radiopharmaceuticals
is critically important in achieving high purity using the smallest amount of
precursors for labelling. The DOTA-IBA used in this study is a new precursor and
the addition of DOTA allowed the precursor dosage to be reduced to microgram
levels. This can significantly reduce the side effects of bisphosphonates for
the benefit of patients. Our results show that the radiochemical purity of the
68Ga-DOTA-IBA marker was >97% for the specific labelling conditions used. These
findings demonstrate the high stability of the compound and its utility as an
effective radiopharmaceutical.

Our in vitro data showed that 68Ga-DOTA-IBA is stable at room temperature (26 ±
2°C) and in saline after preparation and that it remains radiochemically pure at
> 97% after 4 h. 68Ga-DOTA-IBA was less stable at room temperature (26 ± 2°C),
in saline at 37°C and in serum but the overall stability was fair. The results
of the plasma protein binding rate showed that 68Ga-DOTA-IBA had a higher plasma
protein binding rate compared to 99mTc-MDP which has also been observed in other
studies (6). These observations may be related to the large molecular weight of
DOTA-IBA with a large MDP that can more effectively bind to plasma proteins.

The safety of radiopharmaceuticals is critically important and the aim is to
minimize the required dose to maximize imaging or therapeutic efficacy. We
showed that after the administration of different doses of 68Ga-DOTA-IBA, the
mice were not significantly abnormal compared to animals in the control group.
These data indicate that 68Ga-DOTA-IBA has low toxicity and a strong safety
profile supporting its use for subsequent labelling of therapeutic nucleophiles.
From the in vivo distribution of 68Ga-DOTA-IBA in mice, it can be seen that
68Ga-DOTA-IBA shows rapid blood clearance because 68Ga-DOTA-IBA is mostly
excreted through the urinary tract, so the uptake by the kidneys is relatively
high (this is related to the kidneys as the main excretory organ). We observed
that bone has a high uptake of 68Ga-DOTA-IBA that is maintained for 4 h. It also
has a high target to non-target ratio of 68Ga-DOTA-IBA suggesting that it has
strong bone-targeting properties. The findings are consistent with the previous
results of other 68Ga–bisphosphonate agents (5). In the mouse model imaging
studies, 68Ga-DOTA-IBA had a high uptake at the lesion and a high target to
non-target ratio.

DOTA-IBA contains DOTA and is convenient, efficient and highly labelled when
chelating with metal ions and requires very low amounts of precursors. According
to our imaging studies, 68Ga-DOTA-IBA was sensitive and had a high target to
non-target ratio for bone metastases. If the nuclide is replaced by the
therapeutic nuclide 177Lu/225Ac and labelled as 177Lu/225Ac -DOTA-IBA, it is
expected that 68Ga/177Lu/225Ac-DOTA-IBA could potentially be used for the
diagnosis and treatment of bone metastases.

Despite the interesting observations reported in this study, our approach has
several limitations that need to be refined in future studies. Although 5
volunteers were recruited for the imaging study, the overall sample size in this
study was small and did not allow for accurate diagnostic assessment. The
comparative study of 68Ga-DOTA-IBA with sodium fluoride was not covered in this
study and will be further explored in subsequent studies. Follow-up studies will
be performed in larger patient cohorts to validate our findings to facilitate
the widespread clinical application of our approach in patients with bone
metastases.


5. CONCLUSIONS

In this study, a novel positron-labelled bisphosphonate radiopharmaceutical,
68Ga-DOTA-IBA, was successfully prepared. This new imaging agent is simple to
prepare, requires a short reaction time, has a high label yield and is stable in
vitro. Toxicity results showed that it is safe and non-toxic. 68Ga-DOTA-IBA has
good bone targeting properties, has a high target to non-target ratio and is
rapidly cleared from the body. Preclinical PET/CT images demonstrated that
68Ga-DOTA-IBA has a higher bone targeting and a higher target to non-target
ratio for bone metastases. 68Ga-DOTA-IBA is a bone-friendly positron
radiopharmaceutical with excellent properties that can be used for the imaging
of bone metastases.


DATA AVAILABILITY STATEMENT

The original contributions presented in the study are included in the
article/Supplementary Material. Further inquiries can be directed to the
corresponding authors.


ETHICS STATEMENT

This study was performed in line with the principles of the Declaration of
Helsinki. Study approval was obtained from the hospital’s ethics committee and
conducted between September 2021 and August 2022 (Ethics committee approval No.:
KY2022114) and (Clinical Ethics Registration Number: ChiCTR2200064487). The
patients/participants provided their written informed consent to participate in
this study.


AUTHOR CONTRIBUTIONS

All authors listed have made a substantial, direct, and intellectual
contribution to the work and approved it for publication.


FUNDING

This study was supported in part by research foundation projects from Luzhou
Science & Technology Department (20107) and The Affiliated Hospital of Southwest
Medical University (20087).


CONFLICT OF INTEREST

The authors declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential
conflict of interest.


PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not
necessarily represent those of their affiliated organizations, or those of the
publisher, the editors and the reviewers. Any product that may be evaluated in
this article, or claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.


SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fonc.2022.1027792/full#supplementary-material


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Keywords: DOTA-IBA, 68 Ga, PET/CT, 99m Tc-MDP, SPECT

Citation: Wang Y, Wang Q, Chen Z, Yang J, Liu H, Peng D, Lei L, Liu L, Wang L,
Xing N, Qiu L, Feng Y and Chen Y (2022) Preparation, biological characterization
and preliminary human imaging studies of 68Ga-DOTA-IBA. Front. Oncol.
12:1027792. doi: 10.3389/fonc.2022.1027792

Received: 25 August 2022; Accepted: 01 November 2022;
Published: 14 December 2022.

Edited by:

Francoise Degoul, Institut National de la Santé et de la Recherche Médicale
(INSERM), France

Reviewed by:

Nan Li, Beijing Cancer Hospital, China
Francoise Degoul, Institut National de la Santé et de la Recherche Médicale
(INSERM), France

Copyright © 2022 Wang, Wang, Chen, Yang, Liu, Peng, Lei, Liu, Wang, Xing, Qiu,
Feng and Chen. This is an open-access article distributed under the terms of the
Creative Commons Attribution License (CC BY). The use, distribution or
reproduction in other forums is permitted, provided the original author(s) and
the copyright owner(s) are credited and that the original publication in this
journal is cited, in accordance with accepted academic practice. No use,
distribution or reproduction is permitted which does not comply with these
terms.

*Correspondence: Lin Qiu, qiulin17111210041@163.com; Yue Feng,
fengyue200@163.com; Yue Chen, chenyue5523@126.com

†These authors have contributed equally to this work



Disclaimer: All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations, or
those of the publisher, the editors and the reviewers. Any product that may be
evaluated in this article or claim that may be made by its manufacturer is not
guaranteed or endorsed by the publisher.




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