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. 2021 Sep 3;12(10):1553–1558. doi: 10.1021/acsmedchemlett.1c00350

Synthesis and Preclinical Evaluation of [68Ga]SP94 for Micro-PET Imaging of GRP78 Expression in Hepatocellular Carcinoma

Yifei Xu †, Jinhui Jiang ‡,*, Hui Wang ‡, Wenjing Yu ‡, Guoping Sun †,*
PMCID: PMC8521616  PMID: 34676037

Abstract

graphic file with name ml1c00350_0005.jpg

Glucose-regulated protein 78 (GRP78) is overexpressed in a wide variety of solid tumors, serving as a well-characterized target for tumor imaging or therapy. In this work, we developed a GRP78-responsive radiotracer (DOTA-68Ga)-Gly-Gly-Gly-Ser-Phe-Ser-Ile-Ile-His-Thr-Pro-Ile-Leu-Pro-Leu-Gly-Gly-Cys ([68Ga]SP94) for hepatocellular carcinoma (HCC) micro-PET imaging. DOTA-SP94 was synthesized by solid phase synthesis and then radiolabeled with 68GaCl3 with >99% radiochemical purity. The expression levels of GRP78 in HepG2 cells were confirmed by Western blotting. In vitro and in vivo study of [68Ga]SP94 showed high stability and high uptake in GRP78-overexpressing HepG2 cells and tumor, fast clearance, and low nontarget uptake. Micro-PET images showed excellent tumor accumulation of [68Ga]SP94 in the HepG2-implanted nude mice tumor model. Additionally, the radiotracer uptake in HepG2 tumors can be blocked by unlabeled DOTA-SP94, suggesting that the tracer uptake by HCC was receptor-mediated. We envision that our radiotracer can be used for noninvasive imaging of HCC and is worthy of further clinical investigations.

Keywords: GRP78, micro-PET imaging, [68Ga]SP94, molecular probe, hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with high morbidity and mortality.1,2 HCC typically develops on a background of chronic liver cirrhosis or disease in 90% of all cases, and the overall survival (OS) rate for 5 years is less than 13% in China.3 Despite significant development being made in the management of HCC, including surgical resection, radiofrequency ablation, liver transplantation, targeted drug treatment, and interventional therapy, the prognosis of patients with HCC remains poor, mainly because of the high rate of diagnosis at advanced stages, and this limits their effective treatments.4−8 Thus, early diagnosis and accurate staging are critical for a favorable prognosis and clinical outcome of patients with HCC.

Positron-emission tomography (PET), using radiotracers to visualize biological processes with high sensitivity, plays an important role in the diagnosis, staging, treatment, and prognosis of tumors clinically.9,10 As compared to other routine modalities, such as ultrasonography (US),11 computed tomography (CT),12 and magnetic resonance imaging (MRI),13 PET can noninvasively detect the metabolism and molecular processes of cancer at the cellular level. Recently, as an alternative of 18F (T1/2 = 109.8 min), 68Ga (T1/2= 67.7 min) has attracted more and more attention of researchers due to its easy formation and simple labeling process.1468Ga can be obtained from a 68Ge–68Ga generator, and 68Ga radiotracers are prepared by labeling the isotope to chelators such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) with higher affinity.15

Glucose-regulated protein 78 (GRP78) is a member of the Heat Shock Protein 70 (HSP70) family that is overexpressed in a wide variety of human cancers such as breast, prostate, glioma, and liver.16 Generally, there are three main mechanisms mediated by GRP78 for tumor progression: (1) promotion of tumor-associated angiogenesis, (2) enhancement of tumor cell proliferation, and (3) protection of tumor cells against apoptosis.17 Therefore, GRP78 can promote tumor survival, proliferation, metastasis, and resistance to a wide variety of chemotherapies in both dormant and proliferating cancer cells. Retrospective studies revealed that high-level GRP78 expression predicts poor survival for cancer patients, and the intensity of expression is significantly associated with survival and clinical recurrence.18,19 There is a clinical need for accurate determination of the GRP78 levels of tumors because of its prognostic value and the need for identification of patients who would benefit from targeted anti-GRP78 treatment.20−22

Detection of GRP78 expression using PET imaging has key advantages, including (1) the ability to obtain noninvasive total-body imaging procedure; (2) the procedure is operator-independent and can easily be repeated; (3) allowing a more accurate quantitative assessment of the total amount of GRP78 expression in an individual patient. Although several receptor-targeted delivery platforms have so far been reported, such as HSP peptide (WDLAWMFRLPVG),23 VAP peptide (SNTRVAP),24 and anti-KDEL antibodies,25 none of these have reaped significant benefits in clinical trials until now. In 2019, Jiang et al. identified that GRP78 was the membrane receptor of HCC-targeted peptide sequence GGGSFSIIHTPILPL (SP94 for short) using immunoprecipitation and mass spectrum analysis.26 Although 99mTc labeled SP94 peptide has been reported for SPECT/CT imaging, the long half-life and low sensitivity limit its clinical application.27 Positron-emitting radionuclide 68Ga radiotracer using SP94 as the target for PET/CT imaging of GRP78 expression in HCC has not yet been investigated. Therefore, in this work, we developed a GRP78-targeting molecular probe, 68Ga-radiolabled DOTA-SP94 conjugate ([68Ga]SP94, Figure 1A), and evaluated its capability as a specific probe for micro-PET imaging of GRP78 expression in HCC.

Figure 1.

Figure 1

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Synthesis and characterization of [68Ga]SP94. (A) Synthetic scheme of [68Ga]SP94. (B) Typical radio-HPLC chromatogram of [68Ga]SP94. (C) In vitro stability of [68Ga]SP94 in 0.01 mol/L PBS, 0.9% NaCl, MS, and 5% HAS.

We began the study with the synthesis of (DOTA-68Ga)-Gly-Gly-Gly-Ser-Phe-Ser-Ile-Ile-His-Thr-Pro-Ile-Leu-Pro-Leu-Gly-Gly-Cys ([68Ga]SP94). The precursor DOTA-SP94 was synthesized with solid phase peptide synthesis (SPPS) and characterized by NMR and ESI-MS (Figure S1 and Figure S2). 68Ga was eluted from the 68Ge/68Ga generator using 5 mL of 0.1 M HCl, and the eluent (68GaCl3) was used for the next radiolabeling procedure. As shown in Figure 1A, [68Ga]SP94 was obtained by incubation of DOTA-SP94 (20 μg) with 68GaCl3 in pH 4.2 sodium acetate buffer at room temperature for 5 min. Then, the product was purified using a Sep-pak C18 cartridge and passed through a 0.2 μm sterile filter, and the filtrate was diluted in 0.9% sodium chloride injection (0.9% NaCl) for subsequent experiments. The radiochemical purity (RCP) of [68Ga]SP94 was analyzed using radio-HPLC. The retention time of [68Ga]SP94 was 10.9 min, and the radiochemical purity of [68Ga]SP94 was over 99%, as measured by radio-HPLC (Figure 1B, Table S1). The labeling and purification process of [68Ga]SP94 took only 10 min altogether, suggesting a more convenient labeling synthesis with higher yield.

The log P value of [68Ga]SP94 was evaluated in 0.01 M PBS-octanol (v/v = 1/1), and the value was −2.36 ± 0.002, indicating [68Ga]SP94 is highly hydrophilic.

After characterizing the radiotracer [68Ga]SP94, we evaluated its stability in 0.01 mol/L phosphate buffer solution (PBS), 0.9% NaCl, mouse serum (MS), and 5% human serum albumin (HAS) at 37 °C, respectively. After incubation for 30, 60, 120, and 180 min, the solution was measured by radio-HPLC. After 3 h of incubation, as shown in Figure 1C, no significant dissociation or decomposition of the radiotracer was observed, and the radiochemical purity was over 95% as measured by radio-HPLC, indicating that [68Ga]SP94 was stable in vivo and in vitro within the time tested and could be used for further studies.

To validate the high expression of GRP78 in HepG2 cells, using β-actin as an internal standard, we performed Western blot experiments in different types of cells (HepG2 and LO2 cells), and corresponding details are described in the Supporting Information. Human normal liver cells (LO2 cells) were chosen as control cell lines because of the low expression of GRP78. The results showed that HepG2 cells have a positive signal for GRP78 (0.77 ± 0.017% of β-actin), while very weak signal of GRP78 (0.40 ± 0.025% of β-actin) was detected in LO2 cells (****P < 0.0001, Figure 2A and 2B). In vitro cell uptake of [68Ga]SP94 was performed in HepG2 and human normal liver cell (LO2) lines; HepG2 showed highly GRP78 expression, and LO2 was used as negative control. After incubation of cells in 24-well plates for 24 h (5 × 105 cells/well), the medium was replaced with fresh medium containing 37 KBq of [68Ga]SP94 for each well. At 5, 30, 60, 120, and 180 min, cells and medium were harvested for counting the radioactivity using a γ-counter. The cellar uptake rate of [68Ga]SP94 in HepG2 cells (percent in 5 × 105 cells) was significantly higher than that in LO2 cells (Figure 2C). The uptake of [68Ga]SP94 in HepG2 cells was rapid, 2.22 ± 0.29% at 5 min, and reached 29.29 ± 2.15% at 180 min, suggesting that [68Ga]SP94 could be rapidly and efficiently taken up by the HepG2 cells. However, in LO2 cells, the uptake of [68Ga]SP94 was 1.03 ± 0.15 and 16.80 ± 1.24 at 5 and 180 min, respectively. These findings are consistent with previous research results,26,28 indicating GRP78 to be a good, specific target in HCC and demonstrating that [68Ga]SP94 molecular probes have specific receptor targeting properties for GRP78. On the basis of the cell-binding affinity determination, the Kd value reached 8.05 nmol/L (Figure 2D), indicating that [68Ga]SP94 has a higher affinity for GRP78.

Figure 2.

Figure 2

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(A, B) Relative GRP78 protein expressions in HepG2 and LO2 cell lines and representative GRP78 protein expressions were presented as the ratios of GRP78 vs β-actin expressions using Western blotting analysis. ****P < 0.0001. (C) Time course of cellular uptake of [68Ga]SP94 on HepG2 and LO2 cell lines. Five hundred thousand cells were incubated with 37 KBq of [68Ga]SP94. At each time point, cells were harvested to count the radioactivity using a γ-counter. (D) Affinity of [68Ga]SP94 in HepG2 cells.

The pharmacokinetics experiments were carried out in normal Kunming mice (5 weeks). [68Ga]SP94 (0.74 MBq) was injected via the tail vein of each mouse (n = 5) at set intervals (2, 5, 10, 15, 30, 45, 60, and 120 min), and blood from the eyeball of mice was acquired, weighed, and counted using a γ-counter. The result was determined as the percentage of the injected dose per gram organ/tissue (%ID/g), and the parameters of the pharmacokinetics were analyzed by the GraphPad Prism software (GraphPad Software, California, CA, United States). Figure 3 shows the blood time–radioactivity curve of [68Ga]SP94. After intravenously inject with [68Ga]SP94, the blood concentration of the radiotracer decreased with time prolongation, indicating that [68Ga]SP94 quickly distributed to tissues and organs, which will greatly reduce the exposure of patients to radiation.

Figure 3.

Figure 3

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Time course blood concentration of [68Ga]SP94 in HepG2 tumor-bearing mice intravenously injected with 100 μL of [68Ga]SP94 at 0.74 MBq (n = 5 for each group). Blood samples at different time points (2, 5, 10, 15, 30, 45, 60, and 120 min) were collected, weighted, and counted using a γ-counter.

BALB/c nude mice bearing HepG2 tumor xenografts were used to conduct the biodistribution studies. [68Ga]SP94 (0.74 MBq/mouse) in 200 μL of saline was administered via tail vein injection. The mice were sacrificed in groups of five at 0.5, 1, and 2 h postinjection. The tumor and main organs (heart, liver, kidneys, spleen, lungs, stomach, small intestine, large intestine, bone, and muscle) were harvested, weighed, and counted using a γ-counter. Five samples of 1% injected dose were taken out and evaluated for radioactivity, and the mean value was used as a standard. These results were expressed as percent of injected dose per gram (ID%/g). The biodistribution parameters were analyzed using GraphPad Prism software (GraphPad Software, California, CA, United States). The Anhui Medical University approved this study, which abided ethical guidelines. As shown in Figure 4B, of all organs, the kidney showed the highest radioactivity accumulation, and the uptake decreased from 3.53 ± 0.447 to 1.87 ± 0.283%ID/g between 30 and 120 min postinjection, indicating that [68Ga]SP94 is mainly excreted from the urinary system. The radioactivity uptake value in the HepG2 tumor reached 1.41 ± 0.266, 0.55 ± 0.119, and 0.19 ± 0.073% ID/g at 0.5, 1, and 2 h, respectively. Within 2 h, slight [68Ga]SP94 uptake in the liver was observed, 0.82 ± 0.133, 0.62 ± 0.049, and 0.58 ± 0.099% ID/g at 0.5, 1, and 2 h, suggesting that [68Ga]SP94 is partially metabolized by the liver.

Figure 4.

Figure 4

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(A) Representative whole-body coronal micro-PET images of HepG2 tumor-bearing mice at different time points postintravenous injections of 200 μL of 2.96 MBq [68Ga]SP94 (top) or 2.96 MBq [68Ga]SP94 + Block (bottom) via tail veins. White arrows indicate HepG2 tumors. (B) Time course uptake of [68Ga]SP94 in HepG2 tumor, heart, liver, spleen, lump, kidneys, small intestine, pancreas, and muscle. The data were derived from PET quantification (% ID/g, n = 5 for each group). (C) Time course bar graphs of the ratios Tumor-to-Muscle (T/Muscle), Tumor-to-Blood (T/Blood), and Tumor-to- Liver (T/Liver) from the ROIs in part A.

Finally, we employed the radiotracer [68Ga]SP94 for micro-PET imaging of HepG2 tumor in nude mice. BALB/c nude mice bearing HepG2 tumor xenografts with an approximate diameter of 0.8 cm were randomly divided into two groups (n = 3 for each group). One group of the mice was intravenously injected with [68Ga]SP94 as the experimental group, and the other group of mice was coinjected with [68Ga]SP94 and DOTA-SP94 (0.2 g/kg) as the control group. The mice were injected with [68Ga]SP94 (2.96 MBq, 200 μL) via the tail vein and used for micro-PET/CT imaging at 0.5, 1, and 2 h postinjection under anesthesia. For the blocking study, [68Ga]SP94 (2.96 MBq) and DOTA-SP94 (0.2 g/kg) in 200 μL solution of saline were coinjected into nude mice bearing HepG2 tumors. The whole-body static micro-PET/CT images were taken at 0.5, 1, and 2 h postinjection under anesthesia. Semiquantitative analysis of the radioactivity uptake for tumor, blood, muscle, and liver was performed using the average standardized uptake values (SUVs). ROIs were sketched to estimate the SUVs of the radiotracer in each organ. The tumor-to-muscle (ROIs-T/Muscle), tumor-to-blood (ROIs-T/Blood), and tumor-to-liver (ROIs-T/Liver) ratios were calculated according to the SUV values. Time course coronal micro-PET images of the experimental nude mice (i.e., only injected with [68Ga]SP94) showed that higher tumor uptake of [68Ga]SP94 was observed at the time of 0.5 h after injection and then gradually attenuated (top panels of Figure 4A). In contrast, micro-PET images of the control mice (i.e., coinjected with [68Ga]SP94 and DOTA-SP94) showed that, throughout the 2 h scanning, the radiotracer was concentrated in the kidney, leaving the tumors hardly discernible (bottom panels of Figure 4A). The ROIs-T/Blood, ROIs-T/Muscle, and ROIs-T/Liver ratios in the experimental group were 1.75 ± 0.235, 4.40 ± 1.690, and 1.28 ± 0.509 at 0.5 h; 1.49 ± 0.207, 4.41 ± 0.803, and 0.98 ± 0.426 at 1 h; and 1.41 ± 0.155, 3.96 ± 0.497, and 1.08 ± 0.232 at 2 h, respectively. Comparing the ratio of tumor to background tissue after blocking vs no blocking, all ratios were significantly reduced, demonstrating that the probe has an excellent signal-to-noise ratio in HepG2 tumors (Figure 4C). These findings indicate the specific targeting ability of [68Ga]SP94 for GRP78 and its potential to guide clinical applications. Additionally, the radiotracer uptake in HepG2 tumors can be blocked by unlabeled DOTA-SP94, suggesting that the tracer uptake by HCC was receptor-mediated

In summary, we have described the synthesis, quality control, and biological evaluation of a new radiotracer ([68Ga]SP94) for micro-PET imaging of GRP78 expression in HCC. The radiotracer was synthesized in high radiochemical yield and high radiochemical purity. It is stable in vitro and exhibited a higher binding affinity for specific binding to cells expressing GRP78. Biodistribution and micro-PET imaging showed rapid and higher accumulation in HepG2 tumors; the uptake in tumor was closely associated with the level of GRP78 expression. The results support the possibility of using[68Ga]SP94 for PET/CT detection of GRP78-positive tumors in the clinic, especially liver cancers.

Glossary

Abbreviations

HCC

hepatocellular carcinoma

DOTA

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

PET

positron emission tomography

CT

computed tomography

GRP78

glucose-regulated protein 78

[68Ga]SP94

(DOTA-68Ga)-Gly-Gly-Gly-Ser-Phe-Ser-Ile-Ile-His-Thr-Pro-Ile-Leu-Pro-Leu-Gly-Gly-Cys

RCP

the radiochemical purity

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00350.

  • Materials and instruments, cell culture, animal models, Western blotting, in vitro cell-binding assay, syntheses and characterizations of [68Ga]SP94, 1H NMR spectrum, ESI-MS spectrum, HPLC conditions; Scheme S1, synthetic route for [68Ga]SP94; Figure S1, 1H NMR spectrum of DOTA-SP94 (C) in d6-DMSO; Figure S2, ESI-MS spectrum of DOTA-SP94 (C); Table S1, HPLC conditions for Figure 1B (PDF)

The current research was supported by the National Natural Science Foundation of China (Grants 81872047 and 81901779).

The authors declare no competing financial interest.

Supplementary Material

ml1c00350_si_001.pdf (413.5KB, pdf)

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Supplementary Materials

ml1c00350_si_001.pdf (413.5KB, pdf)

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