Targeting of MMP2 activity in malignant tumors with a ⁶⁸Ga-labeled gelatinase inhibitor cyclic peptide

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• 作者：Qinghua Liu^a ; ^{shlqh@126.com" class="auth_mail" title="E-mail the corresponding author} ; Donghui Pan^b ; Chao Cheng^a ; Anyu Zhang^a ; Chao Ma^c ; Lizhen Wang^b ; Dazhi Zhang^d ; Hongrui Liu^e ; Hongdie Jiang^a ; Tao Wang^a ; Yuping Xu^b ; Runlin Yang^b ; Fei Chen^b ; Min Yang^b ; ^{ymzfk@163.com" class="auth_mail" title="E-mail the corresponding author} ; Changjing Zuo^a ; ^{changjing.zuo@qq.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：MMP2 ; matrix metalloproteinase 2 ; C6 ; c(Lys-Ala-His-Trp-Gly-Phe-Thr-Leu-Asp)NH2 ; PET ; positron emission tomography ; NOTA ; 1 ; 4 ; 7-triazacyclononanetriacetic acid ; SPECT ; single photon emission computed tomography ; HPLC ; high-performance liquid chromatography ; HEPES ; 2-[4-(2-hydroxyethyl)-1-piperazinyl] ethanesulfonic acid ; TFA ; trifluoroacetic acid ; %ID/g ; the percent of injected dose to grams of tissue ; p.i ; post-injection ; PBS ; phosphate buffered saline ; DMEM ; Dulbecco&rsquo ; s modified eagle&rsq
• 刊名：Nuclear Medicine and Biology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：42
• 期：12
• 页码：939-944
• 全文大小：693 K

文摘

Elevated levels of gelatinases (matrix metalloproteinases 2/9, i.e., MMP2 and MMP9) are associated with tumor progression, invasion and metastasis, so these enzymes are potential targets for tumor imaging. The peptide c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor. Cy5.5-C6 has been visualized in many tumor models in vivo. However, the sensitivity and penetrance of optical imaging are poor. It is well known that positron emission tomography (PET) has a high detection sensitivity and Gallium-68 (⁶⁸Ga) is an optimal PET radioisotope. Thus, in the present study, we developed a novel ligand, ⁶⁸Ga-NOTA-C6, to image MMP2 activity in tumors.

Methods

C6 was conjugated with the bifunctional chelator NOTA (1,4,7-triazacyclononanetriacetic acid) and labeled with ⁶⁸Ga. In vitro uptake and binding analyses were performed by using SKOV3 cell lines, coincubating with or without the MMP inhibitor doxycycline. The biodistribution and PET imaging were conducted on SKOV3 ovarian tumor models. MMP2 expression in tumors was analyzed by immunohistochemistry (IHC).

Results

The non-decay corrected yield of ⁶⁸Ga-NOTA-C6 was 61.8%–63.3%. ⁶⁸Ga-NOTA-C6 was stable in both physiological saline and human serum. The uptake of ⁶⁸Ga-NOTA-C6 in SKOV3 cells increased with time, and could be blocked by doxycycline in a dose dependent manner. The results of biodistribution and PET imaging showed that high radioactivity concentrations of ⁶⁸Ga-NOTA-C6 occurred in tumors. The ratios of tumor to blood, muscle and ovary and oviduct at 30, 60 and 120 min p.i. were 2.78 ± 0.54, 3.86 ± 0.65, 0.48 ± 0.14, and 1.73 ± 0.36, 10.31 ± 3.12, 1.22 ± 0.10, and 2.50 ± 0.78, 7.03 ± 1.85, 0.97 ± 0.25, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. These data support the possibility of using ⁶⁸Ga-NOTA-C6 in PET to visualize tumors that overexpress MMP2.

Conclusions

⁶⁸Ga-NOTA-C6 is a potential radiopharmaceutical for the imaging of in vivo MMP2 activity in tumors.