Iodinated benzimidazole PARP radiotracer for evaluating PARP1/2 expression in vitro and in vivo

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• 作者：Redmond-Craig Anderson ; Mehran Makvandi ; Kuiying Xu ; Brian P. Lieberman ; Chenbo Zeng ; Daniel A. Pryma ; Robert H. Mach ; ^{rmach@mail.med.upenn.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PARP-inhibitor ; BRCA1/2 ; Cancer imaging ; PARP-2
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：43
• 期：12
• 页码：752-758
• 全文大小：522 K

文摘

PARP inhibitors (PARPi) have the potential to impact cancer therapy in a selective patient population; however, despite current patient selection methods clinical trials have shown mixed response rates. It is therefore clinically useful to determine which patients will respond prior to receiving PARPi therapy. One essential biomarker is to measure the level of PARP enzyme expression in tumors. Small molecule radiotracers have been developed to accurately quantify PARP-1 expression in vitro and in vivo. [¹²⁵I]rong class="boldFont">KX-02-019rong> is the first report of a radioiodinated analogue of the benzimidazole class of PARPi. Herein, we studied the pharmacological properties of [¹²⁵I]rong class="boldFont">KX-02-019rong> as well as the in vivo biodistribution.

Methods

[¹²⁵I]rong class="boldFont">KX-02-019rong> was evaluated in both cancer and non-cancer cell lines. We evaluated the pharmacologic properties of [¹²⁵I]rong class="boldFont">KX-02-019rong> in live cells by measuring enzyme association and dissociation kinetics, saturation, and specificity. In addition, competitive inhibition experiments were carried out with commercially available PARPi. Protein expression was analyzed by Western blot to compare PARP-1 and PARP-2 expression across cell lines studied. The biodistribution was studied in a mouse EMT6 tumor model at time points of 0.5, 1, 2, 4 and 6 h.

Results

[¹²⁵I]rong class="boldFont">KX-02-019rong> showed subtle differences in pharmacological properties in the absence of PARP-2. In addition, [¹²⁵I]rong class="boldFont">KX-02-019rong> was competitively displaced by clinical PARPi. In vivo biodistribution studies showed an increasing tumor to muscle ratio over 6 h as well as fast clearance from healthy tissues.

Conclusion

[¹²⁵I]rong class="boldFont">KX-02-019rong> has binding sites in both PARP1 KO cells as well as PARP2 KO cells showing higher affinity for PARP-2. This observation is supported by a decrease in binding affinity in PARP2 KO cells compared to PARP1 KO cells. The pharmacologic and biological properties of [¹²⁵I]rong class="boldFont">KX-02-019rong> studied in vitro and in vivo showed that this analogue may be useful in determining pharmacokinetic and pharmacodynamic properties of clinical PARPi.