Spacer length effects on in vitro imaging and surface accessibility of fluorescent inhibitors of prostate specific membrane antigen.
Spacer length effects on in vitro imaging and surface accessibility of fluorescent inhibitors of prostate specific membrane antigen.
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间隔区长度对前列腺特异性膜抗原荧光抑制剂的体外成像和表面可及性的影响。
DOI：
10.1016/j.bmcl.2011.09.115
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发表时间：
2011-12-01
影响因子：
2.7
通讯作者：
Berkman, Clifford E.
中科院分区：
文献类型：
--
作者：
Liu, Tiancheng;Nedrow-Byers, Jessie R.;Hopkins, Mark R.;Berkman, Clifford E.
前列腺特异性膜抗原（PSMA），一种II型跨膜蛋白，已成为前列腺癌成像和治疗应用的活性靶点。最近，其各种化学抑制剂支架的开发已被探索用作靶向PSMA阳性肿瘤细胞的治疗或诊断有效载荷的载体。然而，关于对PSMA的亲和力和体外性能，几乎没有努力确定PSMA抑制剂核心与其有效负载分子之间的接头的最佳长度。在我们目前的模型研究中，合成了三种间隔基长度不同的荧光抑制剂（FAM-CTT-54、FAM-X-CTT-54和FAM-PEG 8-CTT-54），并且进一步的酶抑制研究显示了以下方面的连接基长度依赖性变化：抑制效力（IC 50 = 0.41 nM、0.35 nM、1.93 nM）、结合模式（可逆、缓慢可逆、不可逆）。此外，细胞标记成像揭示了间隔子长度相关的荧光强度变化（FAM-X-CTT-54 > FAM-PEG 8-CTT-54 > FAM-CTT-54）。这些结果表明，接头及其长度的选择将是开发下一代前列腺肿瘤靶向成像探针和治疗剂的重要考虑因素，这些探针和治疗剂特异性地定位于肿瘤细胞上的PSMA。
Prostate-specific membrane antigen (PSMA), a type II transmembrane protein, has been becoming an active target for imaging and therapeutic applications for prostate cancer. Recently, the development of its various chemical inhibitor scaffolds has been explored to serve as carriers for therapeutic or diagnostic payloads targeted to PSMA-positive tumor cells. However, there have been few efforts to definitively determine the optimal length of linker between PSMA inhibitor cores and their payload molecules with regard to the affinity to PSMA and in vitro performance. In our present model study, three spacer-length varied fluorescent inhibitors (FAM-CTT-54, FAM-X-CTT-54 and FAM-PEG8-CTT-54) were synthesized, and further enzymatic inhibition studies displayed linker length-dependent changes in: inhibitory potency (IC50 = 0.41 nM, 0.35 nM, 1.93 nM), modes of binding (reversible, slowly reversible, irreversible), respectively. Furthermore, cell-labeling imaging revealed the spacer length-related change of fluorescence intensity (FAM-X-CTT-54 > FAM-PEG8-CTT-54 > FAM-CTT-54). These results suggest that selection of linkers and their lengths will be important considerations in the development of next-generation prostate tumor-targeted imaging probes and therapeutic agents that specifically home to PSMA on tumor cells.
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影响因子：
4.9
作者：
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通讯作者：
Low, Philip S.
影响因子：
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Liu, Tiancheng;Wu, Lisa Y.;Choi, Joseph K.;Berkman, Clifford E.
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Berkman, Clifford E.
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通讯作者：
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