新型制剂分子或助力前列腺癌诊断技术的开发

  前列腺特异性膜抗原（PSMA）是一种存在于健康前列腺细胞表面的蛋白，其往往在前列腺癌细胞表面处于较高的水平，因此PSMA似乎是诊断前列腺癌以及开发特殊靶向疗法的一种新型靶点。近日发表于国际杂志Journal of Nuclear Medicine上的研究论文中，来自德国癌症研究中心的科学家表示，他们开发了一种名为PSMA-617的小分子，其可以特异性地吸附到PSMA上，同时也可以被多种放射性核素所标记。
  当化学性结合到镓-68上时（镓-68是一种较弱的放射性诊断核素），PSMA-617就会在正电子成象术(PET)的帮助下被用于对最小的前列腺癌细胞“组件”进行可视化成像，因此以这种方式医生们就可以在机体其它部位中检测到次级肿瘤，同时也可以对患者的肿瘤进行实时监测。研究者还可以将一种治疗性的放射性核素镥-177吸附到PSMA-617分子上，这种放射性药物会很快被携带PSMA的肿瘤细胞所吸收，随后其就会开始破坏前列腺癌细胞进而对前列腺癌甚至是耐药性的前列腺癌细胞进行靶向性杀灭。
  研究者Uwe Haberkorn说道，目前我们已经可以利用放射性标记的PSMA-617来治疗恶性前列腺癌患者，而医生们同时也会利用治疗性的核素镥-177和锕-225来辅助进行治疗；利用镥标记的放射性药物治疗后，前列腺癌标志物PSA的水平会明显下降70%，而利用锕标记的放射性药物治疗后在所有的患者中都可以观察到治疗效应。
  另外PET/CT成像技术也可以帮助判断肿瘤的转移是否已经被有效控制了，研究者表示这对于后期进行临床试验非常有帮助，后期我们将检测是否PSMA-617分子优于其它的治疗方法；后期研究者将通过更多研究来证实PSMA-617分子的特性，钙分子在肿瘤和转移病灶中可以大量积累，因此其非常有希望作为开发新型抵御前列腺癌疗法的靶点。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer
J Nucl Med    doi: 10.2967/jnumed.114.147413
Martina Benešová1, Martin Schäfer1, Ulrike Bauder-Wüst1, Ali Afshar-Oromieh2, Clemens Kratochwil2, Walter Mier2, Uwe Haberkorn2,3, Klaus Kopka1 and Matthias Eder1
Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed. Methods: The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversed-phase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent 67/68Ga and 177Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. Results: The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [Ki] = 2.34 ± 2.94 nM on LNCaP; Ki = 0.37 ± 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-to-background contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection. Conclusion: The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.