Synthesis and Biological Analysis of Prostate-Specific Membrane Antigen-Targeted Anticancer Prodrugs
Synthesis and Biological Analysis of Prostate-Specific Membrane Antigen-Targeted Anticancer Prodrugs
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DOI：
10.1021/jm100729b
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发表时间：
2010-11-11
影响因子：
7.3
通讯作者：
Low, Philip S.
中科院分区：
文献类型：
--
作者：
Kularatne, Sumith A.;Venkatesh, Chelvam;Low, Philip S.
配体靶向疗法因其具有提高效力和降低毒性的潜力而日益受到重视。然而，随着个性化医疗的出现，已经出现了对配体靶向药物设计的更大通用性的需求，其中每种肿瘤靶向配体应该能够将多种治疗剂递送至相同的肿瘤，每种治疗剂根据其对特定患者的癌症的活性来选择。在这份报告中，我们描述了使用前列腺特异性膜抗原（PSMA）靶向配体提供多种不相关的细胞毒性药物的人前列腺癌（LNCaP）细胞。我们证明，PSMA特异性配体，2-[3-（1，3-二羧基丙基）脲基]戊二酸，是能够介导的靶向杀伤LNCaP细胞与许多不同的治疗弹头。这些结果表明，可以将灵活性设计成配体靶向治疗剂，从而使单一靶向配体能够适应于治疗对不同化疗具有不同敏感性的患者。
Ligand-targeted therapeutics have increased in prominence because of their potential for improved potency and reduced toxicity. However, with the advent of personalized medicine, a need for greater versatility in ligand-targeted drug design has emerged, where each tumor-targeting ligand should be capable of delivering a variety of therapeutic agents to the same tumor, each therapeutic agent being selected for its activity on a specific patient's cancer. In this report, we describe the use of a prostate-specific membrane antigen (PSMA)-targeting ligand to deliver multiple unrelated cytotoxic drugs to human prostate cancer (LNCaP) cells. We demonstrate that the PSMA-specific ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid, is capable of mediating the targeted killing of LNCaP cells with many different therapeutic warheads. These results suggest that flexibility can be designed into ligand-targeted therapeutics, enabling adaptation of a single targeting ligand for the treatment of patients with different sensitivities to different chemotherapies.