Design and cellular delivery of a modified human deoxycytidine kinase with L-nucleoside analogue activity for use in cancer therapy

具有 L-核苷类似物活性的修饰人脱氧胞苷激酶的设计和细胞递送，用于癌症治疗

• 批准号: 160506553
• 负责人: Dr. Theresa Schweizer
• 金额: --
• 依托单位: Arbeitsgruppe Enzym-Biochemie (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/160506553?language=en
• 关键词: Design; cellular; delivery; modified; human

Poor activation and off-target cytotoxicity often limit the efficacy of nucleoside analogue pro-drugs in the clinic. Our aim is to develop a therapeutic strategy which specifically targets tumour cells and increases the efficacy of nucleoside analogue pro-drugs in the treatment of certain cancers. We will modify the enzyme human deoxycytidine kinase (dCK) to enable it to exclusively phosphorylate and activate non-physiological L-nucleosides. The modified dCK will be targeted and delivered to tumour cells by the use of single chain antibodies (scFv) or affibodies. We propose that the confined delivery of our modified dCK to tumour cells and the use of L-nucleoside analogues will provide both increased cytotoxicity and increased specificity in nucleoside analogue chemotherapy.

活性差和脱靶细胞毒性常常限制核苷类似物前药在临床上的功效。我们的目标是开发一种专门针对肿瘤细胞的治疗策略，并提高核苷类似物前药在治疗某些癌症中的功效。我们将修改酶人脱氧胞苷激酶（dCK），使其能够专门磷酸化和激活非生理L-核苷。修饰的dCK将通过使用单链抗体（scFv）或抗体靶向并递送至肿瘤细胞。我们建议，我们的修饰dCK的局限性交付到肿瘤细胞和使用L-核苷类似物将提供增加的细胞毒性和增加的特异性核苷类似物化疗。