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Dual Gene Delivery Reagents From Antiproliferative Alkylphospholipids for Combined Antitumor Therapy
Frontiers in Chemistry ( IF 3.8 ) Pub Date : 2020-08-31 , DOI: 10.3389/fchem.2020.581260
Boris Gaillard , Jean-Serge Remy , Françoise Pons , Luc Lebeau

Alkylphospholipids (APLs) have elicited great interest as antitumor agents due to their unique mode of action on cell membranes. However, their clinical applications have been limited so far by high hemolytic activity. Recently, cationic prodrugs of erufosine, a most promising APL, have been shown to mediate efficient intracellular gene delivery, while preserving the antiproliferative properties of the parent APL. Here, cationic prodrugs of the two APLs that are currently used in the clinic, miltefosine, and perifosine, are investigated and compared to the erufosine prodrugs. Their synthesis, stability, gene delivery and self-assembly properties, and hemolytic activity are discussed in detail. Finally, the potential of the pro-miltefosine and pro-perifosine compounds ME12 and PE12 in combined antitumor therapy is demonstrated using pUNO1-hTRAIL, a plasmid DNA encoding TRAIL, a member of the TNF superfamily. With these pro-APL compounds, we provide a proof of concept for a new promising strategy for cancer therapy combining gene therapy and APL-based chemotherapy.



中文翻译:

来自抗增殖烷基磷脂的双重基因递送试剂用于联合抗肿瘤治疗

烷基磷脂(APL)由于其对细胞膜的独特作用方式,引起了人们对于抗肿瘤药的极大兴趣。然而,迄今为止,它们的临床应用受到高溶血活性的限制。最近,已经证明,最有前途的APL芥子碱的阳离子前药可介导有效的细胞内基因传递,同时保留母体APL的抗增殖特性。在这里,对目前临床上使用的两种APL的阳离子前药miltefosine和periposine进行了研究,并将其与芥酸前药进行了比较。详细讨论了它们的合成,稳定性,基因传递和自组装特性以及溶血活性。最后,米洛磷碱和perifosine化合物的潜力中号E12PE12使用pUNO1-hTRAIL(一种编码TRAIL(TNF超家族成员)的质粒DNA)证明了联合抗肿瘤治疗的作用。借助这些前APL化合物,我们为结合基因疗法和基于APL的化学疗法的新型癌症治疗策略提供了概念验证。

更新日期:2020-10-02
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