Burns Kelly E, Hensley Harvey, Robinson Matthew K, Thévenin Damien
Department of Chemistry, Lehigh University , 6 East Packer Avenue, Bethlehem, Pennsylvania 18015, United States.
Molecular Therapeutics Program, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
Mol Pharm. 2017 Feb 6;14(2):415-422. doi: 10.1021/acs.molpharmaceut.6b00847. Epub 2017 Jan 13.
The targeting of therapeutics specifically to diseased tissue is crucial for the development of successful cancer treatments. The approach here is based on the pH(low) insertion peptide (pHLIP) for the delivery of a potent mitotic inhibitor monomethyl auristatin F (MMAF). We investigated six pHLIP variants conjugated to MMAF to compare their efficacy in vitro against cultured cancer cells. While all pHLIP-MMAF conjugates exhibit potent pH- and concentration-dependent killing, their cytotoxicity profiles are remarkably different. We also show that the lead conjugate exhibits significant therapeutic efficacy in mouse models without overt toxicities. This study confirms pHLIP-monomethyl auristatin conjugates as possible new therapeutic options for cancer treatment and supports their further development.
将治疗药物特异性靶向病变组织对于成功开发癌症治疗方法至关重要。这里的方法是基于pH（低）插入肽（pHLIP）来递送强效有丝分裂抑制剂单甲基澳瑞他汀F（MMAF）。我们研究了六种与MMAF偶联的pHLIP变体，以比较它们在体外对培养癌细胞的疗效。虽然所有pHLIP-MMAF偶联物都表现出强效的pH和浓度依赖性杀伤作用，但其细胞毒性谱却显著不同。我们还表明，先导偶联物在小鼠模型中显示出显著的治疗效果，且无明显毒性。这项研究证实了pHLIP-单甲基澳瑞他汀偶联物作为癌症治疗可能的新治疗选择，并支持其进一步开发。
