Therapeutic Efficacy of a Family of pHLIP-MMAF Conjugates in Cancer Cells and Mouse Models
Therapeutic Efficacy of a Family of pHLIP-MMAF Conjugates in Cancer Cells and Mouse Models
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DOI：
10.1021/acs.molpharmaceut.6b00847
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发表时间：
2017-02-01
影响因子：
4.9
通讯作者：
Thevenin, Damien
中科院分区：
文献类型：
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作者：
Burns, Kelly E.;Hensley, Harvey;Thevenin, Damien
专门针对患病组织的治疗对于成功开发癌症治疗至关重要。该方法基于 pH（低）插入肽 (pHLIP)，用于递送有效的有丝分裂抑制剂单甲基 auristatin F (MMAF)。我们研究了与 MMAF 缀合的六种 pHLIP 变体，以比较它们在体外对培养癌细胞的功效。虽然所有 pHLIP MMAF 缀合物均表现出有效的 pH 和浓度依赖性杀伤作用，但它们的细胞毒性特征却截然不同。我们还表明，先导缀合物在小鼠模型中表现出显着的治疗功效，且没有明显的毒性。这项研究证实 pHLIP-单甲基 auristatin 缀合物作为癌症治疗的可能新治疗选择，并支持其进一步发展。
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.