Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation
Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation
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DOI：
10.1158/1078-0432.ccr-14-3000
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发表时间：
2015-05-15
影响因子：
11.5
通讯作者：
Kufe, Donald
中科院分区：
文献类型：
--
作者：
Hasegawa, Masanori;Sinha, Raj Kumar;Kufe, Donald
目的：MUC 1-C癌蛋白是一种细胞内靶点，可被细胞穿透肽抑制剂药物化。然而，由于不利的药代动力学参数和有限的细胞穿透能力，用于治疗癌症的肽基药物的开发一直是一个挑战。实验设计：研究了MUC 1-C抑制剂GO-203在新型聚合物纳米颗粒中的包封对MUC 1-C信号传导和功能的细胞内靶向的影响。我们的研究结果表明，负载GO-203到四嵌段聚乳酸（PLA）-聚乙二醇（PEG）-聚丙二醇（PPG）-PEG共聚物是可以实现的，并且，值得注意的是，通过增加PEG链长增强。此外，我们发现GO-203从这些纳米颗粒的释放在至少7天内是可控的。GO-203/纳米颗粒在体外治疗MUC 1-C阳性乳腺癌和肺癌细胞比未包封的GO-203更有效，给药频率更低。此外，用G 0 -203/纳米颗粒处理阻断MUC 1-C同源二聚化，与靶向效应一致。G 0 -203/纳米颗粒治疗也有效下调TIGAR，破坏氧化还原平衡，并抑制癌细胞的自我更新能力。值得注意的是，每周向携带同系或异种移植肿瘤的小鼠施用GO-203/纳米颗粒与消退相关，所述消退与每天施用GO-203时发现的消退相当。因此，这些发现定义了一种有效的方法，用于（i）在聚合物PLA中持续施用GO-203（ii）靶向癌细胞中的MUC 1-C的PEG-PPG-PEG纳米颗粒和（ii）其他抗癌肽药物的潜在递送。（C）2015年AACR。
Purpose: The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell-penetrating capabilities.Experimental Design: Encapsulation of the MUC1-C inhibitor GO-203 in novel polymeric nanoparticles was studied for effects on intracellular targeting of MUC1-C signaling and function.Results: Our results show that loading GO-203 into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and, notably, is enhanced by increasing PEG chain length. In addition, we found that release of GO-203 from these nanoparticles is controllable over at least 7 days. GO-203/nanoparticle treatment of MUC1-C-positive breast and lung cancer cells in vitro was more active with less frequent dosing than that achieved with nonencapsulated GO-203. Moreover, treatment with GO-203/nanoparticles blocked MUC1-C homodimerization, consistent with on-target effects. GO-203/nanoparticle treatment was also effective in downregulating TIGAR, disrupting redox balance, and inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/nanoparticles to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable with those found when dosing on a daily basis with GO-203.Conclusions: These findings thus define an effective approach for (i) sustained administration of GO-203 in polymeric PLA(PEG-PPG-PEG) nanoparticles to target MUC1-C in cancer cells and (ii) the potential delivery of other anticancer peptide drugs. (C)2015 AACR.