Induction of cancer cell death by self-assembling nanostructures incorporating a cytotoxic peptide.
Induction of cancer cell death by self-assembling nanostructures incorporating a cytotoxic peptide.
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DOI：
10.1158/0008-5472.can-09-3267
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Stupp SI
中科院分区：
文献类型：
--
作者：
Standley SM;Toft DJ;Cheng H;Soukasene S;Chen J;Raja SM;Band V;Band H;Cryns VL;Stupp SI
纳米技术为癌症治疗提供了新的载体。纳米平台的潜在优势包括改善药物动力学，包裹细胞毒剂，促进治疗药物在肿瘤微环境中的积累，以及改善治疗结构和生物活性。在这里，我们报道了一种新型的两亲性分子的设计，这种分子自组装成纳米结构，用于细胞内递送细胞毒肽。具体地说，已知通过膜破坏诱导癌细胞死亡的阳离子α-螺旋(KLAKLAK)2多肽被整合到多肽两亲性(PA)中，该多肽自组装成具有生物活性的圆柱形纳米纤维。PAS是由疏水的烷基尾巴、β-Sheet形成肽和自组装后显示在纳米纤维表面的生物活性多肽组成的。包括(KLAKLAK)2的PA纳米结构很容易被乳腺癌细胞内化，而(KLAKLAK)2肽本身不具有细胞渗透性。(KLAKLAK)2纳米结构，而不是单独的多肽，也通过caspase非依赖和Bax/Bak非依赖的机制与膜破裂相关地诱导乳腺癌细胞死亡。值得注意的是，(KLAKLAK)2纳米结构在转化的乳腺上皮细胞中比未转化的细胞更强烈地诱导细胞死亡，这表明了一定程度的肿瘤选择性。我们的结果提供了原理证明，自组装的Pas可以被合理地设计成能够有效地将细胞毒肽输送到癌细胞的纳米结构。
Nanotechnology offers novel delivery vehicles for cancer therapeutics. Potential advantages of nanoscale platforms include improved pharmacokinetics, encapsulation of cytotoxic agents, enhanced accumulation of therapeutics in the tumor microenvironment, and improved therapeutic structures and bioactivity. Here we report the design of a novel amphiphilic molecule that self-assembles into nanostructures for intracellular delivery of cytotoxic peptides. Specifically, a cationic α-helical (KLAKLAK)2 peptide that is known to induce cancer cell death by membrane disruption was integrated into a peptide amphiphile (PA) that self-assembles into bioactive, cylindrical nanofibers. PAs are composed of a hydrophobic alkyl tail, a β-sheet forming peptide, and a bioactive peptide that is displayed on the surface of the nanofiber after self-assembly. PA nanostructures that included (KLAKLAK)2 were readily internalized by breast cancer cells, in contrast to the (KLAKLAK)2 peptide that on its own was not cell permeable. (KLAKLAK)2 nanostructures, but not the peptides alone, also induced breast cancer cell death by caspase-independent and Bax/Bak-independent mechanisms associated with membrane disruption. Significantly, (KLAKLAK)2 nanostructures induced cell death more robustly in transformed breast epithelial cells than in untransformed cells, suggesting a degree of tumor selectivity. Our results provide proof-of-principle that self-assembling PAs can be rationally designed to generate nanostructures that can efficiently deliver cytotoxic peptides to cancer cells.