Organ-specific cell-penetrating peptides (CPPs) are a class of molecules that can be highly effective at delivering therapeutic cargoes, and they are currently of great interest in cancer treatment strategies. Herein, we describe a new CPP (amino acid sequence serine-isoleucine-tyrosine-valine, or SIWV) that homes to glioblastoma multiforme (GBM) brain tumor tissues with remarkable specificity in vitro and in vivo. The SIWV sequence was identified from an isoform of annexin-A3 (AA3H), a membrane-interacting human protein. The mechanism of intracellular permeation is proposed to follow a caveolin-mediated endocytotic pathway, based on in vitro and in vivo receptor inhibition and genetic knockdown studies. Feasibility as a targeting agent for therapeutics is demonstrated in a GBM xenograft mouse model, where porous silicon nanoparticles (pSiNPs) containing the clinically relevant anticancer drug SN-38 are grafted with SIWV via a poly-(ethylene glycol) (PEG) linker. The formulation shows enhanced in vivo targeting ability relative to a formulation employing a scrambled control peptide, and significant (P < 0.05) therapeutic efficacy relative to free SN-38 in the GBM xenograft animal model.

中文翻译：

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脑肿瘤归巢四肽提供了一种纳米疗法，可以更有效地治疗胶质母细胞瘤小鼠模型。

器官特异性细胞穿透肽（CPPs）是一类可以高度有效地递送治疗药物的分子，目前它们在癌症治疗策略中引起了极大的兴趣。在这里，我们描述了一种新的CPP（氨基酸序列丝氨酸-异亮氨酸-酪氨酸-缬氨酸，或SIWV），它在体外和体内具有明显的特异性，可归因于多形性胶质母细胞瘤（GBM）脑肿瘤组织。从膜联蛋白-人膜相互作用蛋白膜联蛋白-A3（AA3H）的同工型中识别出SIWV序列。胞内渗透的机理提出遵循小窝蛋白介导的内吞途径中，基于在体外和体内受体抑制和基因敲低研究。在GBM异种移植小鼠模型中证明了作为治疗剂靶向剂的可行性，其中包含临床相关抗癌药物SN-38的多孔硅纳米颗粒（pSiNPs）通过聚（乙二醇）（PEG）接头与SIWV移植。相对于采用加扰对照肽的制剂，该制剂显示出增强的体内靶向能力，并且在GBM异种移植动物模型中相对于游离SN-38具有显着的（P＜0.05）治疗功效。