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The presence of glutamate residues on the PAS sequence of the stimuli-sensitive nano-ferritin improves in vivo biodistribution and mitoxantrone encapsulation homogeneity
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2018-02-20 , DOI: 10.1016/j.jconrel.2018.02.025
Elisabetta Falvo , Francesca Malagrinò , Alessandro Arcovito , Francesco Fazi , Gianni Colotti , Elisa Tremante , Patrizio Di Micco , Aldo Braca , Roberta Opri , Alessandro Giuffrè , Giulio Fracasso , Pierpaolo Ceci

A genetically engineered human ferritin heavy chain (HFt)-based construct has been recently shown by our group to efficiently entrap and deliver doxorubicin to cancer cells. This construct, named HFt-MP-PAS, contained a tumor-selective sequence (MP) responsive to proteolytic cleavage by tumor proteases (MMPs), located between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). HFt-MP-PAS displayed excellent therapeutic efficacy in xenogenic pancreatic and head and neck cancer models in vivo, leading to a significant increase in overall animal survivals. Here we report a new construct obtained by the genetic insertion of two glutamate residues in the PAS sequence of HFt-MP-PAS. Such new construct, named HFt-MP-PASE, is characterized by improved performances as drug biodistribution in a xenogenic pancreatic cancer model in vivo.

Moreover, HFt-MP-PASE efficiently encapsulates the anti-cancer drug mitoxantrone (MIT), and the resulting MIT-loaded nanoparticles proved to be more soluble and monodispersed than the HFt-MP-PAS counterparts. Importantly, in vitro MIT-loaded HFt-MP-PASE kills several cancer cell lines of different origin (colon, breast, sarcoma and pancreas) at least as efficiently as the free drug. Finally, our MIT loaded protein nanocages allowed in vivo an impressive incrementing of the drug accumulation in the tumor with respect to the free drug.



中文翻译:

刺激敏感的纳米铁蛋白的PAS序列上谷氨酸残基的存在改善了体内生物分布和米托蒽醌封装的同质性

我们的研究小组最近显示了一种基于基因工程的人铁蛋白重链(HFt)的构建体,可以有效地捕获阿霉素并将其运送至癌细胞。这种名为HFt-MP-PAS的构建体包含一个对肿瘤蛋白酶(MMP)进行蛋白水解切割反应的肿瘤选择性序列(MP),位于每个HFt亚基和富含脯氨酸(P),丝氨酸的外部屏蔽多肽序列之间( S)和丙氨酸(A)残基(PAS)。HFt-MP-PAS在异种胰腺癌和头颈癌体内模型显示出优异的治疗功效,导致总体动物存活率显着提高。在这里,我们报告了通过在HFt-MP-PAS的PAS序列中两个谷氨酸残基的基因插入获得的新构建体。这种称为HFt-MP-PASE的新构建体的特征在于在异种胰腺癌体内模型作为药物生物分布的改善的性能。

此外,HFt-MP-PASE有效地封装了抗癌药米托蒽醌(MIT),并且与HFt-MP-PAS对应物相比,负载的MIT纳米颗粒具有更高的溶解度和单分散性。重要的是,体外加载MIT的HFt-MP-PASE至少可以杀死游离来源的几种癌细胞(结肠,乳腺,肉瘤和胰腺)。最终,我们的MIT负载蛋白纳米笼相对于游离药物在体内显着增加了肿瘤中药物的积累。

更新日期:2018-02-20
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