当前位置: X-MOL 学术Acta Biomater. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
A refined cocktailing of pro-apoptotic nanoparticles boosts anti-tumor activity.
Acta Biomaterialia ( IF 9.7 ) Pub Date : 2020-06-27 , DOI: 10.1016/j.actbio.2020.06.033
Laura Sánchez-García 1 , Rita Sala 2 , Naroa Serna 1 , Patricia Álamo 2 , Eloi Parladé 3 , Lorena Alba-Castellón 4 , Eric Voltà-Durán 1 , Alejandro Sánchez-Chardi 5 , Ugutz Unzueta 6 , Esther Vázquez 1 , Ramón Mangues 2 , Antonio Villaverde 1
Affiliation  

A functional 29 amino acid-segment of the helix α5 from the human BAX protein has been engineered for production in recombinant bacteria as self-assembling, GFP-containing fluorescent nanoparticles, which are targeted to the tumoral marker CXCR4. These nanoparticles, of around 34 nm in diameter, show a moderate tumor biodistribution and limited antitumoral effect when systemically administered to mouse models of human CXCR4+ colorectal cancer (at 300 μg dose). However, if such BAX nanoparticles are co-administered in cocktail with equivalent nanoparticulate versions of BAK and PUMA proteins at the same total protein dose (300 μg), protein biodistribution and stability in tumor is largely improved, as determined by fluorescence profiles. This fact leads to a potent and faster destruction of tumor tissues when compared to individual pro-apoptotic factors. The analysis and interpretation of the boosted effect, from both the structural and functional sides, offers clues for the design of more efficient nanomedicines and theragnostic agents in oncology based on precise cocktails of human proteins.

Statement of significance

Several human pro-apoptotic peptides (namely BAK, BAX and PUMA) have been engineered as self-assembling protein nanoparticles targeted to the tumoral marker CXCR4. The systemic administration of the same final amounts of those materials as single drugs, or as combinations of two or three of them, shows disparate intensities of antitumoral effects in a mouse model of human colorectal cancer, which are boosted in the triple combination on a non-additive basis. The superiority of the combined administration of pro-apoptotic agents, acting at different levels of the apoptotic cascade, opens a plethora of possibilities for the development of effective and selective cancer therapies based on the precise cocktailing of pro-apoptotic nanoparticulate agents.



中文翻译:

促凋亡纳米颗粒的精制鸡尾酒增强了抗肿瘤活性。

来自人BAX蛋白的螺旋α5的功能性29个氨基酸段已被工程化,可在重组细菌中生产为自组装,含GFP的荧光纳米粒子,其靶向肿瘤标记物CXCR4。这些纳米粒子直径约34 nm,当全身施用于人类CXCR4 +小鼠模型时,显示出中等的肿瘤生物分布和有限的抗肿瘤作用大肠癌(300μg剂量)。但是,如果将这种BAX纳米颗粒与BAK和PUMA蛋白的等效纳米颗粒形式以相同的总蛋白剂量(300μg)掺入鸡尾酒中,则通过荧光图谱可以确定,蛋白的生物分布和稳定性在很大程度上得到了改善。与单独的促凋亡因子相比,该事实导致有效且更快地破坏肿瘤组织。从结构和功能两方面对增强效应的分析和解释,为基于人类蛋白质的精确混合物设计更有效的纳米药物和肿瘤治疗剂提供了线索。

重要声明

几种人类促凋亡肽(即BAK,BAX和PUMA)已​​被工程化为靶向肿瘤标记物CXCR4的自组装蛋白纳米颗粒。与单一药物或两种或三种药物的组合相同最终量的这些材料的系统性给药,在人类结直肠癌的小鼠模型中显示出不同的抗肿瘤作用强度,在非结肠癌的三联组合中得到增强-加法基础。在不同水平的细胞凋亡级联反应中联合使用促凋亡剂的优越性,为基于促凋亡纳米颗粒剂的精确混合物开发有效和选择性的癌症疗法开辟了许多可能性。

更新日期:2020-08-05
down
wechat
bug