肿瘤微环境诱导多肽聚合物原位组装行为研究

吉垒; 张雪豪; 杨子欣; 乔增莹; 王浩

doi:10.11777/j.issn1000-3304.2019.19039

您当前的位置：

首页 >

文章列表页 >

肿瘤微环境诱导多肽聚合物原位组装行为研究

研究论文 | 更新时间：2021-01-26

- 肿瘤微环境诱导多肽聚合物原位组装行为研究
- Microenvironment-induced in situ Self-assembly of Polymer-Peptide Conjugates
- 高分子学报 2019年50卷第6期页码：642-652
- 作者机构：
  
  1.华中农业大学理学院　武汉 430070
  2.国家纳米科学中心中国科学院纳米生物效应与安全性重点实验室中国科学院纳米科学卓越创新中心　北京 100190
- 作者简介：
  
  E-mail: zixinyang@mail.hzau.edu.cn
  E-mail: wanghao@nanoctr.cn
- 基金信息：
  
  中国科学院纳米生物效应与安全性重点实验室2018开放课题(基金号 NSKF201803)资助()
- DOI：10.11777/j.issn1000-3304.2019.19039
  中图分类号：
- 纸质出版日期：2019-6，
  
  网络出版日期：2019-5-5，
  
  收稿日期：2019-2-25，
  
  修回日期：2019-3-25，
扫描看全文
吉垒, 张雪豪, 杨子欣, 乔增莹, 王浩. 肿瘤微环境诱导多肽聚合物原位组装行为研究[J]. 高分子学报, 2019,50(6):642-652.

Lei Ji, Xue-hao Zhang, Zi-xin Yang, Zeng-ying Qiao, Hao Wang. Microenvironment-induced in situ Self-assembly of Polymer-Peptide Conjugates[J]. Acta Polymerica Sinica, 2019,50(6):642-652.
吉垒, 张雪豪, 杨子欣, 乔增莹, 王浩. 肿瘤微环境诱导多肽聚合物原位组装行为研究[J]. 高分子学报, 2019,50(6):642-652. DOI： 10.11777/j.issn1000-3304.2019.19039.

Lei Ji, Xue-hao Zhang, Zi-xin Yang, Zeng-ying Qiao, Hao Wang. Microenvironment-induced in situ Self-assembly of Polymer-Peptide Conjugates[J]. Acta Polymerica Sinica, 2019,50(6):642-652. DOI： 10.11777/j.issn1000-3304.2019.19039.

摘要

设计合成了一种pH响应型的多肽聚合物，在中性条件下能够以聚合物单链的形式存在，在肿瘤微环境弱酸的刺激下发生聚集，提升入胞能力，从而实现对肿瘤细胞的高效杀伤. 首先，通过迈克尔加成的方法合成了一系列生物相容性较好的

-硫代酸酯聚合物，并利用固相合成方法合成了治疗肽和穿膜肽2种多肽. 然后，将治疗肽修饰上一种酸敏感基团，并将2种多肽通过迈克尔加成反应与聚合物共价连接. 得到的多肽聚合物能够在中性水溶液中以单链形式稳定存在，而在pH = 6.5条件下发生聚集. 最后，在细胞层面对多肽聚合物进行研究，发现其在微酸性条件下可以通过内吞作用进入到肿瘤细胞，并具有更高的抗肿瘤能力.

Abstract

The "

in vivo

self-assembly” strategy was adopted to improve the efficacy of polymer-peptide conjugates (PPCs) in tumor destruction. Briefly

a pH-sensitive PPC was designed and synthesized

which could penetrate deep into the solid tumors as a single chain. Such single chain would subsequently respond to the mildly acidic environment inside the solid tumor and assemble into a ball

thereby acquiring higher internalization capacity and achieving an enhanced therapeutic function. The major work in this research is as follows. First

several

-thioester polymers were synthesized

via

a condensation polymerization

and two peptides were produced by solid-phase peptide synthesis. One of the peptides was modified with a pH-sensitive group

cis

-aconitic anhydride

and then as-designed polymer-peptide conjugates were prepared by coupling the peptides with polymers through the Michael addition. The PPC products remained stable in a single stranded form under the neutral aqueous condition but aggregated at pH = 6.5. According to TEM observation

the size of PPCs in a pH = 6.5 solution increased from 17 nm to 88 nm in 12 h due to self-assembly

while no obvious size change was noticed under the pH = 7.4 condition. The PPCs modified with DBD group (PS-KFx-CAA-DBD) were dissolved in PBS at different pHs for FL measurement; the FL intensity was significantly increased at pH = 6.5 but barely changed at pH = 7.4

which verified acid-induced aggregation. The mechanism of peptide cytotoxicity is rooted in the destructive effect of

-helix structure on mitochondria membranes. Within 12 h

the content of

-helix structure increased slightly from 19.5% to 25.8% at pH = 7.4 but markedly to 58.9% at pH = 6.5. Based on the rapid hydrolysis of PPCs at pH = 6.5

the better recovery of

-helix structure implied a higher therapeutic activity. Therefore

this

in vivo

self-assembly strategy enables the peptide nanomaterials to penetrate deeper into the tumor cells and thus endows them with enhanced therapeutic efficacy.

关键词

体内自组装pH响应型多肽聚合物肿瘤

Keywords

In vivo self-assemblypH-sensitivePolymer-peptide conjugatesTumour

references

Shapira A, Livney Y D, Broxterman H J, Assaraf Y G . Drug Resist Update , 2011 . 14 ( 3 ): 150 - 163 . DOI:10.1016/j.drup.2011.01.003http://doi.org/10.1016/j.drup.2011.01.003 .

Amjad M W, Kesharwani P, Amin M C I M, Iyer A K . Prog Polym Sci , 2017 . 64 154 - 181 . DOI:10.1016/j.progpolymsci.2016.09.008http://doi.org/10.1016/j.progpolymsci.2016.09.008 .

Nakamura Y, Mochida A, Choyke P L, Kobayashi H . Bioconjugate Chem , 2016 . 27 ( 10 ): 2225 - 2238 . DOI:10.1021/acs.bioconjchem.6b00437http://doi.org/10.1021/acs.bioconjchem.6b00437 .

Li T Y, Xiang W T, Li F, Xu H P . Biomaterials , 2018 . 157 17 - 25 . DOI:10.1016/j.biomaterials.2017.12.001http://doi.org/10.1016/j.biomaterials.2017.12.001 .

Park J H, Lee S, Kim J H, Park K, Kim K, Kwon I C . Prog Polym Sci , 2008 . 33 ( 1 ): 113 - 137 . DOI:10.1016/j.progpolymsci.2007.09.003http://doi.org/10.1016/j.progpolymsci.2007.09.003 .

Wilhelm S, Tavares A J, Dai Q, Ohta S, Audet J, Dvorak H F, Chan W C . Nat Rev Mater , 2016 . 1 ( 5 ): 16014 DOI:10.1038/natrevmats.2016.14http://doi.org/10.1038/natrevmats.2016.14 .

Li H J, Du J Z, Du X J, Xu C F, Sun C Y, Wang H X, Wang J . Proc Natl Acad Sci , 2016 . 113 ( 15 ): 4164 - 4169 . DOI:10.1073/pnas.1522080113http://doi.org/10.1073/pnas.1522080113 .

Cun X, Ruan S, Chen J, Zhang L, Li J, He Q, Gao H . Acta Biomater , 2016 . 31 186 - 196 . DOI:10.1016/j.actbio.2015.12.002http://doi.org/10.1016/j.actbio.2015.12.002 .

Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, Terada Y, Kano M R, Miyazono K, Uesaka M, Nishiyama N, Kataoka K . Nat Nanotechnol , 2011 . 6 ( 12 ): 815 - 823 . DOI:10.1038/nnano.2011.166http://doi.org/10.1038/nnano.2011.166 .

Perrault S D, Walkey C, Jennings T, Fischer H C, Chan W C . Nano Lett , 2009 . 9 ( 5 ): 1909 - 1915 . DOI:10.1021/nl900031yhttp://doi.org/10.1021/nl900031y .

Zhou J, Du X, Chen X, Wang J, Zhou N, Wu D, Xu B . J Am Chem Soc , 2018 . 140 ( 6 ): 2301 - 2308 . DOI:10.1021/jacs.7b12368http://doi.org/10.1021/jacs.7b12368 .

Hu X L, Zhai S D, Liu G H, Da X, Liang H J, Liu S Y . Adv Mater , 2018 . 30 ( 21 ): 1706307 DOI:10.1002/adma.v30.21http://doi.org/10.1002/adma.v30.21 .

Lei Q, Wang S B, Hu J J, Lin Y X, Zhu C H, Rong L, Zhang X Z . ACS Nano , 2017 . 11 ( 7 ): 7201 - 7214 . DOI:10.1021/acsnano.7b03088http://doi.org/10.1021/acsnano.7b03088 .

Wang F Y K, Gao J Y, Xiao J G, Du J Z . Nano Lett , 2018 . 18 ( 9 ): 5562 - 5568 . DOI:10.1021/acs.nanolett.8b01985http://doi.org/10.1021/acs.nanolett.8b01985 .

Fraden S, Kamien R D . Biophys J , 2000 . 78 ( 5 ): 2189 - 2190 . DOI:10.1016/S0006-3495(00)76767-1http://doi.org/10.1016/S0006-3495(00)76767-1 .

Gao X, Yang S, Zhao C, Ren Y, Wei D . Angew Chem Int Ed , 2014 . 53 ( 51 ): 14027 - 14030 . DOI:10.1002/anie.v53.51http://doi.org/10.1002/anie.v53.51 .

Yang P P, Zhao X X, Xu A P, Wang L, Wang H . J Mat Chem B , 2016 . 4 ( 15 ): 2662 - 2668 . DOI:10.1039/C6TB00097Ehttp://doi.org/10.1039/C6TB00097E .

Yang P P, Luo Q, Qi G B, Gao Y J, Li B N, Zhang J P, Wang L, Wang H . Adv Mater , 2017 . 29 ( 15 ): 1605869 DOI:10.1002/adma.201605869http://doi.org/10.1002/adma.201605869 .

Liu W J, Zhang D, Li L L, Qiao Z Y, Zhang J C, Zhao Y X, Qi G B, Wan D, Pan J, Wang H . ACS Appl Mater Interfaces , 2016 . 8 ( 35 ): 22875 - 22883 . DOI:10.1021/acsami.6b07049http://doi.org/10.1021/acsami.6b07049 .

Wang L, Yang P P, Zhao X X, Wang H . Nanoscale , 2016 . 8 ( 5 ): 2488 - 2509 . DOI:10.1039/C5NR07437Ahttp://doi.org/10.1039/C5NR07437A .

Li L L, Ma H L, Qi G B, Zhang D, Yu F, Hu Z, Wang H . Adv Mater , 2016 . 28 ( 2 ): 254 - 262 . DOI:10.1002/adma.201503437http://doi.org/10.1002/adma.201503437 .

Petros R A, DeSimone J M . Nat Rev Drug Discov , 2010 . 9 ( 8 ): 615 - 627 . DOI:10.1038/nrd2591http://doi.org/10.1038/nrd2591 .

Cong Y, Ji L, Gao Y J, Liu F H, Cheng D B, Hu Z Y, Qiao Z Y, Wang H . Angew Chem Int Ed , 2019 . 58 ( 14 ): 4632 - 4637 . DOI:10.1002/anie.201900135http://doi.org/10.1002/anie.201900135 .

Yousif L F, Stewart K M, Kelley S O . ChemBioChem , 2009 . 10 ( 12 ): 1939 - 1950 . DOI:10.1002/cbic.v10:12http://doi.org/10.1002/cbic.v10:12 .

Okabe K, Inada N, Gota C, Harada Y, Funatsu T, Uchiyama S . Nat Commun , 2012 . ( 3 ): 705 .

Molla M R, Prasad P, Thayumanavan S . J Am Chem Soc , 2015 . 137 ( 23 ): 7286 - 7289 . DOI:10.1021/jacs.5b04285http://doi.org/10.1021/jacs.5b04285 .

Sreerama N, Woody R W . Anal Biochem , 2000 . 287 ( 2 ): 252 - 260 . DOI:10.1006/abio.2000.4880http://doi.org/10.1006/abio.2000.4880 .

更多指标>

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

体内自组装多肽纳米材料及其在肿瘤诊疗中的研究进展