低黏附性正电纳米胶囊用于耐药性细菌生物被膜感染治疗

刘晨晖; 曹京京; 赵宇; 郑春雄; 郑雅丹; 刘琦; 张展展; 刘阳

doi:10.11777/j.issn1000-3304.2019.18220

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低黏附性正电纳米胶囊用于耐药性细菌生物被膜感染治疗

研究论文 | 更新时间：2021-01-26

- 低黏附性正电纳米胶囊用于耐药性细菌生物被膜感染治疗
- Low-adhesive, Positively Charged Nanocapsule for the Treatment of Drug-resistant Bacterial Biofilm Infection
- 高分子学报 2019年50卷第3期页码：300-310
- 作者机构：
  
  功能高分子材料教育部重点实验室南开大学化学系　天津 300071
- 作者简介：
  
  E-mail: yliu@nankai.edu.cn Yang Liu, E-mail: yliu@nankai.edu.cn
- 基金信息：
  
  科技部重点研发专项“纳米科技”(项目号 2018YFA0209700)、国家自然科学基金(基金号 51673100)、天津市自然科学基金(基金号18JCQNJC03600)和双一流高校建设经费(南开大学)资助()
- DOI：10.11777/j.issn1000-3304.2019.18220
  中图分类号：
- 纸质出版日期：2019-3，
  
  网络出版日期：2019-1-30，
  
  收稿日期：2018-10-16，
  
  修回日期：2018-12-25，
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刘晨晖, 曹京京, 赵宇, 郑春雄, 郑雅丹, 刘琦, 张展展, 刘阳. 低黏附性正电纳米胶囊用于耐药性细菌生物被膜感染治疗[J]. 高分子学报, 2019,50(3):300-310.

Chen-hui Liu, Jing-jing Cao, Yu Zhao, Chun-xiong Zheng, Ya-dan Zheng, Qi Liu, Zhan-zhan Zhang, Yang Liu. Low-adhesive, Positively Charged Nanocapsule for the Treatment of Drug-resistant Bacterial Biofilm Infection[J]. Acta Polymerica Sinica, 2019,50(3):300-310.
刘晨晖, 曹京京, 赵宇, 郑春雄, 郑雅丹, 刘琦, 张展展, 刘阳. 低黏附性正电纳米胶囊用于耐药性细菌生物被膜感染治疗[J]. 高分子学报, 2019,50(3):300-310. DOI： 10.11777/j.issn1000-3304.2019.18220.

Chen-hui Liu, Jing-jing Cao, Yu Zhao, Chun-xiong Zheng, Ya-dan Zheng, Qi Liu, Zhan-zhan Zhang, Yang Liu. Low-adhesive, Positively Charged Nanocapsule for the Treatment of Drug-resistant Bacterial Biofilm Infection[J]. Acta Polymerica Sinica, 2019,50(3):300-310. DOI： 10.11777/j.issn1000-3304.2019.18220.

摘要

为了增强抗生素在生物被膜内部的渗透性能，并使其在生物被膜底部富集，设计了一种新颖的具有强渗透性和酸响应快速释放药物能力的纳米胶囊. 这种纳米载药体系由酸响应内核和强渗透性外壳两部分组成. 其中，纳米药物载体的内核由席夫碱键桥联的聚己内酯(bi-PCL)共沉淀形成，外壳则通过原位聚合的方法在其表面形成一层富含2-甲基丙烯酰氧乙基磷酸胆碱(MPC)和

-(2-氨基丙基)甲基丙烯酰胺(APM)的无规交联网状聚合物. 由于纳米胶囊表面由正电性的pAPM和低黏附性的pMPC共聚构成，在两者协同作用下，纳米胶囊可迅速渗透至生物被膜底部，同时由bi-PCL构成的内核在生物被膜内部酸性环境刺激下快速断键释放负载的药物. 基于这一结构，该纳米胶囊可在给药后短时间内实现药物富集于生物被膜底部，从而快速有效地杀伤生物被膜内部的细菌，显著提高对生物被膜相关细菌感染的治疗效果.

Abstract

Microbes with the biofilm mode of growth are highly resistant against antibiotics partially due to the ineffective antibiotic penetration to the depth of a biofilm where the bacteria reside and proliferate. To enhance the penetration of antibiotics

we herein demonstrated a delivery nanocapsule that could deliver antibiotics deeply into the deep layer of the biofilm and release the antibiotics inside. The delivery nanocapsule performs a core-shell structure. The core is formed

via

nanoprecipitation with two different types of antibiotics in the presence of an acid-liable polymer

which allows the effective release of the antibiotics in response to the acidic environment when reaching the deep layer of the biofilm. The shell of the delivery nanocapsule is synthesized by co-polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) and

-(3-Aminopropyl) methacrylamide hydrochloride (APM) to form a cationic and protein adsorption-resistant film encapsulating around the core. Such a core-shell structure could effectively reduce the diffusion resistance of the delivery nanocapsule into the biofilm

resulting in an enhanced penetration capability. Confocal laser scanning macroscopy (CLSM) imaging demonstrated that the nanocapsule could efficiently penetrate into the mature biofilms formed by

S. aureus

ATCC12600

GFP

. Moreover

such nanocapsules could load multiple drugs simultaneously

allowing the spontaneously co-delivery of various types of antibiotics into the biofilm. Exemplified with piperacillin and tazobactam

the co-delivery of the two types of antibiotics with the nanocapsule resulted in the synergetic therapeutic effect on the

-lactam resistance bacteria of

S. aureus

ATCC43300

achieving an efficient eradication of the bacteria embedded in the biofilm. In conclusion

the nanocapsule-based delivery system assisted with antibiotics in penetrating into the deep layer of biofilm and released the antibiotics in response to the acidic environment of the biofilm. Compared to directly applying antibiotics to the biofilm

the delivery of antibiotics with the nanocapsule exhibited more effective penetration and accumulation deeply inside the layer

achieving a more efficient eradication of the residual bacteria in the biofilm.

关键词

生物被膜纳米胶囊响应性聚合物两性离子聚合物

Keywords

BiofilmNanocapsuleResponsive polymerZwitterionic polymer

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