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
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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N-(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.
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 copolymerization of 2-methacryloyloxyethyl phosphorylcholine(MPC) and N-(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 β-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.
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 copolymerization of 2-methacryloyloxyethyl phosphorylcholine(MPC) and N-(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 β-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.
引文
1 Hu D F,Li H,Wang B L,Ye Z,Lei W X,Jia F,Jin Q,Ren K F,Ji J.ACS Nano,2017,11(9):9330-9339
2 Zhang P B,Li S L,Chen H,Wang X Y,Liu L B,Lv F T,Wang S.ACS Appl Mater Interfaces,2017,9(20):16933-16938
3 Flemming H C,Wingender J,Szewzyk U,Steinberg P,Rice S A,Kjelleberg S.Nat Rev Microbiol,2016,14(9):563-575
4 Li X N,Yeh Y C,Giri K,Mout R,Landis R F,Prakash Y S,Rotello V M.Chem Commun,2015,51(2):282-285
5 Olsen I.Eur J Clin Microbiol Infect Dis,2015,34(5):877-886
6 Zheng C X,Zhao Y,Liu Y.Chinese J Polym Sci,2017,36(3):322-346
7 Tran N,Tran P A.ChemPhysChem,2012,13(10):2481-2494
8 Song Tao(宋涛),Xi Yuejing(奚悦静),Du Jianzhong(杜建忠).Acta Polymerica Sinica(高分子学报),2018,(1):119-128
9 Li Yaming(李亚民),Liu Shiyong(刘世勇).Acta Polymerica Sinica(高分子学报),2017,(7):1178-1190
10 Guo Q Q,Zhao Y,Dai X M,Zhang T Q,Yu Y J,Zhang X G,Li C X.ACS Appl Mater Interfaces,2017,9(20):16834-16847
11 Mu H B,Guo F,Niu H,Liu Q J,Wang S C,Duan J Y.Int J Mol Sci,2014,15(12):22296-22308
12 Forrest M L,Yanez J A,Remsberg C M,Ohgami Y,Kwon G S,Davies N M.Pharm Res,2008,25(1):194-206
13 Wang B D,Xu C J,Xie J,Yang Z Y,Sun S H.J Am Chem Soc,2008,130(44):14436-14437
14 Reisch A,Runser A,Arntz Y,Mély Y,Klymchenko A S.ACS Nano,2015,9(5):5104-5116
15 Zhang Z Z,Gu Y,Liu Q,Zheng C X,Xu L F,An L Y,Jin X,Liu Y,Shi L Q.Small,2018,14(33):1801865
16 Liu Y,Du J J,Yan M,Lau M Y,Hu J,Han H,Yang O O,Liang S,Wei W,Wang H,Li J M,Zhu X Y,Shi L Q,Chen W,Ji C,Lu Y F.Nat Nanotechnol,2013,8(3):187-192
17 Liu Y,Busscher H J,Zhao B,Li Y F,Zhang Z K,van der Mei H C,Ren Y J,Shi L Q.ACS Nano,2016,10(4):4779-4789
18 Duan F,Feng X C,Jin Y,Liu D W,Yang X J,Zhou G Q,Liu D D,Li Z H,Liang X J,Zhang J C.Biomaterials,2017,144:155-165
2 Zhang P B,Li S L,Chen H,Wang X Y,Liu L B,Lv F T,Wang S.ACS Appl Mater Interfaces,2017,9(20):16933-16938
3 Flemming H C,Wingender J,Szewzyk U,Steinberg P,Rice S A,Kjelleberg S.Nat Rev Microbiol,2016,14(9):563-575
4 Li X N,Yeh Y C,Giri K,Mout R,Landis R F,Prakash Y S,Rotello V M.Chem Commun,2015,51(2):282-285
5 Olsen I.Eur J Clin Microbiol Infect Dis,2015,34(5):877-886
6 Zheng C X,Zhao Y,Liu Y.Chinese J Polym Sci,2017,36(3):322-346
7 Tran N,Tran P A.ChemPhysChem,2012,13(10):2481-2494
8 Song Tao(宋涛),Xi Yuejing(奚悦静),Du Jianzhong(杜建忠).Acta Polymerica Sinica(高分子学报),2018,(1):119-128
9 Li Yaming(李亚民),Liu Shiyong(刘世勇).Acta Polymerica Sinica(高分子学报),2017,(7):1178-1190
10 Guo Q Q,Zhao Y,Dai X M,Zhang T Q,Yu Y J,Zhang X G,Li C X.ACS Appl Mater Interfaces,2017,9(20):16834-16847
11 Mu H B,Guo F,Niu H,Liu Q J,Wang S C,Duan J Y.Int J Mol Sci,2014,15(12):22296-22308
12 Forrest M L,Yanez J A,Remsberg C M,Ohgami Y,Kwon G S,Davies N M.Pharm Res,2008,25(1):194-206
13 Wang B D,Xu C J,Xie J,Yang Z Y,Sun S H.J Am Chem Soc,2008,130(44):14436-14437
14 Reisch A,Runser A,Arntz Y,Mély Y,Klymchenko A S.ACS Nano,2015,9(5):5104-5116
15 Zhang Z Z,Gu Y,Liu Q,Zheng C X,Xu L F,An L Y,Jin X,Liu Y,Shi L Q.Small,2018,14(33):1801865
16 Liu Y,Du J J,Yan M,Lau M Y,Hu J,Han H,Yang O O,Liang S,Wei W,Wang H,Li J M,Zhu X Y,Shi L Q,Chen W,Ji C,Lu Y F.Nat Nanotechnol,2013,8(3):187-192
17 Liu Y,Busscher H J,Zhao B,Li Y F,Zhang Z K,van der Mei H C,Ren Y J,Shi L Q.ACS Nano,2016,10(4):4779-4789
18 Duan F,Feng X C,Jin Y,Liu D W,Yang X J,Zhou G Q,Liu D D,Li Z H,Liang X J,Zhang J C.Biomaterials,2017,144:155-165