细菌感染微环境响应性高分子材料用于细菌感染性疾病的治疗
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摘要
自从1928年青霉素被发现以来,抗生素的使用极大降低了细菌感染性疾病的发病率和死亡率,拯救了数千万的生命。然而,随着抗生素的广泛使用及滥用,抗生素耐药问题已成为全球性公共卫生安全问题。此外,传统给药模式下的抗生素疗法存在多种问题:抗生素给药后被快速代谢从体内排出,只有少部分药物到达感染部位,生物利用率低,使得临床中往往需要大剂量给药、长周期治疗,这导致显著毒副作用;抗生素对生物膜内细菌治疗效果差,难以在胞内富集,且难以杀伤胞内存活细菌,导致慢性感染和复发性感染。针对传统抗生素给药模式存在的问题,利用纳米技术递送抗生素显示出很好的应用前景。纳米颗粒可以改善难溶药物的溶解性,改善抗生素的代谢动力学和组织分布,克服组织和细胞屏障。随着纳米药物输送体系研究的不断深入,研究者们利用细菌感染后微环境中致病因子(如磷酸酶、磷脂酶、蛋白酶、毒素等)致病因子表达显著增高、pH值下降呈微酸性、局部温度上升等,设计刺激响应性高分子纳米材料,用于抗生素的递送。该策略使药物选择性在细菌感染部位释放,显著改善药物生物利用率,提高药物对生物膜相关感染、胞内感染等感染性疾病的治疗效果,并降低药物的毒副作用。然而,纳米颗粒递送抗生素对耐药细菌特别是多重耐药菌感染性疾病的治疗仍存在很大的局限性。针对抗生素的耐药问题,抗菌肽及其类似物由于具有广谱抗菌活性及低致耐药性而受到广泛关注。然而,这类抗菌剂具有强细胞毒性,限制了其临床应用。研究者利用上述细菌感染微环境,设计对酸性环境或细菌酶响应的抗菌高分子材料,使其在正常组织中呈现低细胞毒性,而在细菌感染环境下被活化或者暴露出抗菌肽,从而高效杀伤耐药细菌。本文介绍了传统抗生素疗法存在的问题,总结了近10年来感染微环境响应性高分子纳米颗粒作为抗生素递送载体、感染微环境响应性的抗菌高分子的设计及在细菌感染性疾病治疗中的应用,并展望感染微环境响应性高分子材料的发展趋势及前景。
Since the discovery of penicillin in 1928,the application of antibiotics has greatly reduced the morbidity and mortality of bacterial infectious diseases,and numerous lives are survived from bacterial infection. However,with the widespread use and abuse of antibiotics,antimicrobial resistance has become a global public health issue. In addition,there are several problems that traditional antibiotic therapies encounter. Specifically speaking,the antibiotics are rapidly metabolized and excreted from body after administration,only a few drugs reach the infected site and the bioavailability was low. In this case,high doses and long period treatments are required in clinical application,which lead to notable side effects.Besides,the poor therapeutic effect of antibiotics against biofilm infections and intracellular infections is also a pressing issue,leading to chronic infections and recurrent infections.In view of the problems existing in the traditional antibiotic delivery mode,the delivery of antibiotics by nanoparticles is proposed and shows great potential in the treatment of bacterial infection,which can improve the solubility of poorly soluble drugs,improve the pharmacokinetics and biodistribution of antibiotics,and overcome the tissue and cell barriers. Inspired by the fact that the physiological and physical microenvironment of bacterial infection sites is different from normal tissues,polymeric nanoparticles,that are responsive to the unique infectious microenvironments,have been developed to deliver antibiotics. These strategies remarkably improve the bioavailability and biodistribution of antibiotics,enhance the therapeutic efficacy of antibiotics against intracellular and biofilm infections,as well as attenuate the side effects.However,the delivery of antibiotics by nanoparticles shows limitations in the treatments of drug-resistant bacteria and especially for multidrug-resistant bacteria. Aiming at the problems of antibiotic resistance,antimicrobial peptides and their analogues have attracted extensive attention worldwide,since they exhibit broad-spectrum antibacterial activity with the less like-hood to develop drug resistance. Nevertheless,the cytotoxicity of these antibacterial agents hinders their clinical applications. For the sake of solving this problem,researchers designed responsive antimicrobial polymers that exhibited low toxicity in normal tissues,and transformed to active form to effectively kill drug-resistant bacteria when triggered by the acid infectious environment or bacterial enzymes in the infectious environment.In this review,we gave a brief introduction on the existing issues on traditional antimicrobial therapy,and an overview and current perspectiveson the development infection-microenvironment responsive polymeric nanoparticles as carriers of antibiotics and the infection-responsive antimicrobial polymers for the treatment of bacterial infectious diseases over the past decade.
Since the discovery of penicillin in 1928,the application of antibiotics has greatly reduced the morbidity and mortality of bacterial infectious diseases,and numerous lives are survived from bacterial infection. However,with the widespread use and abuse of antibiotics,antimicrobial resistance has become a global public health issue. In addition,there are several problems that traditional antibiotic therapies encounter. Specifically speaking,the antibiotics are rapidly metabolized and excreted from body after administration,only a few drugs reach the infected site and the bioavailability was low. In this case,high doses and long period treatments are required in clinical application,which lead to notable side effects.Besides,the poor therapeutic effect of antibiotics against biofilm infections and intracellular infections is also a pressing issue,leading to chronic infections and recurrent infections.In view of the problems existing in the traditional antibiotic delivery mode,the delivery of antibiotics by nanoparticles is proposed and shows great potential in the treatment of bacterial infection,which can improve the solubility of poorly soluble drugs,improve the pharmacokinetics and biodistribution of antibiotics,and overcome the tissue and cell barriers. Inspired by the fact that the physiological and physical microenvironment of bacterial infection sites is different from normal tissues,polymeric nanoparticles,that are responsive to the unique infectious microenvironments,have been developed to deliver antibiotics. These strategies remarkably improve the bioavailability and biodistribution of antibiotics,enhance the therapeutic efficacy of antibiotics against intracellular and biofilm infections,as well as attenuate the side effects.However,the delivery of antibiotics by nanoparticles shows limitations in the treatments of drug-resistant bacteria and especially for multidrug-resistant bacteria. Aiming at the problems of antibiotic resistance,antimicrobial peptides and their analogues have attracted extensive attention worldwide,since they exhibit broad-spectrum antibacterial activity with the less like-hood to develop drug resistance. Nevertheless,the cytotoxicity of these antibacterial agents hinders their clinical applications. For the sake of solving this problem,researchers designed responsive antimicrobial polymers that exhibited low toxicity in normal tissues,and transformed to active form to effectively kill drug-resistant bacteria when triggered by the acid infectious environment or bacterial enzymes in the infectious environment.In this review,we gave a brief introduction on the existing issues on traditional antimicrobial therapy,and an overview and current perspectiveson the development infection-microenvironment responsive polymeric nanoparticles as carriers of antibiotics and the infection-responsive antimicrobial polymers for the treatment of bacterial infectious diseases over the past decade.
引文
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2 Ning X,Lee S,Wang Z,et al.Nature Materials,2011,10,602.
3 Viswanathan V K,Linsey J S.In:39thIEEE Frontiers in Education Conference,Imagining and Engineering Future CSET Education.San Antonio,TX,USA,2009,pp.6.
4 CDC.Mmwr Morbidity&Mortality Weekly Report,1999,48,326.
5 Levy S B,Marshall B.Nature Medicine,2004,10,S122.
6 O’Neill J.Nature Reviews Drug Discovery,2016,15,526.
7 WHO.Global priority list of antibiotic-resistant bacteria to guide research,discovery,and development of new antibiotics.World Health Organization,2017.
8 Ilias K,Helen G.Expert Opinion on Pharmacotherapy,2014,15(10),1351.
9 Pogue J M,Lee J,Marchaim D,et al.Clinical Infectious Diseases,2011,53(9),879.
10 Sommer M O,Dantas G.Current Opinion in Microbiology,2011,14(5),556.
11 Flemming H C,Wingender J.Nature Reviews Microbiology,2010,8(9),623.
12 Hallstoodley L,Costerton J W,Stoodley P.Nature Reviews Microbiology,2004,2(2),95.
13 Davies D.Nature Reviews Drug Discovery,2003,2(2),114.
14 Mah T F C,O’Toole G A.Trends in Microbiology,2001,9(1),34.
15 Xiong M H,Bao Y,Yang X Z,et al.Advanced Drug Delivery Reviews,2014,78,63.
16 Costerton J W,Stewart P S,Greenberg,E P.Science,1999,284(5418),1318.
17 Suci P A,Mittelman M W,Yu F P,et al.Antimicrobial Agents and Chemotherapy,1994,38(9),2125.
18 Hoyle B D,Wong C K,Costerton J W.Canadian Journal of Microbiology,1992,38(11),1214.
19 de Carvalho C C.Recent Patents on Biotechnology,2007,1(1),49.
20 Weiss G,Schaible U E.Immunological Reviews,2015,264(1),182.
21 Pintoalphandary H,Andremont A,Couvreur P.International Journal of Antimicrobial Agents,2000,13(3),155.
22 Breedlove B,Cohen M L.Holt,Rinehart and Winston,2014,20(7),1268.
23 WHO.Antimicrobial resistance:global report on surveillance.World Health Organization,2014,pp.257.
24 Tenover F C.American Journal of Medicine,2006,34(5,Supplement),S3.
25 Poole K.Journal of Pharmacy&Pharmacology,2001,53(3),283.
26 Rep M M M W.Morbidity&Mortality Weekly Report,2002,51(26),565.
27 Oh J K,Drumright R,Siegwart D J,et al.Progress in Polymer Science,2008,33(4),448.
28 Fleige E,Quadir M A,Haag R.Advanced Drug Delivery Reviews,2012,64(9),866.
29 Gao W,Chan J M,Farokhzad O C.Molecular Pharmaceutics,2010,7(6),1913.
30 Gao W,Chen Y,Zhang Y,et al.Advanced Drug Delivery Reviews,2018,127,46.
31 Yamamoto S,Yamazaki S,Shimizu T,et al.Medicine,2016,95(21),e3628.
32 Mercier R C,Stumpo C,Rybak M J.Journal of Antimicrobial Chemotherapy,2002,50(1),19.
33 Radovic-Moreno A F,Lu T K,Puscasu V A,et al.ACS Nano,2012,6(5),4279.
34 Chu L,Gao H,Cheng T,et al.Chemical Communications,2016,52(37),6265.
35 Liu Y,Busscher H J,Zhao B,et al.ACS Nano,2016,10(4),4779.
36 Liu Y,Mei H C V D,Zhao B,et al.Advanced Functional Materials,2017,27(44),1701974.
37 Li L L,Xu J H,Qi G B,et al.ACS Nano,2014,8(5),4975.
38 Xiong M H,Wu J,Wang Y C,et al.Macromolecules,2009,42(4),893.
39 Xiong M H,Li Y J,Bao Y,et al.Advanced Materials,2012,24(46),6175.
40 Xiong M H,Bao Y,Yang X Z,et al.Journal of the American Chemical Society,2012,134(9),4355.
41 Li Y,Liu G,Wang X,et al.Angewandte Chemie International Edition,2016,55(5),1760.
42 Wright G D.Chemical Communications,2011,47(14),4055.
43 Xiong M,Lee M W,Mansbach,et al.Proceedings of the National Academy of Sciences USA,2015,112(43),13155.
44 Kazemzadeh-Narbat M,Kindrachuk J,Duan K,et al.Biomaterials,2010,31(36),9519.
45 Ng V W,Ke X,Lee A L,et al.Advanced Materials,2013,25(46),6730.
46 Jürgen Harder,Zasloff M.Antimicrobial Peptides:Role in Human Health and Disease.Cham Springer,2016.
47 Marr A K,Gooderham W J,Hancock R E.Current Opinion in Pharmacology,2006,6(5),468.
48 Fjell C D,Hiss J A,Hancock R E W,et al.Nature Reviews Drug Discovery,2012,11(1),37.
49 Xiong M H,Bao Y,Xu X,et al.Proceedings of the National Academy of Sciences USA,2017,114(48),12675.
50 Xiong M H,Han Z,Song Z,et al.Angewandte Chemie International Edition,2017,56,10826.
51 Xu L,He C,Hui L,et al.ACS Applied Materials&Interfaces,2015,7(50),27602.
52 Jiang Y,Yang X,Zhu R,et al.Macromolecules,2013,46(10),3959.
53 Qi G B,Zhang D,Liu F H,et al.Advanced Materials,2017,29(36),1703461.
54 Komnatnyy V V,Chiang W C,Tolker-Nielsen T,et al.Angewandte Chemie International Edition,2014,53(2),439.
55 Cado G,Aslam R,Séon L,et al.Advanced Functional Materials,2013,23(38),4801.