Functional Nanomaterials For Anti-biofilm Therapy

Bacterial biofilms are associated in 65% of bacterial infections and in more than80% of chronic infections,causing severe diseases on various organs and medical instruments.Antibiotic therapy is the conventional way for the treatment of bacterial diseases.However,the involvement of bacterial biofilms often leads to the failure of treatments because of the high antibiotic resistance of biofilms.Due to the excellent size effects,physicochemical properties and the designable ability,nanomaterials show great potential for treating biofilm infections.In this thesis,two nanomaterial-based therapeutic strategies were proposed for the treatment of biofilm infections.In nanomaterial-based antibiotic therapy,size and charge adaptive nanoparticles are used as antibiotic delivery vehicles for enhancing biofilm penetration and retention to improve antibiotic therapy against biofilms.In addition,quorum sensing inhibitor loaded nanoparticles are used to interfere the microenvironments of biofilms for enhance the antibiotic susceptibility.In nanomaterial-based non-antibiotic therapy,bacterial-targeted supramolecular photosensitizer delivery vehicles are designed for improving the antibacterial effects of photodynamic therapy against biofilms,and safety of the treatments.This article mainly contains the researches in the following aspects:1.Size and charge adaptive clustered nanoparticles for anti-biofilm therapyThe(AZM)-conjugated clustered nanoparticles(denoted as AZM-DA NPs)are prepared by electrostatic complexation between AZM conjugated amino-ended poly(amidoamine)dendrimer(PAMAM)and 2,3-dimethyl maleic anhydride(DA)modified poly(ethylene glycol)-polylysine(PEG-PLys).It is noteworthy that the AZMDA NPs can disassemble in an acidic biofilm microenvironment(p H 6.0),leading to the release of secondary AZM-conjugated PAMAM nanoparticles(PAMAM-AZM NPs).PAMAM-AZM NPs with small size and positive charge are beneficial for improved penetration and retention inside biofilms,enhanced permeabilization of the bacterial membrane,and increased internalization of AZM,thus exhibiting excellent antibiofilm activities.AZM-DA NPs are also favorable as long-term antibacterial agents due to the reduced occurrence of drug resistance.In vivo therapeutic performance is confirmed by the reduced bacterial burden and the alleviated inflammation in the chronic lung infection model.This research not only develops an innovative strategy for antibiotic delivery in vivo but also provides an effective way for the management of biofilm-associated infections.2.Quorum sensing inhibitor loaded nanoparticles for enhancing the antibiotic therapy against biofilmsThe infectious microenvironment targeted curcumin(Cur)loaded nanoparticles(denoted as anti-CD54@Cur-DA NPs)are prepared by electrostatic complexation between Cur loaded amino-ended poly(amidoamine)dendrimer(PAMAM)and 2,3-dimethyl maleic anhydride(DA)modified Biotin-poly(ethylene glycol)-polylysine(Biotin-PEG-PLys),and further modification of anti-CD54 by biotin-avidin interaction.The Cur-DA NPs can inhibit bacterial Quorum Sensing(QS),resulting the reduction of the extracellular cell matrix(EPS)in biofilm,and the down-regulation of bacterial efflux pump genes,thus enhance the anti-biofilm effects of antibiotics(Penicillin G,Ciprofloxacin,and Tobramycin)in vitro.Moreover,the anti-CD54 can bind to the ligands of vascular endothelial cell in infectious sites,which are favorable for the targeted delivery of anti-CD54@Cur-DA NPs.After arriving the infectious sites,PAMAM/Cur can be released in the acid microenvironments(p H 6.0),and penetrate into biofilms.The in vivo anti-biofilm results further confirmed the therapeutic effects of the nanoparticles.This research provides an effective way to enhance the anti-biofilm effects of antibiotics by inhibiting the QS and interfering the microenvironments of biofilms.3.Bacteria-targeted supramolecular photosensitizer delivery vehicles for photodynamic ablation against biofilmsBacteria-targeted photosensitizer delivery micelles are fabricated by α-cyclodextrin(α-CD)/polyethylene glycol(PEG)supramolecular assembly.Hydrophilic antimicrobial peptide(AMP)Magainin I is covalently bound with PEG,working as a bacterial targeting group as well as the stabilizing shell of the supramolecular micelles.Photosensitizer Chlorin e6(Ce6)is grafted onto α-CD.The micelles exhibit excellent bacterial targeting effects.Compared to α-CD-Ce6,the supramolecular micelles possess enhanced biofilm killing ability against Gram(-)Pseudomonas aeruginosa biofilms and Gram(+)methicillin resistant Staphylococcus aureus(MRSA)biofilms while reducing cytotoxicity to NIH/3T3 model cells.