Investigations Into The Applications Of Cyclic Topology And Functionalized Nanosilver In Biomedicine

Cyclic polymers have different structure and properties from linear analogues,which play an important role in biomedical field with extensive attention.Here,the effects of cyclic topology on the stability of nanomicelles in high-salt or protein solutions and on the antibacterial or antibiofilm properties of cationic polymers were investigated.It is proved that cyclic topology can enhance the stability of micelles and improve the antibacterial and antibiofilm properties of cationic polymers.In addition,we also constructed phenylboric acid functionalized silver nanoparticles to improve the antibacterial property and selectivity of silver nanoparticles,which enhance the utilization of silver nanoparticles.These works have developed the application of cyclic topology and surface functionalization in biomedicine.The specific three parts of research are as follows.1.Amphiphilic diblock(PCL-PEG,polycaprolactone-poly(ethylene glycol))and triblock(PCL-PEG-PCL,polycaprolactone-poly(ethylene glycol)-polycaprolactone)copolymers were synthesized by ring-opening polymerization of ε-caprolactone using polyethylene glycol(PEG)as a macromolecular initiator.The conventional micelles were prepared from diblock copolymer PCL-PEG,while the flower-shaped micelles were prepared from triblock copolymer PCL-PEG-PCL with a ring-like hydrophilic PEG shell.The experimental results show that the stability of micelles in salt and protein solutions is closely related to the topological structure of the hydrophilic surface.Flower-shaped micelles are smaller in size and more compact,which can form a dense PEG network in the hydrophilic surface layer and bound water well.Therefore,the flower-shaped micelles can be stably dispersed in high-salt aqueous solutions without obvious aggregation.However,traditional micelles couldn’t disperse stably in aqueous solution with high salt concentration,which would aggregate with size enlarged because of salting-out effect.Due to the absence of terminal groups on the surface and the compact shell structure,flower-shaped micelles exhibit low absorption towards proteins.After evaluating the size changes of micelles in protein solution,we found that flower-shaped micelles showed stably dispersed in protein solution for a long time without obvious size change and aggregation.Traditional micelles rapidly adsorb proteins and gradually aggregate after exposed to protein.This method provides a new idea for the construction of stable micelles from aggregation.2.Cyclic cationic polymers were successfully synthesized by anionic ring-opening polymerization initiated by rhodanine and subsequent thiol-ene click reaction.Meanwhile,the linear analogues were successfully synthesized by ring-opening polymerization initiated by trithiocarbonate.By evaluating the bactericidal,bacteriostatic and antibiofilm properties of the cyclic and linear cationic polymers,it is found that the cyclic cationic polymer has enhanced antibacterial and antibiofilm effects.After investigating the antibacterial mechanism of cationic polymers and the properties of cyclic topology,the advantage of cyclic cationic polymers in anti-bacteria was explained.In addition,compared with linear analogues,the circular topology endows the cationic polymer with stronger penetration in the biofilm,so the bactericidal effect for biofilm bacteria is increased by 5-7 times,and the inhibition effect of biofilm growth is increased by 2-3 times.Wound infection model was also established and the cyclic polycation showed stronger antibacterial effect in vivo than linear analogues.This study showed the effect of cyclic topology on the antibacterial performance of cationic polymers,providing a feasible and promising strategy for increasing the penetration of antibacterial drugs into biofilms and promoting the development of cationic polymers for the treatment of biofilm-related infections.3.Phenylboric acid functionalized silver nanoparticles(AgNPs-PBAn)have been designed and synthesized,which show broad antibacterial activity.The phenylboronic acid groups on the surface of AgNPs-PBAn could form covalent bonds with the cis-diol groups of lipopolysaccharide or teichoic acid on the bacterial surface,which highly promoted the interaction between AgNPs-PBAn and bacteria,improving the utilization of nano-silver,resulting in a very strong enhancement of their antibacterial action via membrane disruption.The scanning electron microscopy images revealed that the accumulation of phenylboronic acid-functionalized AgNPs on the bacterial surface is much more than that of bare AgNPs.Importantly,the bactericidal results showed that the antibacterial efficiency of the phenylboronic acid-functionalized AgNPs on Gramnegative(E.coli and P.aeruginosa)or Gram-positive bacteria(B.subtilis and S.aureus)is 32 or 8 times higher than that of bare AgNPs.Moreover,AgNPs-PBAn showed a high selectivity toward bacteria with an IC50(half maximal inhibitory concentration for mammalian cells)more than 160 times of MBC(minimum bactericidal concentration).In the model of E.coli-infected wound in vivo,AgNPs-PBAn could effectively kill the bacteria with an accelerated wound healing.This study demonstrates that the functionalization of phenylboronic acid on surface is an efficient way to improve the antibacterial activity and selectivity of silver nanoparticles,which provides a new method for the development of antibacterial materials with high efficiency and selectivity.