Elaboration on the architecture of pH-sensitive surface charge-adaptive micelles with enhanced penetration and bactericidal activity in biofilms.

ABSTRACT:

Background

Biofilm formation is one of the main reasons for persistent bacterial infections. Recently, pH-sensitive copolymers have fascinated incredible attention to tackle biofilm-related infections. However, the proper incorporation of pH-sensitive segments in the polymer chains, which could significantly affect the biofilms targeting ability, has not been particularly investigated. Herein, we synthesized three types of pH-sensitive copolymers based on poly (β-amino ester) (PAE), poly (lactic-co-glycolic acid) (PLA) and polyethylene glycol (PEG), PAE-PLA-mPEG (A-L-E), PLA-PAE-mPEG (L-A-E) and PLA-PEG-PAE (L-E-A) to address this issue.

Results

The three copolymers could self-assemble into micelles (M_A-L-E, M_L-A-E and M_L-E-A) in aqueous medium. Compared with M_A-L-E and M_L-A-E, placing the PAE at the distal PEG end of PLA-PEG to yield PLA-PEG-PAE (M_L-E-A) was characterized with proper triggering pH, fully biofilm penetration, and high cell membrane binding affinity. Further loaded with Triclosan (TCS), M_L-E-A/TCS could efficiently kill the bacteria either in planktonic or biofilm mode. We reasoned that PAE segments would be preferentially placed near the surface and distant from the hydrophobic PLA segments. This would increase the magnitude of surface charge-switching capability, as the cationic PAE⁺ would easily disassociate from the inner core without conquering the additional hydrophobic force arising from covalent linkage with PLA segments, and rapidly rise to the outermost layer of the micellar surface due to the relative hydrophilicity. This was significant in that it could enable the micelles immediately change its surface charge where localized acidity occurred, and efficiently bind themselves to the bacterial surface where they became hydrolyzed by bacterial lipases to stimulate release of encapsulated TCS even a relatively short residence time to prevent rapid wash-out. In vivo therapeutic performance of M_L-E-A/TCS was evaluated on a classical biofilm infection model, implant-related biofilm infection. The result suggested that M_L-E-A/TCS was effective for the treatment of implant-related biofilm infection, which was proved by the efficient clearance of biofilm-contaminated catheters and the recovery of surrounding infected tissues.

Conclusions

In summary, elaboration on the architecture of pH-sensitive copolymers was the first step to target biofilm. The M_L-E-A structure may represent an interesting future direction in the treatment of biofilm-relevant infections associated with acidity.

SUBMITTER: Guo R 

PROVIDER: S-EPMC8344171 | biostudies-literature |

REPOSITORIES: biostudies-literature