Conjugated Hyperbranched Polymer Photosensitizer Based Covalently Linked Micelles for Broad-Spectrum Bacterial Treatment.

Abstract

The development of efficient and stable therapeutic platforms for achieving broad-spectrum antibacterial photodynamic therapy (aPDT) remains a critical challenge in combating microbial resistance. Herein, through three cascaded molecular engineering steps, a hyperbranched polymer based covalently linked micelle is developed to show highly broad-spectrum aPDT efficacy. First, through precise molecular structural optimization, a conjugated hyperbranched polymer photosensitizer TSeHP with far-red/near-infrared emission and high reactive oxygen species (ROS) generation efficiency is developed and synthesized from an AB₂-type monomer, which is also featured with large number of terminal alkyne groups in its periphery. Subsequently, through azide-alkyne click chemistry reaction, TSeHP is decorated with polyethylene glycol (PEG) to form covalently linked micelles TSeHP-PEG with much better stability during biomedical applications, as compared to conventional micelles or nanoparticles. Finally, to further confer targeting capability and inherent antibacterial properties, TSeHP-PEG is covalently conjugated with a hydrophilic antimicrobial peptide, yielding TSeHP-P with good biocompatibility. Microbiological assays demonstrate that TSeHP-P enables real-time imaging and exhibits potent broad-spectrum antibacterial photodynamic activity against pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), via membrane disruption. Moreover, TSeHP-P demonstrates excellent performance in accelerating the healing process of MRSA-infected wounds in rats, showing good potential in infective therapeutic applications.