Structural Engineering of Cationic Block Copolymer Architectures for Selective Breaching of Prokaryotic and Eukaryotic Biological Species

Positively charged antimicrobial polymers are known to cause severe damage to biological systems, and thus synthetic strategies are urgently required to design next-generation nontoxic cationic macromolecular architectures for healthcare applications. Here, we report a structural-engineering strategy to build cationic linear and star-block copolymer nanoarchitectures having identical chemical composition, molar mass, nanoparticle size, and positive surface charge, yet they differ distinctly in their biological action in breaching prokaryotic species such as <i>E. coli</i> (Gram-negative bacteria) without affecting eukaryotic species like red-blood and mammalian cells. For this purpose, linear and star-block structures are built on a polycaprolactone biodegradable platform having an imidazolium positive handle. Under physiological conditions, the linear architecture exhibits toxicity indiscriminately to all biological species, whereas its star counterpart is remarkably selective in membrane breaching action toward bacteria while maintaining inertness toward eukaryotic species. Confocal microscopy analysis of HPTS fluorescent dye-loaded star-polymer nanoparticles substantiated their antimicrobial action in <i>E. coli</i>. Tissue-penetrable near-infrared fluorescent dye (IR-780) loaded NP aided the <i>in vivo</i> biodistribution analysis and <i>ex vivo</i> quantification of cationic species' accumulations in vital organs in mice. Azithromycin, a clinical water-insoluble macrolide, is delivered from the star platform to accomplish synergistic antimicrobial activity by the combination of bactericidal-bacteriostatic action of the polymer carrier and drug together in a single system.