Cationic Poly(benzyl ether)s as Self-Immolative Antimicrobial Polymers

Abstract

Self-immolative polymers (SIMPs) are macromolecules that spontaneously undergo depolymerization into small molecules when triggered by specific external stimuli. We report here the first examples of antimicrobial SIMPs with potent, rapid, and broad-spectrum bactericidal activity. Their antibacterial and hemolytic activities were examined as a function of cationic functionality. Polymers bearing primary ammonium cationic groups showed more potent bactericidal activity against Escherichia coli, relative to tertiary and quaternary ammonium counterparts, whereas the quaternary ammonium polymers showed the lowest hemolytic toxicity. These antibacterial polycations undergo end-to-end depolymerization when triggered by an externally applied stimulus. Specifically, poly(benzyl ether)s end-capped with a silyl ether group and bearing pendant allyl side chains were converted to polycations by photoinitiated thiol-ene radical addition using cysteamine HCl. The intact polycations are stable in solution, but they spontaneously unzip into their component monomers upon exposure to fluoride ions, with excellent sensitivity and selectivity. Upon triggered depolymerization, the antibacterial potency was largely retained but the hemolytic toxicity was substantially reduced. Thus, we reveal the first example of a self-immolative antibacterial polymer platform that will enable antibacterial materials to spontaneously unzip into biologically active small molecules upon the introduction of a specifically designed stimulus.

Biomimetic antimicrobial polymers: recent advances in molecular design

“…Ergene and Palermo developed the first generation of selfimmolative antibacterial polymers 122 (Fig. 15).…”

Stimuli‐Responsive Prodrug Chemistries for Drug Delivery

“…Ph [16][17][18][19][20][21]65,67] Enzyme [23][24][25][26][27][28][29][64][65][66] Oxidative [31][32][33][34][35][36][37][38]58,59,62,69] Redox [41][42][43][44][45][46][47]62,64,[66][67][68][69] Self-immolative [50][51][52][53][54][55][56][57]68]…”

“…The stimuli-responsive self-immolative polymer concept has been used to develop sacrificial layer materials for the controlled release of actives in the presence of triggering conditions. [55] Ergene et al [56] reported the first example of a self-immolative polycation exerting a fast and broad-spectrum antimicrobial activity. The polycation comprised cysteamine-functionalized poly (benzyl ethers) with silyl end-capping, and retained antibacterial activity upon depolymerization after fluorine-specific treatment.…”

Designing single trigger/dual-response release and degradation into amine-functional hyperbranched-polydendron nanoprecipitates

“…15 Encapsulation, release and degradation studies of assembled materials offers the potential to create delivery vehicles that may enhance the formulation capability and efficacy of small molecules in a range of applications from pharmaceutical drug delivery through to agrochemicals, antimicrobials and cosmetics. 16 In each of these cases, the degradability of the building block structures to smaller subunits that may be benign, either in an in vivo context or in the wider environment, is very important and has been the aim of materials such as selfimmolative polymers 17,18 and triggers including reduction, 19 hydrolysis, 20 temperature, 21 chemical, 22 and light enhanced 23 mechanisms.…”