Cationic Poly(α-L-ornithine)-grafted Zinc(Ⅱ) Phthalocyanine With Aggregation-induced Photothermal Effect For Combating Bacteria

Non-antibiotic antibacterial strategies,such as antimicrobial peptides（AMPs）and phototherapy,are regarded as a potentially effective treatment for the infectious diseases caused by antibiotic-resistance bacteria,especially“superbugs”.Phthalocyanine,a second generation of photosensitizer,demonstrates great potentials for efficient phototherapy capabilities owing to their robust stability（chemo-,thermo-and photo-stability）and long absorption wavelength maxima(λ_max>660 nm).Phthalocyanine cored star-shaped polymers can inherit their photophysical properties and improve their solubilities.Star-shaped antibacterial polypeptides,a member of star-shaped polymers,have unique topological structures and polypeptides shell,along with broad-spectrum antibacterial activity.Thus,star-shaped phthalocyanine-polypeptides,fabricated from phthalocyanine and polypeptides,can synergistically killing drug-resistance bacteria through intrinsic antibacterial activity and phototherapy.In this work,a near-infrared dye tetraamino zinc（II）phthalocyanine（ZnTAPc）with four terminal primary amino groups was firstly synthesized,followed by ring-opening polymerization of Nε-benzyloxycarbonyl-L-ornithine-N-carboxyanhydride（ZLO-NCA）with ZnTAPc as the initiator to prepare a library of four-armed star-shaped poly（α-L-ornithine）_n-grafted tetraamino zinc（II）phthalocyanine（ZnTAPc-g-PLO_n）,which innovatively conjugated ZnTAPc and cationic PLO via covalent attachment for obtaining novel functional bactericidal nano-agents with combining photosensitizer and antibacterial polypeptide into one simple compound.Benefit from the unique molecular structure composed of an inner hydrophobic ZnTAPc core and a peripheral hydrophilic PLO shell,the as-prepared ZnTAPc-g-PLO_n can spontaneously self-assemble into aggregates in aqueous solutions,and denoted them as“nanostructured antibacterial photosensitizer aggregates（NAPSAs）”.The prepared NAPSAs display excellent water solubility,high stability and high photothermal conversion efficiency（35.8%）.In the dark,in vitro antibacterial and hemolytic tests demonstrated that NAPSAs exhibit excellent antibacterial activity while low toxicity toward mice red blood cells,following repeated use of this kind of antibacterial nanomaterials do not induce drug-resistance development,which regard as the typical characteristics of AMPs analogues.Under the 730 nm laser irradiation,significant improvement in bactericidal potency is observed due to the localized hyperthermal derived from NAPSAs.The bacterial mechanism is recognized as following process:（1）the peripheral cationic PLO corona can depolarize bacterial membrane following resulting in bacterial membrane disorder and disruption,and（2）in situ hyperthermia derived from ZnTAPc further induce the thermal damage of bacterial membrane.Thus,it is expected to employ the nanostructured phthalocyanine-polypeptide aggregates to the field of treatment of infectious diseases caused by multi-drug resistance bacteria,to provide design considerations for exploring novel non-antibiotic bactericidal strategies,and to carry out preclinical trials for clinical translation.