Design and synthesis of thymine modified phthalocyanine for Aβ protofibrils photodegradation and Aβ peptide aggregation inhibition

摘要

The formation and accumulation of toxic amyloid beta (Aβ) protofibrils in brain is recognized as the pathological hallmark of alzheimer’s disease (AD). Recent research indicated that photodynamic therapy (PDT) has potential to treat AD because reactive oxygen species (ROS) generated by photosensitizers (PS) could degrades Aβ protofibrils. Al3+and Fe3+were found at markedly high levels on and around Aβ protofibrils comparing with the normal part of brain. Based on this, a thymine modified Zn phthalocyanine (T-ZnPc), which can specific recognize and has strong affinity with Fe3+and Al3+, was designed and synthesized. The recognize, affinity, Aβ protofibrils degradation and neuro protection process were monitored via ultraviolet absorption spectrometry (UV), fluorescence emission spectrum, transmission electron microscopy (TEM), flow cytometer and thiazolyl blue tetrazolium bromide (MTT) assay. The results revealed that such affinity effect greatly increases the molar extinction coefficient (from 1.70?×?104to 4.67?×?104and 3.30?×?104after forming Fe-T-ZnPc and Al-T-ZnPc) and activates PDT activity of T-ZnPc to generate abundant ROS to degrade Aβ protofibrils (62% and 81% degradation by Al-T-ZnPc and Fe-T-ZnPc) and prevent its neurotoxicity based on the statistical differences analysis. Besides, T-ZnPc could inhibit new Aβ protofibrils formation and the chelation effect could reduce the free Fe3+and Al3+concentration in brain, which could be also helpful for AD treatment.