Design And Synthesis Of Novel Silver/Zinc-Coordinated Azapyrrolidones For Biological Application

Phototherapy with non-invasiveness,low toxicity and high spatiotemporal selectivity,has become a research hotspot in the field of cancer treatment.Traditional phototherapy excites phototherapy agents via short-wavelength light.However,short-wavelength light limits phototherapeutic effects to reach deep tissues.Comparatively,the phototherapy conducted by long-wavelength light has enhanced penetration depth,which has gotten extensive attention.Photodynamic therapy（PDT）and photothermal therapy（PTT）are the main research fields of phototherapy.However,the supply of oxygen is hindered from the hypoxic microenvironment in tumor in a single photodynamic process,which restricts the photodynamic efficacy.Besides,during a single photothermal process,the overexpression of heat shock proteins（HSPs）provides some cancer cells free from photothermal damage.In this regard,the combination of two phototherapies can make up for the shortages of their therapeutic effect.In the view of the above points,here in,a series of PDT/PTT combined long-wavelength phototherapy agent were studied.Aza-pyrrolidines possess excellent long-wavelength light absorption ability,easy structural modification and tunable photophysical and photochemical performance.Herein,a series of metal-coordinated aza-pyrrolidines with near-infrared light absorption were designed and synthesized.The photodynamic and photothermal effects of the agents were investigated.The research contents include the following two aspects:1.Design and synthesis of zinc-coordinated aza-pyrrolidines and their application in photodynamic and photothermal synergistic therapyThree kinds of zinc（Ⅱ）aza-pyrrolidine complexes（Zn ADP1-Zn ADP3）with different group in the proximal arms of the aza-pyrrolidine ligands were designed and synthesized.The effect of electron-donating ability of substituents on the absorption spectra,photodynamic properties and photothermal effects was studied.Furthermore,coordinating aza-pyrrolidine with cheap and readily available zinc can result in the red-shift of absorption peaks,which is suitable for the treatment of tumors in deep tissues.The phototherapy agent suitable for the biological environment was obtained by using hydrophilic nano-coating.The efficacy of phototherapy was tested at the level of cells and living bodies.The results of cell and nude mice experiments show that this type of PDT/PTT combined phototherapy agent can effectively eliminate cancer cells and inhibit tumor growth,which provides a new solution for the design of cheap and efficient agents for phototherapy combined with PDT/PTT in the future.2.Design and synthesis of triphenylphosphine-silver-coordinated aza-pyrrolidines and their application in photodynamic and photothermal synergistic therapyTriphenylphosphine-silver（I）-coordinated aza-pyrrolidines（Ag1-Ag3）were designed and synthesized.The enhanced photodynamic effect of aza-pyrrolidine was obtained through the heavy atom effect of silver.Among them,Ag3 has long-wavelength absorption,excellent photoinduced singlet oxygen generation performance and photothermal conversion ability.In order to enhance its water solubility nanoparticle（Ag3 NPs）were prepared by nanocoating the complex with amphiphilic DSPE-m PEG₂₀₀₀.The tests in the solution show that Ag3 NPs has excellent photodynamic and photothermal effects.Through a series of cell experiments,it was found that Ag3 NPs have excellent pro-apoptotic ability,indicating that they have good anti-cancer effects via phototherapy.These results indicate that the silver（I）-coordinated aza-pyrrolidines designed through the heavy atom effect have a promising future in clinical application as PDT/PTT combined phototherapy agents.