【作者】 安富豪；

【导师】 孙绚；

【作者基本信息】 山东大学 ， 化学， 2023， 硕士

【摘要】 肿瘤作为人类生命健康面临的最大威胁之一,目前临床上的治疗手段如手术、放疗、化疗等,都存在明显的缺陷,如适用范围窄,毒副作用高,难以彻底根治等等。因此,迫切需要开发新型的治疗手段来协同对抗治疗恶性肿瘤。近年来,光热治疗以其高效抗癌、低毒副作用、微创等优点,引起人们的广泛关注。光热治疗的核心在于光热转换材料的开发。理想的光热材料应该在近红外(NIR)区域有较高的摩尔消光系数,良好的水溶性和在生物条件下的光稳定性及低的暗毒性。目前光热转换材料主要分为无机纳米材料和有机分子两类。无机材料普遍存在生物相容性差、毒性大和结构难以调控的问题。相对而言,有机分子有更好的生物相容性,低毒性,生物体内易于代谢和结构便于调控等优点。苝酰亚胺(PDI)分子具有较大的离域电子结构,在可见光区有很强的吸收,分子结构稳定,易于修饰合成,是潜在的优良光热转换材料。本论文设计合成了具有高光热转换效率和良好光热稳定性的新型PDI衍生物,并对其光物理性质和抗肿瘤性能进行了深入研究。本论文的主要研究内容如下:1、硫代苝酰亚胺复合纳米材料的设计及光热抗肿瘤性能研究在近红外(NIR)窗口中开发具有高光热转换效率的有机分子是光热治疗领域一个重要且具有挑战性的课题。通过硫原子取代苝酰亚胺中的羰基氧,合成了一系列硫取代苝酰亚胺(PDI-4CHA-S)衍生物,为揭示硫取代对高光热转换效率(PCE)光热剂(PTCAs)光物理性质的影响提供了契机。硫原子参与分子内电荷转移(ICT),导致吸收光谱发生显著红移。同时,ICT与硫原子的重原子效应共同促进了系间窜越(ISC),从而在光激发下产生活性氧(ROS)。有趣的是,ROS的量子产率随着S取代数量的增加而降低,这是在多S取代情况下ICT衰减的结果。总体而言,硫取代氧对ISC的促进作用与ICT对辐射跃迁的淬灭和吸收的增强相比微不足道,因此激发态的PDI-4CHA-S分子能量主要以热的形式耗散,从而导致在808 nm激光照射下达到88.0%的超高PCE。值得一提的是,三硫取代的PDI-4CHA-3S在第二个近红外(NIR-Ⅱ)窗口(1064 nm)表现出超高的PCE。硫代PDI衍生物优异的光热性能和光稳定性为其近红外光热治疗提供了广阔的应用前景。2、J-聚集苝酰亚胺衍生物的制备及近红外光热性能转换性能研究苝酰亚胺分子是具有较大的π共轭平面型分子结构,π-π相互作用和氢键导致其极易发生聚集。聚集体的生成对PDI分子的光物理性质如吸收、荧光等有很大影响,从而极大地影响光热转化性能。因此,我们通过在PDI湾位修饰4-氨基三苯胺给电子基团(PDI-TAP),使得其与PDI骨架发生强的ICT作用,致使其吸收发生红移,淬灭荧光。进而将PDI-TPA包覆于二氧化硅纳米胶囊内部,形成了 J-聚集体。纳米胶囊的外部亲水性基团使得胶囊在水溶液中稳定分散,从而有效解决了有机分子水溶性差的问题。J-聚集体的形成有利于吸收光谱进一步红移,荧光进一步被淬灭,有利于提高光热转换效率。随后在808 nm激光照射下显示出良好的光热转换效果和光热稳定性,为光热诊疗剂的制备提供了一种新的可能。更多还原

【Abstract】 Cancer is one of the biggest threats to human life and health.The current clinical treatment methods,such as surgery,radiotherapy and chemotherapy,all have obvious shortcomings,such as narrow application scope,high toxic and side effects,and difficult to be completely cured.Therefore,there is an urgent need to develop new therapeutic means to coordinate the treatment of malignant tumors.In recent years,photothermal therapy has attracted wide attention due to its advantages such as high anticancer efficiency,low toxicity and minimally invasive.The core of photothermal therapy lies in the development of photothermal conversion materials.The ideal photothermal materials have high molar extinction coefficient,good water solubility,light stability and low dark toxicity in the near infrared(NIR)region.The present photothermal conversion materials can be divided into inorganic nanomaterials and organic molecules.Inorganic materials are generally facing the problems of poor biocompatibility,high toxicity and difficult structure regulation.In contrast,organic molecules have the advantages of better biocompatibility,low toxicity,easy metabolism in organism and easy structure regulation.Peryleneimide(PDI)derivatives have a large delocalized electronic structure,strong absorption in the visible region,robust molecular structure,easy to modify and synthesize,and are potential excellent photothermal conversion materials.In this thesis,novel PDI derivatives with high photothermal conversion efficiency and good photostability were designed and synthesized,and their photophysical properties and anti-tumor properties were studied in depth.The main research contents of this thesis are as follows:1.Design of a composite nanomaterial based on thionated peryleneimide and the study on its photothermal antitumor performance.Development of organic molecules with high photothermal conversion efficiency(PCE)in the near-infrared(NIR)window is a vital yet challenging topic in the field of photothermal therapy.A series of thionated perylenediimides(PDI-4CHA-S)derivatives have been synthesized by replacing carboxylic oxygens in imides with sulfur atoms,providing chances to unravel the effect of thionation on the photophysical properties toward photothermal agents(PTAs)with high PCE.In the presence of the electron-donating substituents at the bay-position,sulfur atoms participate in the intramolecular charge transfer(ICT),which induces remarkable redshifl in the absorption maximum.Meanwhile,the ICT together with the heavy atoms effect of sulfur atoms promotes the intersystem crossing(ISC),resulting in the generation of the active oxygen species(ROS)upon photoexcitation.Interestingly,the quantum yield of ROS decreases with increasing the number of S-substitutes,which is the resultant of the attenuated ICT in the case of multiple S-substitution.Overall,the promotion in ISC due to thionation is negligible compared to the quenching of the radiation transition and enhancement of the absorption coefficient caused by ICT,hence the energy of the excited PDI-4CHA-S molecules is depleted mainly in the form of heat,leading to the ultrahigh PCE of 88.0%under 808 nm laser irradiation.The trithionated PDI-4CHA-3S performs surprisingly high PCE in the second near-infrared(NIR-Ⅱ)window(1064 nm)in particular.The superior photothermal effect and excellent photostability of the thionated PDI derivative provide them promising photothermal agents for NIR photothermal therapy.2.Preparation of J-aggregation of peryleneimide derivatives and study on its near-infrared photothermal conversion performance.PDI molecules have a large π-conjugated planar structure and are prone to aggregate in aqueous solution due to the strong intermolecular interactions including π-π interactions and hydrogen bonding.The formation of aggregates has a great influence on the photophysical properties of PDI molecules such as absorption and fluorescence,which greatly affects the photothermal conversion performance.Accordingly,we have bay-positions of PDI with 4-amino-trianiline electron-donating group(PDI-TAP)to induce strong ICT interaction with the PDI skeleton,resulting in large redshift of absorption and strong fluorescence quenching.Furthermore,PDI-TPA was coated inside silica nanocapsules(SNCs)to form J-aggregation.The external hydrophilic groups make the SNC disperse stably in aqueous solution,which helps solving the problem of poor water solubility of organic molecules.The formation of J-aggregation is conducive to further redshift of absorption spectrum and quenching of fluorescence,which will greatly improve the photothermal conversion efficiency.Subsequently,it showed good photothermal conversion effect and photothermal stability under 808 nm laser irradiation,which provided a new possibility for the preparation of photothermal diagnosis and treatment agent.更多还原