Design And Preparation Of Phototheranostic Nanoagents Based On Perylene Diimide Towards Cancer Theranostics

Phototheranostics is an advanced medical technology that provides minimally invasive,accurate and rapid cancer diagnosis and treatment.Organic phototheranostic agents,taking the advantages of easy modification,multiple functionalization and high biological safety,have shown great potentials in the development of new phototheranostic agents.However,most organic phototheranostic agents have the following problems:（ⅰ）the absorption band mostly in the near-infrared region,and the limited tissue penetration;（ⅱ）the single performance and treatment methods brought by the design strategy,the not adjustable photophysical properties,and not adaptation to the complex tumor microenvironment;（ⅲ）having serious side effects due to use of high-power and high-heat methods.Perylenediimides（PDI）-based chromophores with excellent stability and photophysical properties as well as straightforward chemical modification have been widely applied as phototherapy agents.In view of the relationship between chemical modification and performance regulation of PDI,the appropriate molecular structure design and water-soluble modification strategies were employed to modulate its photophysical properties,nanoscale properties,and multifunctionalization for antitumor applications in this thesis.In response to the above problems,based on PDI,novel PDI derivatives with different phototherapeutic properties were synthesized by chemical modification strategies such as sulfur atom substitution,construction"Donor-Acceptor"（D-A）structures,and extendedπ-conjugation.Furthermore,multiple functionalization of perylene imide,such as water-solublility,the ability to load and control drug release,and specific barrier penetration,were achieved by controllable reactive radical polymerization or physical encapsulation.The prepared PDI nano-phototheranostic agents realized multimodal,mild,deep penetrating tumor theranostics.The main contents are as follows:（1）We used the substitution of carbonyl groups with sulfur atoms to design theranostic agents with controllable fluorescent,photodynamic and photothermal effects in on-demand biomedical applications.The photophysical properties of the perylenediimide could be adjusted by controlling the number of sulfur atoms substituted for the carbonyl group at the imide position.The initial and 4-tert-butyl phenol-substituted perylenediimide was fluorescent molecular.The gradient red shifts of the absorption peak and the remarkable quenched fluorescence of thionated PDIs were achieved through the increase of sulfur-substituted degree.The monothionated PDI（PDI-1S）became photodynamic from the original fluorescent PDI-O.With the increase of thionation degree,their ¹O₂ quantum yields were gradually reduced while their photothermal conversion efficiencies were gradually increased.The tetrathionated PDI（PDI-4S）also became an optimal photothermal agent.Therefore,excitation energy dissipation pathways of PDIs in the phototheranostics of tumor could be manipulated through the only one-step sulfur substitution.Its photophysical performance has realized the transformation from fluorescence to photodynamic and then to photothermal.The fluorescence,photoacoustic imaging and photothermal and photodynamic therapy were verified in vitro and in vivo.This chapter explored the relationship between the degree of thionation and photophysical properties of substituted PDIs,and realized multiple modes of phototheranostics to meet the needs of tumors in different microenvironments.（2）To reduce the inflammatory response and side effects of overheating,the functional PDI macromolecules were synthesized by“D-A”modification strategy and active polymerization method,and they as nano phototheranostics could treat tumors under mild conditions.The introduction of anthraquinone molecules with photosensitive"electron pushing"properties into the"peri"of PDI makes absorbtion red shift to the near-infrared region and have both photothermal and photodynamic properties.Then through controlled active radical polymerization,a water-soluble and temperature-sensitive random copolymer was introduced into the"bay"position to prepare a four-arm star polymer with PDI as a hydrophobic core and a temperature-sensitive polymer as a hydrophilic shell.Under the hydrophilic and hydrophobic effect,the heat shock protein inhibitor was wrapped in it,and finally the PDI nano-photodiagnostic reagent was prepared.The PDI nano-phototheranostics realized combined photothermal and photodynamic therapy.Subsequently,heat shock protein inhibitor was charged onto the polymer to form nano-phototheranostics.Initially,under irradiation with low-power NIR laser light,a small localized temperature increase prompted phase transition of TP to release inhibitors.The released inhibitor reduced the activity of heat shock proteins and the self-protection under stress conditions,and strengthened both photothermal and photodynamic therapy,realizing dual-sensitized antitumor effect.The work in this chapter reported a mild phototherapy nanoagent,which provided a more minimally invasive and efficient phototherapy strategy for cancer in vitro and in vivo.（3）By introducing the"D-A"structure and prolongationπ-conjugation for PDI simultaneously,a NIR-II absorbing（500-1400 nm）N1 was synthesized with good photothermal conversion efficiency.Copolymer F127 was modified by poly-2-methacryloyloxyethyl phosphorylcholine to achieve the ability of crossing blood-brain barrier.N1 was coated in 2PMPC-F127 to prepare nanomaterials which were applied to the photoacoustic imaging and photothermal treatment of deep in-situ brain tumors in mice.It can penetrate the blood brain barrier,penetrate the skull for photoacoustic imaging of deep brain tissue,and achieve good photothermal treatment effect.This work provides NIR-II absorbing organic nanomaterials with excellent photothermal performance for visualization imaging and treatment of deep in-situ tumors.In summary,the present study was application-oriented to regulate the photophysical properties of PDI by introducing sulfur atom substitution,photosensitive"D-A"structure,and extendedπ-conjugation.Further multiple functionalization,such as water-solubility,the ability to load and control drug release,and specific barrier penetration,were achieved by controllable reactive radical polymerization or physical encapsulation.Finally,a photophysical property adjustable,dual-sensitized,double deep penetrating phototheranostics based on PDI were prepared,which realized the mild,multimodal and deep anti-tumor applications.Therefore,this study might promote the development of organic phototheranostics.