Design And Preparation Of Photosensitizers With D-π-A Structure And Their Applications In Multimodal Theranostics Of Tumors

Cancer is an umbrella term for a group of different diseases that can affect any part of the body.A hallmark of cancer is the rapid production of abnormal cells that proliferate uncontrollably and eventually form tumors.The World Health Organization reports that cancer is the second leading cause of death worldwide and is responsible for approximately one in six deaths worldwide.Faced with the significant threat posed by tumors to human health,tumor diagnosis and treatment technologies have been constantly evolving.Traditional imaging techniques have radiation risk at some degree,and can only be used for preoperative imaging,belonging to static imaging methods.The traditional three major cancer treatment methods all have certain limitations.For example,surgical treatment carries a risk of recurrence.Chemotherapy havs significant side effects and are prone to develop drug resistance.Radiotherapy can pose a threat to normal tissue adjacent to cancer.Therefore,the further development of tumor diagnosis and treatment technology is an urgent problem to be solved.Recently,phototheranostic technologies,including near-infrared fluorescence imaging（NIR-FLI）,photodynamic therapy（PDT）,and photothermal therapy（PTT）,have attracted widespread attention due to their non-invasive,spatiotemporal controllability,low toxicity,and integrated theranostics.Photosensitizers（PSs）generate fluorescence or phosphorescence through radiation transitions for optical imaging,and convert light energy into chemical energy or heat energy through non radiation transitions for tumor treatment.Currently,most of the reported PSs mainly include inorganic nanomaterials,such as gold nanoparticles,transition metal compounds,and carbon-based materials,which face issues of nondegradability and potential toxicity in practical applications.The other category is organic commercial dyes such as porphyrins,cyanines,and Ce6.Although they have been widely used in the biological field,they still suffer problems such as insufficient stability,limited production of reactive oxygen species（ROS）,and low photothermal conversion efficiency（PCE）.In the past decade,novel organic PSs with propeller configuration and donor-acceptor（D-A）structure have been gradually developed.On the one hand,these PSs can effectively alleviate the toxicity issue of inorganic nanomaterials,which has attracted much attention;On the other hand,unlike most commercial dyes possessing planar molecular structures,their distorted molecular configurations can significantly inhibit fluorescence quenching,photobleaching and insufficient ROS generation caused byπ-πstacking.In addition,enhanced intramolecular charge transfer（ICT）is also conducive to promoting absorption and emission wavelength redshift,reducing the singlet and triplet energy gap(ΔE_S-T),promoting inter system crossing（ISC）,and activating photodynamic performance.Therefore,organic PSs containing D-π-A structures are considered one of the most promising biological nanomaterials.In this paper,based on the organic PSs with D-π-A structure,we constructed three series of novel organic PSs through molecular engineering,donor engineering,andπbridge engineering strategies,and explored their applications in NIR-FLI guided phototheranostics.These organic nanomaterials exhibited low dark toxicity,significant phototoxicity,good biocompatibility,excellent imaging capabilities,and enhanced tumor ablation effects,providing unique design insights for constructing novel multimodal PSs for diagnosis and treatment.The specific research contents of this paper are as follows:1.In Chapter 2,we adopted a molecular engineering strategy by changing the type of electron donor or the number of acceptors without changing theπbridge,designing and synthesizing a series of organic PSs with D-A,D-A-D or A-D-A structures.Among them,PPR-2CN with an A-D-A structure,employing phenylpyrrolidine（PPR）as the donor and cyano as the acceptor,exhibited the longest fluorescence emission and excellent type I ROS production ability.Theoretical calculations showed that a smallΔE_S-T and relatively large spin orbit coupling constants（SOC）boosted ISC,thereby inducing the generation of ROS.Additionally,the specific glutamate（Glu）and glutathione（GSH）consumption abilities of PPR-2CN inhibited the intracellular biosynthesis of GSH.The decreasing GSH could further cause glutathione peroxidase4（GPX4）inactivation and lipid peroxidation（LPO）,ultimately leading to ferritosis.In this chapter,we firstly realized that single component organic PSs can be simultaneously used as type-I photodynamic reagent and metal-free ferroptosis inducer for NIR-FLI guided multimodal synergistic theranostics.2.In Chapter 3,based on the understanding of the structure and corresponding properties of PSs in Chapter 2,we gradually improved the electron donating ability of donors using a donor strategy without changing theπbridge and acceptor structures,achieving further improvement of phototheranostics.CNTPA-TPA,which employed triphenylamine（TPA）as the electron donor and cyano as the acceptor,possessed the strongest D-A strength and performed the best type-I ROS generation ability.In addition,cyano can also react with Glu and GSH,directly reducing the content of GSH in tumor cells,thereby inducing ferroptosis.The synergistic effects of PDT and ferroptosis will further lead to immunogenic cell death（ICD）,but the immune response is still insufficient.Therefore,anti PD-L1 was utilized to further enhance the immune effects.We successfully cured the primary tumors,effectively suppressed the growth of distal tumors and lung metastasis.In this chapter,we firstly realized that single component organic PSs can be used for NIR-FLI guided ferroptosis assisted photodynamic immunotherapy for multimodal collaborative theranostics of tumors.3.In Chapter 4,without altering the donor and acceptor structures,we constructed a series of organic PSs with benzene,furan,or thiophene asπbridges through aπbridge engineering strategy for mitochondria-targeting synergistic treatment of type I PDT and PTT.By regulating the electron-donating ability of theπbridge and the dihedral angle rotation of the molecule,the main emission peak of STB utilizing thiophene asπbridge was beyond 790 nm in solid state,exhibiting excellent superoxide radical(O₂^·-)and hydroxyl radical（·OH）generation capabilities and considerable photothermal conversion ability.Theoretical calculations suggested that STB possesed a strong D-A strength,which was beneficial for decreasingΔE_S-T,promoting ISC and inducing PDT.In addition,higher molar extinction coefficient and freer dihedral angle rotation promoted intramolecular motion,making PCE of STB as high as 51.9%.It is worth mentioning that positively charged STB can actively target the mitochondria of tumor cells through electrostatic interactions,improving their enrichment in the tumor area and enhancing treatment effectiveness.In vitro and in vivo experiments have demonstrated that STB nanoparticles（NPs）significantly inhibited cancer cells proliferation and tumor growth.In this chapter,we realized that single component organic PSs can be used for NIR-FLI and photothermal imaging（PTI）guided efficient type I PDT and PTT synergistic therapy.