Development And Application Of Near-infrared Second Window Fluorescent Small Molecule Integrated With Photothermal And Chemotherapy

Integrating diagnosis and treatment functions into one system is an emerging strategy to fight with cancer.In 1998,John Funkhouser proposed the concept of theranostic.To date,many researchers have developed different types of theranostic agents which can be mainly divided into two types: one is the nanoplatform which encapsulates the commonly used anti-tumor drugs and diagnostic probes together;the other is biomolecules coupled with diagnostic and therapeutic drugs.The active drug molecules are coupled with reporting moieties such as fluorescent agents through chemical bonds to achieve theranostic capabilities.Compared with the first nearinfrared window(NIR-I,700-900nm),the small organic fluorescent molecules in the second near infrared window(NIR-Ⅱ,1000-1700nm)show higher imaging performance because of the significant merits of enhanced tissue penetration depth,less light absorption and scattering,lower autofluorescence,and higher imaging resolution.Organic fluorescent molecules represent the most promising class of optical imaging agents for clinical translation.Chemotherapy is still one of the most widely used methods for cancer treatment today.However,most chemotherapeutic drugs suffer problems such as low therapeutic index,multi-drug resistance,multiple side effects,and high toxicity to normal cells which reduce treatment efficacy.As a new noninvasive and controllable tumor treatment method,photothermal treatment(PTT)has attracted extensive attention from researchers because it only targets local cancer tissues with thermal ablation and has little impact on surrounding normal tissues.The main purpose of this thesis is to develop and biological evaluate novel organic small molecule NIR-Ⅱ theranostic probes.Most of the single coupled organic theranostic probes are limited to visible or NIR-I fluorescence imaging.The preparation of multi-component nanoplatform is complicated,difficult to quality control,and poor reproducibility.Based on the commonly used donor-acceptor-donor(D-A-D)type NIR-Ⅱ imaging molecule structure,a new type of organic small molecule NIR-Ⅱ theranostic probe was designed and synthesized.The main research work is summarized as follows:The bis(2-chloroethyl)amino group,the active moiety of nitrogen mustard drugs,was introduced into the donor triphenylamine to obtain the compound NM.In order to increase water solubility,NM was encapsulated by m DSPE-PEG-2K to form the nanoparticles named as NM-NPs.The maximum absorption peak of NM-NPs was about 850 nm,and the maximum emission wavelength was at 1100 nm.The quantum yield of NM-NPs in water was determined to be 0.083%,and the photothermal conversion efficiency was 47.38%.Through MTT cytotoxicity experiment,Hoechst cell staining assay,colony formation experiment and live/dead cell staining experiment,it was found that the NM-NPs showed good chemotherapeutic effect which was enhanced by combining with PTT.In addition,it also had the ability for NIR-Ⅱfluorescence imaging.Under different long-pass filters(1000 LP,1250 LP,1400 LP),the imaging resolution of the mice blood vessels was gradually improved with the increase of the wavelength.The animal model of A549 subcutaneous tumor was established.The effect of chemotherapy and PTT synergistic treatment was evaluated by intratumoral injection of NM-NPs.The results demonstrated that the synergistic treatment groups had the best therapeutic effect.The tumors of some mice were completely cured and disappeared within two weeks.During the treatment period,the body weight of the mice did not change significantly.The main organs(heart,liver,spleen,lung,and kidney)were resected after treatment and examined by H&E staining showing no significant damage.Subsequent acute and long-term toxicity experiments also confirmed the in vivo safety of NM-NPs.Conclusively,this work has designed and synthesized a new type of organic small molecule based NIR-Ⅱ theranostics probe.The current study on in vitro and in vivo experiments indicate that the new compound based theranostic agent has good therapeutic and imaging capabilities.It provides a new strategy for development of small organic molecule NIR-Ⅱ theranostic probe for cancer in the era of precision medicine.