Conjugated Material Based Composite Nanobioprobes And Their Applications In Tumor-Targeting Diagnosis And Treatment

Phototherapy,including photodynamic therapy?PDT?and photothermal therapy?PTT?,has received wide attention in recent years for its good efficacy in cancer treatment.As a local cancer treatment method,phototherapy is currently the least traumatic treatment as compared with traditional chemotherapy.Photosensitizer?PS?can produce highly cytotoxic reactive oxygen species?ROS?,especially singlet oxygen?¹O₂?after irradiation,or activated PS may cause local high temperature,leading to apoptosis and necrosis.At the same time,the introduction of fluorescence imaging?FL?and photoacoustic imaging?PA?into phototherapy,which are emerging imaging technologies in the field of biomedical research,can guide and dynamically monitor the treatment process in real time,and evaluate the therapeutic effect.This is conducive to improving the recovery rate and survival rate of cancer.In recent years,the research and applications of organic conjugated materials have attracted great attention in the field of biomedicine due to their strong light absorption,high fluorescence quantum efficiency,good photostability,low biotoxicity,and because they are easy to be designed and synthesized by chemical methods to adjust optoelectronic properties.Among them,the conjugated materials with two-photon?TP?absorption property can realize near-infrared excitation,and exhibit the advantages of large penetration depth,high spatial resolution,and low autofluorescence interference as a fluorescent contrast agent,which is more conducive to biological applications.However,the existing materials also have some problems in direct biological application,such as poor water solubility,low biocompatibility,lack of tumor targeting,and single function.Hyaluronic acid?HA?is a polysaccharide biopolymer with good biocompatibility,easy chemical modification,and active tumor targeting based on the specific binding of HA to CD44 receptor.In this thesis,hyaluronic acid was combined with fluorescent and photoacoustic materials to obtain composite nanomaterials with good biocompatibility and tumor targeting.At the same time,bimodal imaging of fluorescence and photoacoustic imaging,as well as photothermal andphotodynamic synergistic therapy were realized.We connected HA with BFVPBT——a conjugated material with two-photon absorption via a reductive disulfide bond to obtain the amphiphilic polymer HA-SS-BFVPBT,which was then combined with two excellent probe materials,indocyanine green?ICG?and single-walled carbon nanotube?SWCNT?.The specific research are as follows:1.The near-infrared dye ICG was coated with HA-SS-BFVPBT through supramolecular self-assembly to obtain composite nanoprobe——ICG@HA-SS-BFVPBT.ICG is currently the only NIR fluorescent dye approved by the US Food and Drug Administration?FDA?for clinical use,but it has the disadvantages of poor water solubility and photobleaching.In vitro studies have shown that the water solubility,photothermal and photodynamic properties of the material are greatly improved.In addition,due to the presence of hyaluronic acid and disulfide bonds in the structure,it can target tumor and release probe in response to the high expression of glutathione and hyaluronidase in tumor,achieving fluorescence activation.Confocal two-photon laser scanning microscopy confirmed the fluorescence imaging in HeLa cells and the effect of PTT/PDT/TPPDT triple phototherapy.Using HeLa nude mouse model,it is further proved that the nanomaterial can achieve better FL/PA dual-modal tumor-targeting imaging effect and phototherapy effect than ICG.2.The composite nanomaterial HA-SS-BFVPBT/SWCNT was prepared by supramolecular self-assembly of HA-SS-BFVPBT and single-walled carbon nanotubes?SWCNT?.SWCNT is an excellent photothermal and photoacoustic material,whose water solubility is greatly improved by this composite method.In vitro studies have shown that the composite material has good photothermal,photodynamic and photoacoustic properties,and the HeLa cell model confirms its fluorescence imaging and phototherapy effects.Studies have shown that HA-SS-BFVPBT/SWCNT is expected to achieve FL/PA dual-modal imaging and PTT/TPPDT synergistic treatment.