Application Of Gold Nanomaterials Loaded With Photosensitizers In The Diagnosis And Treatment Of Tumors

Cancer poses a great threat to human health,and its morbidity and mortality are increasing year by year.Traditional cancer treatments include surgery,chemotherapy and radiation therapy.However,chemotherapeutic drugs are easily spread to the normal tissues of patients,they possess poor pharmacokinetics and have high side effects.Radiation therapy is limited by the cumulative radiation doses.Nano drug carriers can increase the absorption and stability of drugs,thereby reducing the side effects of chemotherapy and radiotherapy.In recent years,gold nanomaterials have been widely used in biomedical fields including drug delivery,photothermal therapy,computed tomography due to their unique physical and chemical properties,such as good biocompatibility,easy synthesis and surface modification,and strong optical properties.Therefore,a series of drug delivery systems based on gold nanomaterials for cancer targeted therapy have been developed.The main research contents are as follows:1.We developed the polypeptide-modified gold nanoclusters(GNCs)-based nanoprobes for tumor-targeted near-infrared fluorescence imaging and chemophotodynamic therapy.The nanoprobe consists of four parts: i)polyethylene glycol(PEG)shell,increase blood circulation time and improve the biocompatibility of the nanomaterials;ii)MMP2 polypeptide for tumor targeting(CPLGVRGRGDS);iii)cisaconitic anhydride modified doxorubicin(CAD)to realize pH-responsive drug release;iv)photosensitizer chlorin e6(Ce6)for for photodynamic therapy and fluorescence imaging.In vitro experiments showed that the synthesized nanoprobes were efficiently taken up by A549 cells compared with free Ce6 and doxorubicin,thereby significantly increasing the mortality of tumor cells.For in vivo experiments,the nanoprobes exhibited excellent tumor targeting ability and long blood circulation time,and could significantly inhibit tumor growth.Our results help to advance the design of combination strategies to improve the efficacy of imaging-guided cancer treatment.2.Gold nanostars(GNS)have good photothermal conversion efficiency and photoacoustic signals,which can be used in photothermal therapy and photoacoustic imaging.In the first part of our study,we found that MMP2 polypeptide have good targeting properties.On this basis,we developed a new nano drug delivery system GNS@BSA/I-MMP2 NPs.GNS were modified with bovine serum albumin(BSA),matrix metalloproteinase(MMP-2)polypeptide(AC-GPLGIAGQ)and IR-780 iodide for targeted lung cancer photoacoustic imaging(PA)/near infrared(NIR)fluorescence imaging and enhanced photothermotherapy(PTT)/photodynamic therapy.MMP2 polypeptides served as the targeting ligand,IR-780 iodide acted as the near infrared fluorescence imaging agent and PTT/PDT agent,while GNS functioned as the carrier of IR-780 molecules,and performed PA imaging and PTT.Dynamic light scattering and CCK-8 studies showed that GNS@BSA/I-MMP2 nanoprobes have good stability and biocompatibility under physiological conditions.Subsequent in vitro studies confirmed that GNS@BSA/I-MMP2 NPs were efficiently taken up by A549 cancer cells and exhibited significant anti-tumor effects.In addition,GNS@BSA/I-MMP2 NPs could specifically target tumors and significantly inhibit tumor growth,and their antitumor effects mainly through the synergistic effects of photodynamic therapy and photothermal therapy based on GNS and IR-780.These findings suggest the potential of GNS@BSA/I-MMP2 NPs as the targeted PA imaging/near-infrared imaging probe for tumor diagnosis and combination therapy with the single light source.3.The cytotoxicity and unique tumor tropic properties of cytokine-induced killer(CIK)cells make them have broad application prospects in the field of tumor immunotherapy and delivery systems.In this part,a novel CIK cells loaded Ce6-induced gold nanoclusters self-assembled nanomaterials were constructed for targeted imaging and combined treatment of gastric cancer.A novel and facile approach was developed to assemble glutathione(GSH)modified GNCs into spherical nanoparticles using Chlorin e6(Ce6)as a directing agent.It was demonstrated that the GNCs were readily self-assembled into highly stable and monodispersed spherical aggregates in the presence of Ce6.The size of the self-assembled GNCs-Ce6 nanoparticles(GNCs-Ce6 NPs)could be easily controlled by adjusting the molar ratio between GSH grafted onto GNCs and Ce6 molecules.The as-prepared GNCs-Ce6 NPs was coupled with CD3 antibody(Ab)and further used to label CIK cells to create a CIK cell-based drug delivery system(Ce6-GNCs-Ab-CIK).The results showed that Ce6-GNCs-Ab-CIK exhibited specific targeting to cancer cells and excellent therapeutic efficacy toward MGC-803 cells with laser irradiation.Fluorescence imaging in vivo indicated that Ce6-GNCs-Ab-CIK gradually accumulated in the tumor region of the MGC-803 tumorbearing mice due to the tumor-tropic properties of CIK cells.Additionally,the high tumor-targeting efficiency of Ce6-GNCs-Ab-CIK resulted in enhanced tumor suppression upon laser irradiation in comparison with Ce6-GNCs-Ab NPs.Benefiting from the synergistic therapeutic effect between GNCs-Ce6-Ab NPs and CIK cells,the GNCs-Ce6-Ab-CIK strategy may present an ideal cancer theranostic platform for tumor imaging and therapy.