| Chemotherapy has been widely used in the clinical treatment of cancer,but it may be harmful to normal body tissues and tumours can become resistant to it.Phototherapy has received much attention as an advanced cancer treatment method due to its low cytotoxicity,high spatio-temporal selectivity and non-invasive nature,including photothermal therapy(PTT)and photodynamic therapy(PDT).In addition,chemodynamic therapy(CDT)often works synergistically with PTT and PDT due to its advantages of requiring no external energy,low cytotoxicity and responsiveness to the tumour microenvironment.The heat generated by PTT helps to increase intratumoural blood flow and oxygenation,thus promoting the production of reactive oxygen species and enhancing the effects of PDT and CDT.Therefore,PTT/PDT/CDT synergistic therapy has broad application prospects in the biomedical field.Fluorescence imaging(FLI)is a non-invasive imaging technique with the advantages of high sensitivity,quick response,low hazard and low cost,while photoacoustic imaging(PAI)is an emerging non-invasive imaging technique with high penetration depth and high spatial resolution.Combining FLI/PAI with various cancer treatment methods can achieve precise diagnosis and therapy of tumours.Diketopyrrolopyrrole(DPP)has a high potential for tumor phototherapy applications due to its excellent photothermal and photoacoustic properties,certain singlet oxygen generation capacity,low dark toxicity,and easiness to achieve near infrared absorption.Polydopamine(PDA)is a polymer obtained from the self-polymerization of dopamine and has the advantages of high photothermal conversion efficiency,easy preparation,easy modification and good biocompatibility.Hyaluronic acid(HA)is a linear macromolecular mucopolysaccharide with the advantages of good biocompatibility,ease of modification and active tumour targeting.This thesis combines the advantages of DPP derivatives,PDA and HA to design two multifunctional composite nanoparticles(NPs)that can target tumours in both passive and active manner,effectively reducing non-specific damage to normal tissues,and perform synergistic treatment with PTT,PDT,CDT and chemotherapy under the guidance of fluorescence and photoacoustic imaging to achieve better therapeutic results.Details of the study are as follows:1.With DPP as the electron acceptor(A),thiophene as the π-conjugated bridge and triphenylamine as the electron donor(D),TTDPP,a derivative with D-π-A-π-D structure,was obtained.After the terminal reductive amination reaction of ethylenediamine(EDA)with oligomeric HA,TTDPP was attached to the other end of EDA to obtain the amphiphilic polymer HA-EDA-TTDPP.The endmodification of HA can avoid occupying the carboxyl group on its main chain,thus ensuring that the tumour targeting of HA is not affected.The iron ion(Fe3+)is premixed with dopamine to form coordination bonds between Fe3+ and dopamine,and then dopamine self-polymerizes under weak alkaline conditions to obtain Fe3+-ligated PDA nanospheres(FePDA),in which Fe3+ can effectively enhance the photothermal effect of PDA,and also generate cytotoxic reactive oxygen species(·OH)by Fenton reaction with a large amount of glutathione(GSH)and H2O2 in the tumour microenvironment.The therapeutic effect on tumours is further enhanced by the Fenton reaction with large amounts of glutathione(GSH)and H2O2 to produce cytotoxic reactive oxygen species(·OH).The self-assembly of HA-EDA-TTDPP with FePDA is then performed to enhance the photothermal effect and photoacoustic imaging signal of the material,and the obtained FePDA@HA-EDA-TTDPP NPs achieved a photothermal conversion efficiency of 67.4%and a singlet oxygen yield of 10.4%,which effectively produce ·OH in the tumour microenvironment.It is confirmed by solution and HeLa cell experiments that FePDA@HA-EDA-TTDPP NPs have good tumor targeting,photoacoustic imaging and combined PTT/PDT/CDT therapeutic effects.2.To further enhance the therapeutic effect of the material,the chemotherapeutic drug adriamycin(DOX)is encapsulated in the NPs;meanwhile,to enhance the targeting drug release ability of the NPs,cysteamine(CYS)with a disulfide bond(S-S)is used to connect the ends of TTDPP and hyaluronic acid instead,resulting in FePDA/DOX@HA-CYS-TTDPP NPs.HA is degraded by the high concentration of HA enzymes secreted by the tumour cells,while the disulfide bond is cleaved by GSH overexpressed in the tumour cells,thus releasing DOX.The fluorescence of DOX is recovered because it is far away from PDA.Thus,FePDA/DOX@HA-CYS-TTDPP NPs are able to respond to the tumour microenvironment for targeted drug release and fluorescence imaging with a photothermal conversion efficiency of 65.6%,a singlet oxygen yield of 9.9%.It is confirmed by solution and HeLa cell experiments that FePDA/DOX@HA-CYS-TTDPP NPs can carry out the synergistic treatment of PTT/PDT/CDT/chemotherapy under the guidance of fluorescence and photoacoustic imaging,and the inhibition rate on HeLa tumour cells is higher than the former nanomaterial without DOX loading. |
