Fluorescence Image-guided Hydrogel/nano-drug Delivery System For Tumor Chemotherapy-immune Combined Therapy

Because of the complexity of cancer,it is difficult to cure cancer completely with a single treatment.Synergistic treatments have played an important role against tumor because they can merge the advantages of various treatment methods and avoid the limitations of single treatment.Chemo-immunotherapy as an important synergistic method has gained wide attention.In addition to their respective roles,chemotherapy and immunotherapy can also promote each other's therapeutic effects.With the development of biomaterials and drugs for tumor immunotherapy,the mediation of biomaterials provides new strategies for chemo-immunotherapy.To achieve precise treatment,multi-spectral fluorescence imaging technology is used to objectively evaluate the behavior of drugs,adjuvants and cells in vivo,effectively realize the real-time tracking and monitoring of drugs,carrier materials and immune cells,and dynamically reveal the correlation between drug release and tumor treatment.In this paper,a chemo-immunotherapy system was constructed to improve tumor therapeutic effect based on ?-cyclodextrin/polyethylene glycol(?-CD/PEG)thermosensitive hydrogel with nano-carrier.Moreover,chemotherapeutic drugs,adjuvants and cells were tracked by multi-spectral fluorescence imaging to reveal the dynamic process of chemo-immunotherapy.This project is divided into two parts as follows.In the first part,a dual fluorescence imaging-guided programmed delivery system was designed to modulate tumor microenvironment for effective chemo-immunotherapy.DOX and CpG nanoparticles were loaded into ?-CD/PEG thermosensitive hydrogel to form a dual continuous release system.DOX as a small molecule can be quickly released from the hydrogel to kill tumor cells and induce immunogenic cell death to produce tumor antigen and DAMPs,and then act with the sustained and slow release of CpG to improve the anti-tumor effect.Dual fluorescence imaging-guided programmed delivery was tracked by the fluorescence of DOX and CpG NP,respectively.Moreover,the immune cells from tumor microenvironment were further analyzed to reveal the possible mechanism of chemo-immunotherapy including cytotoxic CD8+T lymphocytes,myeloid-derived suppressor cells and M2-like tumor-associated macrophages.Based on the co-stimulation of DOX and CpG nanoparticles,the tumor microenvironment was positively regulated toward tumor-suppressive condition to generate stronger immune response for efficient chemo-immunotherapy.In the second part,we designed a chemo-immunotherapy system combined with DC and a pH-sensitive immune adjuvant-DOX nano-prodrug through hydrogel/nano system.The pH sensitive nano prodrug system can enhance tumor-specific accumulation and reduce the side effects of DOX.Dox released from nanoparticles can induce tumor cells to generate tumor antigens.The tumor antigens and adjuvants interact with DC to promote the antigen presentation level and enhance the immune response ability.The hydrogel scaffold can not only support a platform for the interaction between antigens,adjuvants and DC,but also provide a better growth microenvironment for DC to maintain DC viability.The combined hydrogel/nanoadjuvant system merged immunogenically dying tumor cells,DCs and adjuvants,which induce strong CTL killing effect.They remarkably increased the infiltration of effector T cells,alleviate the intratumoral immunosuppressive microenvironment and maximize the immune effect of the vaccine for improving the cancer immunotherapy.In addition,real-time tracking of immune cells,chemotherapeutic drugs,and immune adjuvants can be achieved to reveal their in vivo process through multispectral fluorescence imaging technology.In summary,two visible systems of chemo-immunotherapy system based on the ?-CD/PEG hydrogel/nano-delivery system were successfully constructed.The drug release and tumor therapy was monitored by multispectral fluorescence imaging.The results showed that both combination systems had more obvious anti-tumor effect compared with a single system.Furthermore,chemotherapy can enhance tumor immunogenicity and reverse immunosuppressive tumor microenvironment,while immunotherapy can enhance the drugs sensitivity.Their combination can reduce the side effects and improve the anti-tumor effect.In addition,multispectral fluorescence imaging provides an efficient,real-time and non-invasive method for evaluating the delivery process of tumor chemotherapy-immunotherapy.Fluorescence imaging-guided chemo-immunotherapy system has an important application prospect for precise tumor therapy.