Oxygenated Nano-liquid Perfluorocarbons For Enhanced Chemo-radiotherapy And Photodynamic Therapy Of Hypoxic Tumors

Objective:Chemo-radiotherapy,a traditional method for tumor therapy,has been playing an important role in cancer treatment.However,chemotherapy drugs could lead to systemic toxicity and hypoxia in tumors could limit the theraputic efficacy of radiotherapy for tumors.Lowering the systemic toxicity of chemotherapy drugs and mediating hypoxia are key solutions to improving chemo-radiotherapy for tumors.Apart from optimizing traditional tumor therapy,novel methods for tumor therapy,sunch as photodynamic therapy,have provided new ideas for cancer treatment.Photodynamic therapy for cancer is also severely limited by hypoxia and light toxicity.Targeting the common hypoxia and toxicity confronted by chemo-radiotherapy and photodynamic therapy,two different drug nanocarriers are constructed in this study based on the high adherence of liquid perfluorocarbons to oxygen so as to explore the role of liquid perfluorocarbons in enhancing chemo-radiotherapy and photodynamic therapy and to realize safer and more effective tumor therapy.Methods:PFCE@cisPt(IV)-Lip was obtained by innovatively combining PFCE nanodroplets with cisplatin prodrugs,which could be reduced to PFCE@cisPt(II)-Lip in tumor tissues;the basic characterization of PFCE@cisPt(IV)-Lip was tested;the cytotoxicity and enhanced chemo-radiotherapy effect of PFCE@cisPt(IV)-Lip in cell level were investigated by cytotoxicity,DNA damage and clone experiments;the biodistribution and metabolism of PFCE@cisPt(IV)-Lip were explored by in vivo fluorescence imaging;The hypoxia relief in tumors of PFCE@cisPt(IV)-Lip was explored by in vivo photoacoustic imaging and ex vivo immunofluorescence staining;the enhanced chemo-radiotherapy of PFCE@cisPt(IV)-Lip in animal level was explored by in vivo chemo-radiotherapy for hypoxic tumors of mice;the synthesis conditions of hollow mesoporous SiO₂-TCPP were explored and photodynamic sensitizers were binded covalently with SiO₂by taking liquid perfluorocarbons,tetraethyl orthosilicate and photodynamic sensitizers as raw materials.And the photodynamic effect of hollow mesoporous SiO₂-TCPP was initially evaluated in tumor cells and hypoxic-tumor-bearing mice.Results:PFCE@cisPt(IV)-Lip was featured with good stability in different solutions and strong adherence to oxygen;PFCE@cisPt(IV)-Lip could enhance the DNA damage of the chemo-radiotherapy to cells and slow down the proliferation of cells with radiation;PFCE@cisPt(IV)-Lip could efficiently accumulate in tumors in 24 h,and had long blood circulation time up to 24 h;PFCE@cisPt(IV)-Lip could efficiently enhance blood oxygen signal and relieve the hypoxia in subcutaneous tumors of mice;PFCE@cisPt(IV)-Lip could improve the in vivo chemo-radiotherapy effect for hypoxic tumors,prolong the surviving period of mice loaded with tumors to a certain extent and reduce the systemic toxicity of chemo-radiotherapy in mice;the hollow SiO₂-TCPP could be synthesized by utilizing liquid perfluorocarbons,tetraethyl orthosilicate and photodynamic sensitizers through one-pot method;the hollow mesoporous SiO₂-TCPP could effectively kill tumor cells and inhibit the growth of hypoxic tumors by generating enough reactive oxygen species with laser.Conclusions:Based on the high affinity of liquid perfluorocarbons to oxygen,two different kinds of nanodrug carriers were successfully constructed utilizing liquid perfluorocarbons:PFC nanodroplets were firstly combined with cisplatin drugs to obtain PFCE@cisPt(IV)-Lip;PFCE@cisPt(IV)-Lip could mitigate hypoxia in subcutaneous hypoxic tumors effecitively and relieve the systemic toxicity brought by chemodrugs,enhancing the in vivo chemo-radiotherapy effect for hypoxic tumors;the hollow SiO₂-TCPP could be obtained with PFH through one-pot method,simplifying the synthesis of hollow silica and preventing the leak of photosensitizers;the photodynamic effect of hollow mesoporous SiO₂-TCPP could efficiently kill tumor cells and inhibit the growth of subcutaneous hypoxic tumors.