Construction Of Responsive Nanoplatforms Mediates Combined Immune Effects In The Treatment Of Breast Cancer

As the most common cancer among women,breast cancer has a great harm to the patient’s body and one of the most important causes of death.The usual treatment options for breast cancer are surgery,radiation and chemotherapy.The application of these treatment schemes has certain limitations.In recent years,with the development of nanotechnology,there have been more and more researches on breast cancer.Various treatment schemes are combined through different nano platforms to achieve multi-modal treatment of breast cancer.Responsive nanoplatforms are more favored by researchers because of their specific delivery ability.Different from traditional drug delivery platforms,drug delivery platforms have more potential in cancer treatment,because they could improve the solubility and stability of hydrophobic drugs,promote drug release at the target site,and prolong drug blood circulation time.Responsive nanodelivery platforms are another innovation in traditional drug delivery platforms.Due to their unique structure and characteristics,they can be used to respond to changes in the environment where the nanoplatform is located.Stimulation-responsive nanoplatforms can generally use specific stimuli to improve the biosafety of nanomedicine and the controlled release of the drug.Light,magnetic field,p H,etc.Immunotherapy has made considerable progress in clinical practice due to its lower toxicity and higher survival,increasing plausibility and translational effectiveness in preclinical studies and becoming one of the pillars of current cancer treatment.In addition,immunotherapy is different from traditional treatment methods such as surgery,radiotherapy and chemotherapy.It is an indirect treatment means.Drugs introduced into cancer sites through the nano platform are designed to stimulate or utilize the immune system to get rid of cancer cells,or reverse the characteristic immune disorders in cancer,so that the immune system of the human body can produce memory effect on a cancer cell.To further achieve a stronger immune response and expand the therapeutic effect on cancer.In this study,aPD-L1 prodrug and PEG-TK-PS were synthesized through the linkers of reactive oxygen species response,both of which have the ability to release reactive oxygen species response.The properties of the synthesized reactive oxygen species response nanoplatform were evaluated in hydrogel and micelle systems,respectively.These characteristics,including morphology,particle size distribution,particle size,surface potential,reactive oxygen species production capacity,and cell compatibility,were characterized by different means.Reactive oxygen species（ROS）responsiveness was also evaluated by drug release experiments using infrared laser and ultrasound irradiation.In Chapter 2,based on the aPD-L1 prodrug,we constructed a prodrug hydrogel with tumor microenvironment and near-infrared response function to cooperate with aPD-L1immunotherapy for the treatment of breast cancer.In vitro hydrogel formation experiment of the hydrogel nanoplatform proved that the hydrogels all had cross-linked network structure and a large number of nanoparticles were attached to the surface,and the nanoparticles would not affect the cross-linked structure of the hydrogels.The release experiment proved that the on-demand release of aPD-L1 could be achieved under the dual stimulation of hydrogen peroxide and 660nm infrared laser.In vitro cell experiments show that the hydrogel nanoplatform not only has good biocompatibility and biosafety,but also has a good ability to induce immunogenic death under the dual stimulation of near infrared laser and H₂O₂.In vivo experiments of tumorbearing mice,we used the breast cancer model to evaluate the anti-tumor effect and the expression of immune effect of the prodrug hydrogel platform.The results showed that the hydrogel nanoplatform improved the immune response at the tumor site under the dual action of PDT and CDT,reduced the content of Treg cells at the tumor site by increasing the content of effector T cells.It inhibited the growth of primary tumor and distant tumor and inhibited the metastasis of liver and lung tumor.In Chapter 3,we constructed ultrasound-responsive nanopartners based on PEG-TK-PS,which can achieve simultaneous release of chemotherapy drug TPZ-C₁₂ and BTK inhibitor ibrutinib under US conditions.Due to the transformation of O₂ into ¹O₂ in the tumor microenvironment under ultrasonic radiation,the local oxygen content is reduced.Therefore,after the release of the chemotherapy drug TPZ-C₁₂,toxicity is activated,which can achieve the purpose of killing cancer cells through hypoxia.Finally,the combination of ibrutinib can inhibit the aggregation of MDSCs cells and reshape the immune microenvironment inside tumor cells.The TEM image and HPLC release experiments of the nanopartners demonstrate the successful construction of the responsive micelle platform and its capability of ultrasonic responsive release.In vitro cell experiments showed that the nanopartners had good biosafety and phagocytosis ability and could increase the expression of HIF-1αin tumor under ultrasonic stimulation.In vivo tumor-bearing mice,the breast cancer model was used to evaluate the anti-tumor evaluation of the responsive nanopartner platform and the expression of immune effects.The results showed that the responsive prodrug nanoplatform induced hypoxia at the tumor site through SDT,activated TPZ prodrug,augmented immunogenic death,improved immune response to trigger the maturation of DCs and led to the increase of effector T cells.Moreover,MDSCs aggregation caused by tumor hypoxia was eliminated,which significantly inhibited the growth of primary and distant tumors and had a good inhibitory effect on tumor metastasis in liver and lung.In conclusion,we constructed two ROS responsive nanoplatforms to mediate immune effects to achieve multimodal treatment of breast cancer.Such responsive nanoplatforms can achieve in situ activation of chemotherapy drugs or immune adjuvants at tumor sites under external laser or ultrasonic radiation.Thus,it can achieve an increased immune effect,which has a good effect on the growth and metastasis of breast cancer.Therefore,these two responsive nanoplatforms may provide a new way of thinking for tumor drug delivery systems.