The Construction And Application Of Synergistic/Sonogenetics Nanosystem For Tumor Immunotherapy

Immunotherapy is one of the most promising tumor therapies at present.However,there are still two major problems in the treatment process.On the one hand,the therapeutic effect of a single immunotherapy method is often limited.While increasing the dose of drugs will has a risk of immune storm.Therefore,the development of synergistic immunotherapy strategies based on multiple methods is very important to improve the treatment efficacy.On the other hand,current immunotherapy methods are lack of regulation mechanisms so the treatment process is not accurate and is prone to systemic side effects.Therefore,it is urgent to develop strategies with precise regulation for immunotherapy.In view of the above two aspects,this study aimed at synergetic and regulatory properties of immunotherapy.In this paper,we constructed a synergistic immunotherapy nanosystem and a sonogenetics immunotherapy nanosystem respectively then studied their therapeutic applications in mice tumor models.In the second chapter,we designed an efficient synergistic immunotherapy nanosystem to inhibit postoperative recurrence and metastasis of tumors.This system which based on calcium alginate hydrogel was utilized the synergistic immune effect of Cp G oligodeoxynucleotide and anti PDL1 antibody.And by means of the advantages of nanomaterials to realize the synergistic immunotherapy strategies and integration of diagnosis and treatment.In this system,the nanosystem(1)(Cp G+probe@CA)was injected into the tumor situ after surgery.It could enhance the immune response and monitor the tumor recurrence by detecting the changes of CEA probe fluorescence signal.The nanosystem(2)(ICG@CANPs-anti PDL1)was injected into body intravenously.It could relieve the immune suppression and promote the killing effect of T cells then assisted in situ therapy and achieved a synergistic effect to inhibit tumor recurrence and metastasis.The in-vivo and in-vitro results of experiments demonstrated that this system could achieve the synergistic effect of immune response enhancement and immune suppression relief.It had good inhibitory effect and monitoring function in-vivo for 4T1 tumor.In the third chapter,we designed a logical gated sonogenetics nanosystem for precise regulation of tumor cells death.In this system,Msc L I92 L plasmids were delivered to tumor cells through cationic nanoliposomes for expressing Msc L I92 L channel proteins.The Msc L I92 L channels were kept open for a long time by ultrasound then resulted in tumor cells death because of small molecules flow inside and outside the cells out of balance.Through the Msc L I92 L protein expression on tumor cells and ultrasound application on tumor sites,this logic AND gated mechanism could realize the precise regulation of tumor cells death.It could reduce non-specific triggers and systemic side effects.We studied the function of this systemin in Hela,B16 and 4T1 tumor cell lines.The in-vivo and in-vitro results demonstrated that the tumor cells would die seriously under 6 MHz and 15 W ultrasound for 30 min(the B16 cells death rate could reach up to 59%).This strategy as an immunogenicity death inducing strategy has a comprehensive treatment potential based on the body’s immune system.In general,the synergistic immunotherapy nanosystem and the sonogenetics immunotherapy nanosystem we constructed in this paper are expected to provide new strategies and directions for tumor immunotherapy.