Biodegradable Hollow Mesoporous Silica Nanoparticle For Inducing Antitumor Effect By Combining Chemotherapy With Immunotherapy

Objectives: Due to immune system in tumor site is limited by the complex tumor microenvironment,tumor can escape from immune surveillance during the progression.Traditional chemotherapy can induce severe side effects.This project designed a treatment strategy with combination of chemotherapy and immunotherapy,which utilized a kind of biodegradable lipid bilayer-coated hollow mesoporous silica nanoparticle(d HMLB)delivery system.It could realize co-encapsulation and co-delivery of three different antitumor agents to tumor microenvironment,thus activating immune response together with inducing lethal effect on tumor cells by chemotherapy to achieve stronger antitumor effect.Methods: Biodegradable hollow mesoporous silica nanopartic les were prepared by oil-water biphase reaction and template method.All-trans retinoic acid(ATRA),doxorubicin(DOX)and interleukin 2(IL-2)were co-loaded by nanoparticles(A/D/I-d HMLB),and microplate reader and HPLC were used to evaluate in vitro release profiles and pharmacokinetic studies.B16F10 tumor-bearing mice model was established to examine antitumor effect and pulmonary metastasis inhibition ability of A/D/I-d HMLB.Flow cytometric analysis and ELISA detection were conducted to assess immune cells and cytokines from tumor microenvironment,thus to determine the synergstic antitumor mechanism of A/D/I-d HMLB.Results:The monodispersed nanoparticles were prepared with controllable core/shell size,which could degrade completely within 7 days in physiological condition.The coated lipid increased the stability and biocompatibility of nanoparticles.Encapsulation efficiency of ATRA and DOX reached 48.9 ± 7.8% and 23.1 ± 3.5%respectively,and IL-2 adsorption could be as high as 90%.From animal experiment results,A/D/I-d HMLB showed the most obvious antitumor and anti-metastasis effect.Immune analysis demonstrated that immunosuppressive myeloid-derived suppressor cells population decreased,and the expression of cytotoxic T lymphocytes and natural killer cells increased,and cytokines of IFN-? and IL-12 were upregulated,which all above showed that tumor-specific immune response were activated and enhanced.Conclusions: Successful synthesis of d HMLB with good stability and biocompatibility made it feasible to deliver ATRA,DOX and IL-2 simutaneously to tumor site,which realized the combination of chemotherapy and immunotherapy.Based on synergistic effect from three drugs,immunosuppression was relieved and immune system was further activated in tumor microenvironment,which together with chemotherapy produced stronger antitumor efficiency and lower side effects compared with monotherapy.This multidrug delivery system provided a great platform through tumor cells directly killing and tumor microenvironment remodeling for combinatorial chemo-immunotherapy against tumor.