An Intelligent Dendrimer Nanoplatform For Immune Modulation-mediated Combination Tumor Therapy

Cancer has become a major public health issue that seriously threatens the health of all mankind.One of the main reasons for treatment failure of cancer is its extensive metastasis through blood and lymphatic vessels.In recent years,new strategies such as vascular disrupting therapy,photothermal therapy(PTT)and immunotherapy have gained remarkable momentum in cancer treatment.However,the effect of single treatment mode is often unsatisfactory due to its failure in simultaneous inhibition of primary tumor growth and tumor metastasis.Hence,the development of nanoplatforms that can simultaneously inhibit tumor growth and metastasis remains an extreme challenge.Although vascular disrupting therapy represented by the vascular disrupting agent5,6-dimethylxanthenone-4-acetic acid(DMXAA)can cause hemorrhagic necrosis of tumor tissues and activate the immune system,it still cannot effectively eradicate the entire solid tumor.Considering that PTT can effectively kill tumor peripheral cells,and the immunogenic cell death induced by PTT and the immune modulation mediated by DMXAA may jointly activate the antitumor immune response in vivo,combining PTT with vascular disrupting therapy may be an enhanced and complementary strategy.The key of combination therapy is to select appropriate carriers to integrate different therapeutic agents into the same nanoplatform.Poly(amidoamine)(PAMAM)dendrimers have been considered as a promising nanoplatform due to their highly branched structure,good monodispersity and well-defined composition.In this thesis,we use generation 5PAMAM dendrimers as nanocarriers to co-loaded copper sulfide nanoparticles(Cu S NPs)and DMXAA within the internal cavities,and modified the targeted peptide Ly P-1 with polyethylene glycol(PEG)on the surface to construct G5-PEG-Ly P-1-Cu S-DMXAA NPs(GLCD NPs)for immune modulation-mediated combined PTT/vascular disrupting therapy.The research results indicate that the synthesized GLCD NPs possess good colloidal stability,p H-sensitive drug release performance and high photothermal conversion efficiency(59.3%).On the one hand,the combination of PTT and vascular disrupting therapy achieves enhanced killing effect on breast cancer.On the other hand,PTT-induced immunogenic cell death and DMXAA-mediated M1 polarization of tumor-associated macrophages and dendritic cell maturation jointly activate robust antitumor immune response.In addition,GLCD NPs can specifically kill tumor lymphatic endothelial cells through Ly P-1-mediated proapoptotic activity.The simultaneous destruction of tumor blood vessels and lymphatic vessels cut off the two main ways of tumor metastasis,playing a two-pronged role in inhibiting lung metastasis of the breast cancer models.In conclusion,the GLCD NPs we developed have successfully achieved immune modulation-mediated combined PTT/vascular disrupting therapy,providing novel ideas for developing new nanoplatforms for breast cancer treatment.