Biomimetic Nano-lymphatic Vessels For Enhancing Intratumoral Penetration And Antitumor Research

Cancer incidence and fatality rate increase year by year,which has become a serious threat to human life and health of the number one killer.At present,the poor effect of cancer treatment is mainly due to the extremely low delivery efficiency of traditional chemotherapy drugs at the tumor site,even less than 1%,which is also a major challenge in the current scientific research and clinical drug development process.With the rapid development of nanotechnology,nanomedicine have shown great advantages and effects in enhancing drug delivery and anti-tumor therapy.In this study,four kinds of nanomedicine systems were designed for the penetration and delivery of nanomedicine.The main research contents are as follows:(1)The nanomedicine delivery system with double enhanced osmosis was designed and synthesized.Firstly,polydopamine(PDA)nanoparticles with variable size were prepared,followed by adhesion to the chemotherapy drug paclitaxel(PTX),and finally coated with the immune activator C6-ceramide modified tumor cytomembrane to form a nanomedicine.The nanomedicine enhances long circulation in vivo under the effect of immune escape of cytomembrane.At the same time,it is efficiently delivered to the tumor site under the action of homologous targeting.Subsequently,under the excitation of near infrared(NIR)light,the PDA sphere changes from large particles to small particles,so as to be delivered to the tumor center through the gap in the tumor mesenchymal to kill tumor stem cells.In addition,PDA-mediated photothermal therapy,C6-ceramide-mediated immunotherapy and PTX-mediated chemotherapy realize multifunctional combination therapy,which can effectively kill tumor stem cells.The delivery efficiency of the nanomedicine delivery system with double enhanced penetration was 23.22%,compared with 8.54%for ordinary nanomedicines.(2)The photocatalytic biomimetic nano-lymphatic system was designed and synthesized.Firstly,the photocatalyst graphite phase carbon nitride(g-C3N4),chemiluminescent activator luminol and tumor cytomembrane were prepared for photocatalytic tumor interstitial fluid splitting in situ,thus reducing the tumor interstitial fluid pressure(TIFP)at the tumor site to improve the delivery efficiency of nanomedicine.In addition,a large number of reactive oxygen species(ROS)were produced during the photocatalytic process,therefore,it can be used to kill tumors.In this study,we first proposed this method to reduce TIFP and treat it by catalyzing water splitting,and named it hydrodynamic therapy.In the tumor microenvironment,lactic acid as a natural catalyst greatly improved the water splitting rate.The TIFP at the tumor site decreased to 62.11%,and the blood perfusion at the tumor site was significantly enhanced.The final results showed that the delivery efficiency of biomimetic nano-lymphatic system was 15.9 times that of traditional chemotherapy drugs,respectively.(3)The novel bionic nano-lymphatic system was proposed to optimize the delivery efficiency and therapeutic effect.Based on the previous work,the nano-lymphatic system is used to split the interstitial fluid at the tumor site through photo/piezoelectric catalysis,thus enhancing the splitting efficiency.In addition,the separation efficiency of electrons and holes was enhanced by the plasmon resonance effect of Pt,which further enhanced the water splitting efficiency.The results showed that TIFP was reduced to 53.62%after optimization,and the delivery efficiency of nano-lymphatic system was 18.78 times that of common nanomedicine.ROS and Pt(II)produced in the process of water spliting have strong tumor killing effect,and achieve complete cure of tumor.(4)Highly catalytic nano-lymphatic system enhanced hydrodynamic therapy and immunotherapy.On the basis of previous work,crystalline carbon nitride(CCN)was used as the basis of nano-lymphatic system,which enhanced the effect of water splitting,realizing the rapid reduction of interstitial pressure and reducing the content of lactic acid at the tumor site.This strategy was according to the principle that lactic acid can be consumed when the coupling catalytic water splitting,which led to polarization of macrophages towards M1 macrophages,and enhanced the effect of tumor immunotherapy.Finally,the effects of hydrodynamic therapy and immunotherapy were enhanced,and the tumor was completely cured.