Construction Of Nanocarriers Based On Tumor Microenviromental Response And Study On The Drug/Gene Delivery

In this dissertation,three poly-cationic materials were designed to respond to the tumor microenvironment and used to deliver drugs and nucleic acids.This dissertation are summarized as the below:In the first part,we designed a surface liposome membrane modified phenyl boronic acid structure of the ROS-responsive polycationic material(Lip/PDP)carrying vascular growth inhibition gene(siVEGF)for the treatment of colon cancer.The PDP contained a quaternary ammonium salt structure that bind siVEGF efficiently and formed a regular and globular structure.Under the condition of catalase in tumour cells,phenylboronate in the PDP was hydrolyzed,then the positive charge converted to neutral and released the siVEGF.In vitro and in vivo study showed that the liposome-modified PDP/siRNA could increase long circulation,avoid hemolysis,reach the tumor site,effectively inhibit blood vessel growth and down-regulate angiogenesis-related proteins,promote apoptosis and inhibit tumor growth.In the second part,we successfully synthesized a reductive responsive poly-cationic material PSPGP targeting pancreatic cancer cells with an invertable inner and outer layer structure,which could simultaneously deliver PTX and siTR3 for synergetic therapy.PSPGP had good biocompatibility and high drug loading capacity at the physiological conditions and under the reducing conditions PSPGP dissociated to release chemotherapeutic drugs and genes.The drug delivery system could target to the tumor site,down-regulate TR3,Bcl-2 and Survivin apoptosis proteins in the tumor tissue and effectively inhibit tumor growth.In the third part,a reduced-response self-assembled nanocarrier was constructed.The core of the carrier was an inorganic mesoporous silicon material.Mesoporous silica and adamantane were connected by a disulfide bond(-S-S-),amantadine and cyclodextrin linked to a low molecular weight PEI self-assemblly formed a nanocarrier.In order to enhance the targeting ability of the nanocarriers,the azobenzenes attached to the PEG-RGD self-assemble with the nanocarriers to form NPs-RGD.NPs-RGD could carry the chemotherapeutic drug(DOX)and deliver siRNAs that regulated the expression of immune checkpoint-related proteins(siPD-L1).In vitro and in vivo study showed that the nanocarrier system could release the DOX and siPD-Ll when the disulfide bonds broken under the reducing conditions of tumor cells.siPD-L1 entered the cytoplasm and down-regulated the expression of PD-L1 protein to promote the activity of T cells and enhanced the body’s own immunity,effectively combined chemotherapy with immunotherapy to inhibit tumor growth.