Functional Zwitterionic Materials Design And Its Anti-tumor Application

Zwitterionic materials have shown great application prospects in the field of cancer treatment.Zwitterions not only have excellent anti-fouling and antibacterial properties,but can also enhance biocompatibility,reduce adverse immune reactions,prolong circulation time thus promote the absorption of drugs and genes in the body.Therefore,zwitterionic materials have been widely used in the fields of biomedical diagnostic materials,nano-drug carriers,gene carriers and immune factor carriers.Functionalized zwitterionic materials have given zwitterions new functions based on their original performance,such as stimulus responsiveness,targeting,luminescence and heating,etc.This makes functionalized zwitterionic materials more suitable for disease diagnosis and drug,gene delivery under different conditions.In this thesis,we have designed zwitterionic materials with different functions to meet the needs of drug and gene delivery under specific circumstances to enhance the therapeutic effect of cancer.We have achieved the following research results:(1)We introduced the secondary amine into the ? position of the ester bond(-NHCH2CH2COO-),and protected the ester bond with phenylboronic acid which response to ROS signal.The ester bond can generate a hydrogen bond cyclization(HBC)structure in response to ROS,which will cause the ester bond to be broken quickly within 5 hours,much faster than other reported ester bond breakage methods.The ultra-sensitive ester bond will undergo a transition from cation-zwitterion-anion in response to ROS.This transition can enable genes to be effectively carried and released,and the presence of zwitterions greatly reduces the cytotoxicity of the carrier material.Therefore,we have constructed an ultra-sensitive ester bond modified polyamidoamine for gene delivery,which can release genes at very low H2O2(<200 ?M)concentrations and deliver the genes to the nucleus within 2 h.In addition,the gene transfection performance and safety of the vector are superior to the commercial transfection reagent PEI25k.(2)Based on the main component of the cell membrane,phosphatidylcholine(PC-lip),we reversed the position of the zwitterion in its structure,thereby synthesizing a new type of lipid:choline phosphate lipid(CP-lip,reverse lipid).We found that CP-lip have strong interaction with PC-lip,so we used CP-lip as a filler to enhance the performance of traditional liposomes.We found that when the molar ratio of PC-lip to CP-lip is 1/2,the co-assembled liposome(PC-CP-lipo)is more stable,more biocompatible and higher resistant to protein adsorption than other common liposomes.We used Dox-loaded PC-CP-lipo to treat melanoma,and its tumor inhibition rate could reach 86.3%.After combined treatment with Dox@PC-CP-lipo and PD-L1 antibody,the tumor inhibition rate could reach 94.4%,and 60%of the mice did not suffer from tumor recurrence.(3)On the basis of the above work,we used PD-L1 antibody to modify CP-Lip(CP-?PDL),and then assembled CP-Lip/CP-?PDL and carried the drug(Dox)to construct a targeted nano-drug(Dox@tCP-Lipos).The nano-drug could selectively bind to melanoma cells.We found that CP-Lip could be inserted into the cell membrane and interact strongly with the cell membrane,thereby greatly reducing the fluidity and transmembrane transport of the cell membrane.This led to the weakening of the metabolism,reproduction and migration of melanoma cells.After Dox@tCP-Lipos treatment,the tumor was 100%suppressed.