The Study Of Selective Delivery Of Glycosylated Silicon Nanoparticles By Transporters

With the rapid development of nanotechnology,multifunctional nanomaterials are widely used in the treatment of various diseases(such as bacterial infections,malignant tumors,etc.).Among them,silicon nanomaterials with unique optical properties,facile surface modification and high drug loading have received intensive attentions in the field of biological imaging and disease therapy.On the other hand,transporters are important mediators of chemical substances and signal exchange inside and outside biological membranes.It is worthwhile to point out that,there currently exist scanty drug delivery strategies by using transporters to deliver silicon nanomaterials.This thesis aims to develop novel drug delivery systems by using different membrane transporter,which are able to deliver glycosylated silicon nanoparticles into bacteria and mammalian cells and suitable for the treatment of ocular bacterial infection and inhibit neovascularization of cerebral endothelial cells.The main contents are described as follows:Chapter 1:We briefly introduce the structure and function of ATP-binding cassette(ABC)transporters,glucose transporters(GLUTs)and fluorescent silicon nanomaterials.And we then summarize their biological applications,especially for the treatment of bacterial infection and inhibition of angiogenesis by using fluorescent silicon nanomaterials.Furthermore,we clarify the research background,significance and main research content of this paper.Chapter 2:Antisense peptide nucleic acid(asPNA)can limit the expression of specific genes by sequence-directed targeting of mRNA.But the pristine asPNA are unable to enter bacteria freely,which require the assistance of vectors.However,current vehicles for delivering asPNA cannot specifically distinguish between bacterial cells and mammalian cells.As previously reported,bacteria can selectively transport α(1-4)-glycosidically linked glucose polymers via ABC transporters.Inspired by this,we modified the surface of silicon nanoparticles(SiNPs)with glucose polymer(GP)and asPNA(G-SiNPs-asPNA)and specifically delivered asPNA into bacterial cells through ABC transporter on bacterial membrane surface rather than mammalian cells,with bacterial uptake rate of 59.4%.Inside bacteria,G-SiNPs-asPNA specifically binds to the start code region of mRNA of target gene,activates endogenous RNase to degrade Mrna,thereby restricting the expression of the target gene.Its antibacterial rate against multidrug-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus reached 99%.The nanoagent can sensitively detect bacterial keratitis at the concentrations as low as～104 CFU and has significant therapeutic effect on bacterial keratitis and endophthalmitis in mice.Chapter 3:Glioblastoma is a highly invasive tumor with abundant blood vessels,and angiogenesis is crucial to the growth and development of glioblastoma.Therefore,drugs that effectively inhibit angiogenesis can be used to treat glioblastoma.As previously reported,cells can take up glucose through GLUTs.Inspired by this,we synthesize glycosylated silicon nanoparticles made of glucosamine(G)-modified and indocyanine green(ICG)-loaded silicon nanoparticles(GIS).Typically,GIS could be uptaken by human brain microvascular endothelial cells(HBMEC)with high expression of glucose transporters 1(GLUT1)transporter on the membrane surface.Under 808-nm laser irradiation,GIS absorbs light energy and converts it into heat energy,produce photothermal effect in cells,the inhibition rate of cell scratch healing reaches 71.4%,and the inhibition rate of HBMEC cells in vitro tube formation reaches 80.3%.The GIS can effectively destroye the HBMEC cytoskeleton,thus hindering cell migration.Chapter 4:We summarize the main content of the full text,then analyze the innovations and deficiencies and finally propose an improvement plan for the limitations of this thesis.In summary,two kinds of glycosylated silicon nanoagents,namely glucose polymer and glucosamine-modified silicon-based nanoagent,are constructed in this paper,which can enter bacteria and cells via the ABC transporter on the bacterial surface and the GLUT1 transporter on the cellular surface,respectively,and are applied to treat ocular bacterial infections in the mice and inhibit the formation of neovascularization in cerebral endothelial cells.The research aims to develop new drug delivery strategies based on transporters and silicon nanomaterials,providing new avenues for the treatment of bacterial infections and neovascular diseases.