Preparation Of Sulfated Glyconanoparticles And Their Inhibition Of Cancer Cells Growth

Cancer is a major public health problem worldwide.The characteristics of malignant proliferation and escape from apoptosis of cancer cells are closely related to the overexpression of heparan sulfate proteoglycan(HSPG).HSPG is composed of core protein and heparan sulfate sugar chains.Studies have shown that heparan sulfate is a kind of highly sulfated polysaccharides in the glycosaminoglycan family,which plays an important role in the occurrence,development and metastasis of malignant tumors.The sugar chain of heparan sulfate contains many sulfuric acid groups,and its biological activity is related to the density of sulfate group and sulfation site.However,the chemical structure of heparan sulfate is so complex that it is difficult to extract,synthesize and purify,which limits the research on its related functions and applications.Herein,starting from N-acetylglucosamine(N-acetylglucosamine)of heparan sulfate disaccharide unit,we synthesized a series of sulfated GlcNAc derivants with accurately controlled chemical structure based on our previous study.Then,these derivants were modified on the surface of fluorescent silica nanoparticles(FSiNPs)through"Click"chemistry to obtain glyconanoparticles.The effect of glyconanoparticles on the growth of cancer cells was studied.First,starting from GlcNAc,with accurately control of the chemical structure,6 kinds of GlcNAc derivatives with different sites were synthesized.The structures of the compounds were analyzed and identified by infrared spectroscopy and hydrogen nuclear magnetic resonance spectroscopy,respectively.FSiNPs were prepared by inverse microemulsion method.The composition,morphology,size distribution andζ-potential of the FSiNPs were characterized by infrared spectroscopy,transmission electron microscopy and dynamic light scattering technique,respectively.The results show that FSiNPs have uniform particle size,regular morphology,and good dispersibility.The averge size of FSiNPs is about 65 nm in dry state and 71 nm in hydration status.Moreover,FSiNPs have a moderately,negatively charged surface.Second,six kinds of GlcNAc derivants with different sulfation patterns were modified on the surface of FSiNPs to obtain a series of glyconanoparticles.The average size of the particles has increased to 75～86 nm after the modification.The glycosyl density on the surface of FSiNPs has be calculated within the range of 0.24～1.37μmol/m~2 from the thermogravimetric data.The hemolysis rates of both GlcNAc derivants and their corresponding glyconanoparticles have be lower than 1.5%,showing good blood compatibility.Finally,the results of cell experiments show that among the above glyconanoparticles,the3,4,6-O sulfated glyconanoparticles(NP6)can inhibit the growth of cancer cells.The images of laser scanning confocal microscopy have showed the uptake of glyconanoparticles by cancer cells.The assay showed that NP6 could induce cell apoptosis by activating Caspase-3.Western blot results showed that apoptosis was correlated with the expression level of Caspase-3 protein in a concentration dependent manner.In conclusion,sulfated monosaccharide at 3,4,6-O positions are expected to be potential inhibitor after being prepared into glyconanoparticles for inhibiting the growth of cancer cells.