Preparation And Application Of Tumor Biomarker Targeted Hydroxyapatite Nano-Drug

In recent years,with the advantage of their strong targeting abilities,good distribution in vivo,low toxic and side effects,targeted nano-drugs have been widely developed and applied in the tumor treatment.Hydroxyapatite nanoparticles,as the main components in teeth,have the advantages of excellent biocompatibility,biological safety and acid responseTherefore,the inorganic nanoparticles hydroxyapatite is selected as the nano-carrier to design drug-loaded nanoparticles for targeted tumor therapy.Drug loaded hydroxyapatite nanoparticles DOX@HAP was prepared by adjusting the conditions and parameters of the preparation process.In the following works,three tumor biomarkers(GGT-targeted fluorescent dye,polypeptide cRGD and hyaluronic acid)were respectively modified into the surface of hydroxyapatite nanoparticles to design three tumor-targeted nanoparticles for tumor treatment.(1)GGT enzyme targeted nano-drug DDHAP:Tumor biomarker y-glutamyl transpeptidase(GGT)is a glycoprotein which is often overexpressed on the surface of most tumor cell membrane.In this thesis,a GGT enzyme targeted fluorescent dye DFA1 was designed and synthesized,and it was modified on the surface of nano-drugs through the effect of hydrogen bonding to construct GGT enzyme targeted nano-drug DDHAP.After the dye DFA1 recognizes GGT enzyme,nanoparticles enter into tumor cells and release drugs in their acidic microenvironment.Ratio fluorescence imaging realized the monitoring of drug release.The nano-drug DDHAP has significant therapeutic effects on GGT enzyme overexpressed cells,tissues and tumor mouse model experiments.(2)cRGD targeted-nucleus binding nano-drug cRDHAP:cyclic peptide cRGD has a high affinity with tumor biomarker integrin ?v?3.The mechanism of chemotherapeutic drug DOX is to embed into the cell nucleus and inhibit the synthesis of DNA and RNA.In this thesis,RNA binding fluorescent dye Na-RNA was designed and synthesized,and it was modified on the surface of nanoparticles together with the targeting group PEG-cRGD and protecting group PEG,to construct cRGD targeted nucleus-binding nano-drug cRDHAP.After the integrin ?v?3 recognition by cRGD,nanoparticles entered into tumor cells and remove PEG chains in an acidic microenvironment to release loaded drug.The dye Na-RNA on the surface of nanoparticles reacts with RNA in the cell nucleus,increasing the accumulation of nanoparticles in the nucleus and enhancing the therapeutic effect of chemotherapy drugs.The nano-drug showed significant anti-tumor effect in integrin ?v?3 overexpressed tumor mouse models.(3)Oligo hyaluronic acid modified hybrid nano-drug oHA-DOX@MSNs/HAP:hyaluronic acid has a strong binding ability with tumor biomarker CD44 protein.In this thesis,oligo hyaluronic acid and high molecular weight hyaluronic acid modified hybrid nano-drug were designed and prepared.Oligo hyaluronic acid-modified nano-drug have better tumor targeting and rapid drug release ability,and are highly toxic to CD44 overexpressed tumor cells.Nano-drug oHA-DOX@MSNs/HAP has significant anti-tumor effect in tumor mouse model.