Study On The Design, Synthesis, Antitumor Activity Of Novel Peg-conjugated Targeted Antitumor Drugs

How to effectively treat tumors has always been a major challenge for mankind.Although traditional chemotherapeutic drugs such as irinotecan have been proved to have definite anti-tumor effect,most of them often produce serious toxic and side effects due to the lack of targeting,which greatly limits their clinical application.Therefore,the design of targeted antitumor drugs is the focus of current research.Compared with normal cells,some receptors such as Integrins and CD44 are highly expressed on the surface of tumor cells,which provide targets for the design of antitumor drugs.Before this paper based on the traditional chemotherapy drugs and drug policy,with the introduction of a variety of tumor cell surface receptor specificity target molecules and PEG molecular with characteristics of long cycle,build a new type of structure of antitumor drug,make its have targeted function and tumor suppression effects in improving the curative effect of significantly reduced side effects at the same time,in order to provide the innovative for the clinical treatment of the tumor research train of thought.The main research contents of this paper are as follows:1.Preparation and evaluation of antitumor activity of Iritectin conjugated small polypeptide molecules with PEG compounds BGC0209 and BGC0216.Based on the hydroxyl group on Irinoticam,a series of novel pegylated anti-tumor target compounds with active targeting were designed and synthesized by attaching glycine,Linker molecule,four-arm PEG and a variety of targeted peptide small molecules successively.Through in vitro and in vivo antitumor activity tests,the candidate compounds BGC0209 and BGC0216 were found to have significantly better tumor inhibition and toxic side effects than irinotecan and NKTR-102.2.Preparation and antitumor activity evaluation of Irinotecan conjugated polypeptide small molecule and PEG compound BGC0222.Based on the structure of BGC0209,compound BGC0222 was prepared by changing the connection mode of the polypeptide targeting molecule c RGD with irinotecan and four-arm PEG.It was found in nude mouse xenograft model that the compound improved the structural stability while maintaining the high anti-tumor effect and safety of BGC0222.In vitro results showed that the antitumor effect was superior to irinotecan and NKTR-102,and it could specifically bind to V 3 and V 5 to target and inhibit angiogenesis and tumor tissue proliferation.The results of pharmacokinetic and toxicological studies showed that BGC0222 had better pharmacokinetic properties and higher safety than irinotecan,and had clinical development value.3.Preparation and evaluation of antitumor activity of irinotican conjugate A6 small molecule with PEG compound BGC0228.Small peptide Molecule A6 has been reported to specifically bind to tumor surface receptor CD44.Pegylated irinotecan derivative BGC0228 was designed and synthesized by connecting irinotecan with glycine,Linker,four-arm PEG,and targeted peptide molecule A6.In vivo anti-tumor activity screening test showed that BGC0228 had better anti-tumor activity than irinotecan and BGC0222 in a variety of nude mouse transplanted tumor models,showing good broad-spectrum anti-tumor effect and promising clinical application prospect.