Synthesis and performance study of targeted NGR peptide-modified doxorubicin using acid-sensitive hydrazone bond as linker
CHENG Dan-dan
GUO Hu
LI Ke
SHEN Hong-yan
Abstract：Objective:To synthesize doxorubicin precursor with NGR(Asn-Gly-Arg)sequence as target peptide and acid-sensitive hydrazone bond as linker,and investigate the proliferation inhibitory and targeting effects of doxorubicin(DOX)precursor on tumor cells overexpressing aminopeptidase N.Methods:A combination of solid-phase and liquid-phase methods was used to synthesize the DOX precursor,optimize its synthesis process,and probe the acid sensitivity of the stilbene bond;the cytotoxicity and targeting properties of the DOX precursor were then evaluated using human colon cancer cells HT29(aminopeptidase N non-expression)and mouse breast cancer cells 4T1(aminopeptidase N overexpression).Results:When the feeding ratio of peptidylhydrazine and DOX was 4∶1 and the reaction time was 4 h,DOX precursor with high purity could be obtained;the stability of the DOX precursor in methanol was higher than that in water,and its stability was decreased by the increase of acidity,reflecting the acid sensitivity of the germanium bond;and the DOX precursor displayed selective cytotoxicity to the aminopeptidase N receptor overexpressing 4T1 cells.Conclusion:Synthetic DOX prodrug targets the overexpressed aminopeptidase N receptor in tumor cells and has structural stilbene bonds that can be specifically cleaved to release DOX in the weakly acidic tumor microenvironment,thus conferring dual targeting of DOX to mitigate its toxic side effects on normal cells.
Keywords：peptide-drug conjugatesNGR sequencedoxorubicinaminopeptidase Nantitumor drug
Publication Date：2025-01-29
Online Publishing Date：2026-08-14(First online date of this platform, not the publication date of the document)
Pages：5( 205-209 )