There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and th...There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression.The targeted peptide D(RWYD)(abbreviated RD),with nanomolar affinity to integrinα6 was identified by peptide scanning techniques such as alanine scanning,truncation,and D-substitution.Herein,we developed a therapeutic nanoparticle based on the integrinα6-targeted peptide for treating CNS-ALL.The self-assembled proapoptotic nanopeptide_(D)(RWYD)-_(D)(KLAKLAK)_(2)-G_(D)(FFY)(abbreviated RD-KLA-Gffy)contains the integrinα6-targeted peptide RD,the well-known proapoptotic peptide_(D)(KLAKLAK)_(2)(abbreviated KLA),and the self-assembling tetrapeptide GD(FFY)(abbreviated Gffy).The functional mechanism of RD-KLA-Gffy is clarified using different experiments.Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis,thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity.Moreover,the combined use of RD-KLA-Gffy and methotrexate(MTX)shows a potent antitumor effect in treating CNS-ALL,indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX,which shows promise for application in CNS-ALL therapy.展开更多
基金supported by grants from the National Natural Science Foundation of China (81972531, 82373175, 82102775, and 82002466)the Major Scientific and Technological Projects of Guangdong Province (2019B020202002)the Young Talents Program of Sun Yat-sen University Cancer Center (YTP-SYSUCC-0067)
文摘There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression.The targeted peptide D(RWYD)(abbreviated RD),with nanomolar affinity to integrinα6 was identified by peptide scanning techniques such as alanine scanning,truncation,and D-substitution.Herein,we developed a therapeutic nanoparticle based on the integrinα6-targeted peptide for treating CNS-ALL.The self-assembled proapoptotic nanopeptide_(D)(RWYD)-_(D)(KLAKLAK)_(2)-G_(D)(FFY)(abbreviated RD-KLA-Gffy)contains the integrinα6-targeted peptide RD,the well-known proapoptotic peptide_(D)(KLAKLAK)_(2)(abbreviated KLA),and the self-assembling tetrapeptide GD(FFY)(abbreviated Gffy).The functional mechanism of RD-KLA-Gffy is clarified using different experiments.Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis,thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity.Moreover,the combined use of RD-KLA-Gffy and methotrexate(MTX)shows a potent antitumor effect in treating CNS-ALL,indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX,which shows promise for application in CNS-ALL therapy.
