Enhanced anti-cancer effect using MMP-responsive L-asparaginase fused with cell-penetrating 30Kc19 protein

Jina Ryu, Sung Jae Yang, Boram Son, Haein Lee, Jongmin Lee, Jinmyoung Joo, Hee Ho Park, Tai Hyun Park

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

As the acute lymphoblastic leukaemia (ALL) develops, expression of L-asparaginase (ASNase) protein is known to decrease. Therefore, deficiency of the ASNase protein would be regarded as one of the significant indications of the ALL. For the treatment of ALL, recombinant ASNase protein derived from bacterial origin is used which causes cytotoxicity by deprivation of Asn. However, short half-life of the protein is an obstacle for medical use. In order to overcome this limit, recombinant ASNase was fused to 30Kc19 with protein-stabilizing and cell-penetrating properties. As the 30Kc19 protein may induce steric hindrance, we further added a PLGLAG linker sequence (LK) between the ASNase and 30Kc19. The treatment of ASNase-LK-30Kc19 fusion protein demonstrated enhanced stability, cell-penetrating property, and anti-cancer activity. Intracellular delivery of both the non-cleaved and cleaved forms of the protein were observed, suggesting that ASNase acted both internally and externally, performing high anti-cancer activity by effective depletion of intracellular Asn. Additionally, ASNase-LK-30Kc19 showed high selectivity towards cancer cells. In terms of the dosage, releasable ASNase from ASNase-LK-30Kc19 reached the same half-maximal inhibitory concentration at a concentration five times lower than non-releasable ASNase-30Kc19. Altogether, the findings suggest that this fusion approach has potential applications in the treatment of ALL.

Original languageEnglish
Pages (from-to)278-285
Number of pages8
JournalArtificial Cells, Nanomedicine and Biotechnology
Volume50
Issue number1
DOIs
StatePublished - 2022

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) [No. 2020R1A4A3078645, No. 2021R1C1C1014606].

Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • Acute lymphoblastic leukaemia (ALL)
  • Cell penetrating 30Kc19 protein
  • Cleavable linker
  • Fusion protein
  • L-asparaginase (ASNase)
  • Matrix metalloproteinase (MMP)

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