Tumor-specific release of copper-incorporated diethyldithiocarbamate from an optimized apoferritin scaffold enables both potent and safe anti-cancer therapy

Ok Jeong Moon, Chul Joo Yoon, Jun Soo Lee, Hye Hyun Kim, Yong Hwan Seol, Jeewon Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Here we successfully resolved both off-target toxicity and multidrug resistance (MDR) problems, which remain a major challenge in traditional cancer chemotherapy, by adopting an optimized scaffold-conjugated drug - copper ion-incorporated diethyldithiocarbamate (Cu-DDC2) with both permeability-glycoprotein inhibiting- and anti-cancer activities. Cu-DDC2 molecules were loaded onto a human apoferritin-derived, optimized scaffold (AF) in a large quantity (∼120 molecules/AF), which simultaneously enables 1) targeted delivery of the loaded Cu-DDC2 to tumor cells and 2) toxification of Cu-DDC2 only inside tumor cells to eliminate off-target toxicity, the latter being based on tumor cell-specific, proteolytic release of Cu-DDC2 from the AF. Consequently, the AF-conjugated Cu-DDC2 led to notable repression of both human pancreatic and gastric cancer growth in xenograft mice without causing pathological abnormalities in normal tissues/cells. This approach is expected to open up a novel, attractive clinical route for both potent and safe cancer therapy.

Original languageEnglish
Article number145176
JournalChemical Engineering Journal
Volume473
DOIs
Publication statusPublished - 2023 Oct 1

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (Grant No. NRF2019R1A2C3005771). All mice were maintained and handled under the protocol approved by the Korea University Institutional Animal Care and Use Committee (KUIACUC-2021-0030). All animal procedures were performed in accordance with recommendations for the proper use and care of laboratory animals.

Publisher Copyright:
© 2023 Elsevier B.V.

Keywords

  • Cancer cell-specific activation
  • Copper ion-incorporated diethyldithiocarbamate (Cu-DDC)
  • Human apoferritin
  • Multidrug resistance (MDR)
  • Off-target toxicity

ASJC Scopus subject areas

  • General Chemistry
  • Environmental Chemistry
  • General Chemical Engineering
  • Industrial and Manufacturing Engineering

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