Mitochondrial induced and self-monitored intrinsic apoptosis by antitumor theranostic prodrug: In vivo imaging and precise cancer treatment

Rajesh Kumar, Jiyou Han, Hee Joung Lim, Wen Xiu Ren, Ja Yun Lim, Jong-Hoon Kim, Jong Seung Kim

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Activation of apoptosis, the cell death machinery, in tumor cells by organelle-specific delivery of antitumor theranostic agent is the utmost challenge in cancer therapy. Herein, we developed a highly efficient mitochondria-targeting antitumor theranostic prodrug 7 that contained two molecules of drug 5′-deoxy-5-fluorouridine and an apoptotic marker ethidium for self-monitoring intrinsic (mitochondrial) apoptosis after its activation in tumor cells. Theranostic 7 was activated by endogenously produced mitochondrial-overexpressed H2O2 and released drug 5′-deoxy-5-fluorouridine and apoptotic marker ethidium to the tumor cells. The in vitro and in vivo drug release was monitored by observing the fluorescence changes of ethidium. Theranostic 7 exhibited an enhanced cytotoxicity over commercial 5-fluorouracil (an active drug of 5′-deoxy-5-fluorouridine) leading to intrinsic apoptosis monitored by in situ generated ethidium. Enhanced expression of mitochondria-mediated apoptotic genes (NOXA, PUMA, BID, BAX, and BAK), Cyt C, Caspase-3 and -9, and cell surface death receptors was observed after theranostic 7 activation in tumor cells. In vivo and ex vivo xenografts revealed that theranostic 7 significantly inhibited tumor progression and cured the tumor-bearing mice. Such organelle-specific theranostic strategies have great potential for the early diagnosis and precise treatment of cancer.

Original languageEnglish
Pages (from-to)17836-17843
Number of pages8
JournalJournal of the American Chemical Society
Volume136
Issue number51
DOIs
Publication statusPublished - 2014 Dec 24

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

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