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

103 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

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Oncology
Prodrugs
Cell death
Tumors
Ethidium
Apoptosis
Imaging techniques
Cells
Neoplasms
Mitochondria
Chemical activation
Pharmaceutical Preparations
Bearings (structural)
Therapeutics
Organelles
Death Domain Receptors
Cell Death
Cytotoxicity
Heterografts
Fluorouracil

ASJC Scopus subject areas

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

Cite this

Mitochondrial induced and self-monitored intrinsic apoptosis by antitumor theranostic prodrug : In vivo imaging and precise cancer treatment. / Kumar, Rajesh; Han, Jiyou; Lim, Hee Joung; Ren, Wen Xiu; Lim, Ja Yun; Kim, Jong-Hoon; Kim, Jong Seung.

In: Journal of the American Chemical Society, Vol. 136, No. 51, 24.12.2014, p. 17836-17843.

Research output: Contribution to journalArticle

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