Chemical principles for the design of a novel fluorescent probe with high cancer-targeting selectivity and sensitivity

Chi Chih Kang, Wei Chun Huang, Chiung Wen Kouh, Zi Fu Wang, Chih Chien Cho, Cheng Chung Chang, Chiung Lin Wang, Ta Chau Chang, Joachim Seemann, Lily Jun Shen Huang

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Understanding of principles governing selective and sensitive cancer targeting is critical for development of chemicals for cancer diagnostics and treatment. We determined the underlying mechanisms of how a novel fluorescent small organic molecule, 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC), selectively labels cancer cells but not normal cells. We show that BMVC is retained in the lysosomes of normal cells. In cancer cells, BMVC escapes lysosomal retention and localizes to the mitochondria or to the nucleus, where DNA-binding dramatically increases BMVC fluorescence intensity, allowing it to light up only cancer cells. Structure-function analyses of BMVC derivatives show that hydrogen-bonding capacity is a key determinant of lysosomal retention in normal cells, whereas lipophilicity directs these derivatives to the mitochondria or the nucleus in cancer cells. In addition, drug-resistant cancer cells preferentially retain BMVC in their lysosomes compared to drug-sensitive cancer cells, and BMVC can be released from drug-resistant lysosomes using lysosomotropic agents. Our results further our understanding of how properties of cellular organelles differ between normal and cancer cells, which can be exploited for diagnostic and/or therapeutic use. We also provide physiochemical design principles for selective targeting of small molecules to different organelles. Moreover, our results suggest that agents which can increase lysosomal membrane permeability may re-sensitize drug-resistant cancer cells to chemotherapeutic agents.

Original languageEnglish (US)
Pages (from-to)1217-1228
Number of pages12
JournalIntegrative Biology (United Kingdom)
Volume5
Issue number10
DOIs
StatePublished - Oct 2013

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Fluorescent Dyes
Cells
Neoplasms
Mitochondria
Lysosomes
Pharmaceutical Preparations
Organelles
Derivatives
Molecules
Labels
Hydrogen bonds
Therapeutic Uses
Hydrogen Bonding
Fluorescence
Membranes
Permeability
DNA
Light

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Cite this

Chemical principles for the design of a novel fluorescent probe with high cancer-targeting selectivity and sensitivity. / Kang, Chi Chih; Huang, Wei Chun; Kouh, Chiung Wen; Wang, Zi Fu; Cho, Chih Chien; Chang, Cheng Chung; Wang, Chiung Lin; Chang, Ta Chau; Seemann, Joachim; Huang, Lily Jun Shen.

In: Integrative Biology (United Kingdom), Vol. 5, No. 10, 10.2013, p. 1217-1228.

Research output: Contribution to journalArticle

Kang, Chi Chih ; Huang, Wei Chun ; Kouh, Chiung Wen ; Wang, Zi Fu ; Cho, Chih Chien ; Chang, Cheng Chung ; Wang, Chiung Lin ; Chang, Ta Chau ; Seemann, Joachim ; Huang, Lily Jun Shen. / Chemical principles for the design of a novel fluorescent probe with high cancer-targeting selectivity and sensitivity. In: Integrative Biology (United Kingdom). 2013 ; Vol. 5, No. 10. pp. 1217-1228.
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