title: Chemical principles for the design of a novel fluorescent probe with high cancer-targeting selectivity and sensitivity.
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.
authors: Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan. tcchang@po.iams.sinica.edu.tw.
authors: Chi-Chih
authors: CC
authors: Kang
authors: Wei-Chun
authors: WC
authors: Huang
authors: Chiung-Wen
authors: CW
authors: Kouh
authors: Zi-Fu
authors: ZF
authors: Wang
authors: Chih-Chien
authors: CC
authors: Cho
authors: Cheng-Chung
authors: CC
authors: Chang
authors: Chiung-Lin
authors: CL
authors: Wang
authors: Ta-Chau
authors: TC
authors: Chang
authors: Joachim
authors: J
authors: Seemann
authors: Lily Jun-shen
authors: LJ
authors: Huang
mesh_terms: D045744:Cell Line, Tumor; D003287:Contrast Media / Q000138:chemical synthesis; D015195:Drug Design; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D006801:Humans; D015336:Molecular Probe Techniques; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D058990:Molecular Targeted Therapy / Q000379:methods*; D009374:Neoplasms, Experimental / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D003287:Contrast Media; D005456:Fluorescent Dyes; D015335:Molecular Probes
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