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Antiangiogenic and Apoptotic Properties of a Novel Amphiphilic Folate-Heparin-Lithocholate Derivative Having Cellular Internality for Cancer Therapy

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Abstract

Purpose

Anitangiogenic and apoptotic properties of a novel chemically modified heparin derivative with low anticoagulant activity were evaluated on the experimental in vitro and in vivo model.

Materials and Methods

Heparin-lithocholate conjugate (HL) was initially synthesized by covalently bonding lithocholate to heparin. Folate-HL conjugate (FHL) was further synthesized by conjugating folate to HL. Antiangiogenic and apoptotic abilities of HL and FHL were characterized in vitro and in vivo experimentations.

Results

Compared to unmodified heparin, both HL and FHL represented a low anticoagulant activity (38 and 28%, respectively). HL and FHL maintained antiangiogenic activity even further modification from the results of Matrigel plugs assay. FHL specifically induced apoptosis on KB cells having highly expressed folate receptor after cellular internalization. Both administered HL and FHL had similar antiangiogenic activity and inhibitory effect on tumor growth in vivo although FHL induced higher apoptosis on tumor tissues.

Conclusions

In vivo tumor growth inhibition was possibly due to the decrease of vessel density and apoptotic cell death, although antiangiogenic effect of FHL seemed more actively affected on growth inhibition than apoptotic potential in vivo system. Thus, Low anticoagulant FHL having antiangiogenic and apoptotic properties would provide benefits for the development of a new class of anticancer agent.

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Abbreviations

bFGF:

basic fibroblast growth factor

FBS:

fetal bovine serum

FHL:

folate-heparin-lithocholate

FITC:

fluorescein isothiocyanate

FR:

folate receptor

HL:

heparin-lithocholate

MTT:

(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide)

PBS:

phosphate buffered saline

PI:

propidium iodide

TUNEL:

terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling

UFH:

unfractionated heparin

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Acknowledgements

This study was supported by the grant from Next Generation New Technology Development Program of the Korean Ministry of Commerce, Industry, and Energy (Grant no. 10011353).

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Authors and Affiliations

  1. Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, 500-712, South Korea

    Mi Kyung Yu

  2. College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, 151-742, South Korea

    Dong Yun Lee & Youngro Byun

  3. Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, 700-422, South Korea

    Yoo Shin Kim, In San Kim & Rang Woon Park

  4. Biomedical Research Center, Korea Institute of Science and Technology, Seoul, 136-791, South Korea

    Kyeongsoon Park

  5. Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, 138-736, South Korea

    Soo Ah Park, Dai Hyun Son & Sang Yoon Kim

  6. Department of Materials Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 500-712, South Korea

    Gee Young Lee

  7. Department of Pathology, School of Medicine, Chonnam National University, Gwangju, 500-757, South Korea

    Jong Hee Nam

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  1. Mi Kyung Yu
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  9. Sang Yoon Kim
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  12. Youngro Byun
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Correspondence to Youngro Byun.

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These authors contributed equally to this work as first authors.

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Yu, M.K., Lee, D.Y., Kim, Y.S. et al. Antiangiogenic and Apoptotic Properties of a Novel Amphiphilic Folate-Heparin-Lithocholate Derivative Having Cellular Internality for Cancer Therapy. Pharm Res 24, 705–714 (2007). https://doi.org/10.1007/s11095-006-9190-3

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  • DOI: https://doi.org/10.1007/s11095-006-9190-3

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