Multi-stage inhibition in breast cancer metastasis by orally active triple conjugate, LHTD4 (low molecular weight heparin-taurocholate-tetrameric deoxycholate)

Biomaterials
Farzana AlamYoungro Byun

Abstract

Targeting multiple stages in metastatic breast cancer is one of the effective ways to inhibit metastatic progression. To target human metastatic breast cancer as well as improving patient compliance, we developed an orally active low molecular weight heparin (LMWH)-taurocholate conjugated with tetrameric deoxycholic acid, namely LHTD4, which followed by physical complexation with a synthetic bile acid enhancer, DCK. In breast cancer, both transforming growth factor-β1 (TGF-β1) and CXCL12 exhibit enhanced metastatic activity during the initiation and progression stages of breast cancer, thus we direct the focus on investigating the antimetastatic effect of LHTD4/DCK complex by targeting TGF-β1 and CXCL12. Computer simulation study and SPR analysis were performed for the binding confirmation of LHTD4 with TGF-β1 and CXCL12. We carried out in vitro phosphorylation assays of the consecutive receptors of TGF-β1 and CXCL12 (TGF-β1R1 and CXCR4, respectively). Effects of LHTD4 on in vitro cell migration (induced by TGF-β1) and chemotaxis (mediated by CXCL12) were investigated. The in vivo anti-metastatic effect of LHTD4 was evaluated in an accelerated metastasis model and an orthotopic MDA-MB-231 breast cancer model. The obtained KD va...Continue Reading

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Citations

Oct 26, 2016·Glycoconjugate Journal·Nikos A AfratisAchilleas D Theocharis
Jun 17, 2020·Cell Adhesion & Migration·Sai-Nan MaJin-Hai Tang
Jul 29, 2017·Molecular Cancer Research : MCR·Muralidharan AnbalaganBrian G Rowan
Oct 25, 2020·Cancers·Karolina A Zielińska, Vladimir L Katanaev
Apr 3, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Xiaoyan GuNianping Feng
Oct 30, 2018·Bioconjugate Chemistry·Sumeet ManandharSeung Rim Hwang

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