IQCA-TASS: a nano-scaled P-selectin inhibitor capable of targeting thrombus and releasing IQCA/TARGD(S)S in vivo

Wu, Jianhui; Zhu, Haimei; Zhao, Ming; Wang, Yuji; Yang, Guodong; Wang, Yaonan; Zhao, Shunying; Gui, Lin; Zhang, Xiaoyi; Peng, Shiqi

doi:10.1039/c6tb02705a

Cited by 12 publications

(9 citation statements)

References 41 publications

(22 reference statements)

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“…The self-assembly of small molecule has been well documented 43–45. Here, the self-assembly of RGDV-gemcitabine in ultrapure water (1 nM) was explored with its FT(+)-MS spectrum.…”

Section: Resultsmentioning

confidence: 99%

“…It has been demonstrated that RGD-peptide-containing molecules could form nanoparticles having targeting action;43–45 therefore, we hypothesized that by forming nano-particles, RGDV-gemcitabine could target the tumor tissue of the treated S180 tumor-bearing mice. In this regard, the extracts of the homogenates of the tumor tissue, the brain, the heart, the lung, the liver, the spleen, the kidney and the blood of S180 mice treated with NS and 8.4 μmol/kg/day of RGDV-gemcitabine received FT(+)-MS spectrum analysis.…”

Section: Resultsmentioning

confidence: 99%

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RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine

Liu¹,

Mao²,

Zhang³

et al. 2019

IJN

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BackgroundGemcitabine has been widely used as a chemotherapeutic drug. However, drug resistance, short half-life and side effects seriously decrease its chemotherapeutic efficacy.PurposeThe object of preparing RGDV-gemcitabine was to prolong the half-life, to overcome drug resistance and to eliminate bone marrow toxicity of gemcitabine.MethodsArg-Gly-Asp-Val was coupled with gemcitabine, forming 4-(Arg-Gly-Asp-Val-amino)-1-[3,3-difluoro-4-hydroxy-5-(hydroxylmethyl)oxo-lan-2-yl]pyrimidin-2-one (RGDV-gemcitabine) involving 9-step reactions. The advantages of RGDV-gemcitabine to gemcitabine were demonstrated by a series of assays, such as in vitro half-life assay, in vitro drug resistance assay, in vivo anti-tumor assay, in vivo kidney toxicity assay, in vivo liver toxicity assay and in vivo marrow toxicity assay. The nano-features of RGDV-gemcitabine were visualized by TEM, SEM and AFM images. The tumor-targeting action and release of RGDV-gemcitabine were evidenced by FT-MS spectra.ResultsHalf-life and anti-tumor activity of RGDV-gemcitabine were 17-fold longer and 10-fold higher than that of gemcitabine, respectively. RGDV-gemcitabine, but not gemcitabine, showed no kidney toxicity, no liver toxicity, no marrow toxicity and no drug resistance. The advantages attributed to the nanofeatures of RGDV-gemcitabine were targeting tumor tissue and releasing gemcitabine in tumor tissue.ConclusionRGDV-gemcitabine successively overcame the defects of gemcitabine and provided a practical strategy of nano-medicine.

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“…The self-assembly of small molecule has been well documented 43–45. Here, the self-assembly of RGDV-gemcitabine in ultrapure water (1 nM) was explored with its FT(+)-MS spectrum.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine

Liu¹,

Mao²,

Zhang³

et al. 2019

IJN

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“…To explore the manner of MTCA-KKV forming a dimer, the NOESY 2D NMR spectrum was measured 54. In Figure 2C, two interesting cross-peaks are marked with red circles.…”

Section: Resultsmentioning

confidence: 99%

Nano-scaled MTCA-KKV: for targeting thrombus, releasing pharmacophores, inhibiting thrombosis and dissolving blood clots in vivo

Zhao¹,

Li²,

Huang³

et al. 2019

IJN

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Background In vitro (1R,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxyl-Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (MTCA-KKV) adheres activated platelets, targets P-selectin and GPIIb/IIIa. This led to the development of MTCA-KKV as thrombus targeting nano-medicine. Methods MTCA-KKV was characterized by nano-feature, anti-thrombotic activity, thrombolytic activity, thrombus target and targeting release. Results In vivo 0.01 μmol/kg of MTCA-KKV formed nano-particles less than 100 nm in diameter, targeted thrombus, released anti-thrombotic and thrombolytic pharmacophores, prevented thrombosis and dissolved blood clots. Conclusion Based on the profiles of targeting thrombus, targeting release, inhibiting thrombosis and dissolving blood clots MTCA-KKV is a promising nano-medicine.

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“…The docking of 4 classes of anti-tumor β-carbolines and 3 classes of anti-thrombotic tetrahydro-β-carbolines from our sample library towards the active site of P-selectin led to the rational design, and THPDTPI was theoretically assigned a promising inhibitor of P-selectin. Recently the importance of the interactions between the inhibitor with Tyr48 and Tyr94 residues of the active site of P-selectin were disclosed [ 33 ]. The docking showed that THPDTPI can target P-selectin by forming π-π interactions with Tyr44, Tyr48 and Tyr94 residues of its active site, and in turn the emphasis was placed on the contribution of these π-π interactions to THPDTPI targeting P-selectin.…”

Section: Discussionmentioning

confidence: 99%

Docking of THPDTPI: to explore P-selectin as a common target of anti-tumor, anti-thrombotic and anti-inflammatory agent

Zhu

Wang

Song³

et al. 2017

Oncotarget

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The impact of soluble P-selectin on tumor growth, thrombosis and inflammation has been individually documented. Whether the down-regulation of P-selectin expression can simultaneously slow the tumor growth, inhibit the thrombosis and attenuate the inflammatory response remains unknown. In this context, (2′S,5′S)- tetrahydropyrazino[1’,2’:1,6]-di{2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole}-1’,4’-dione (THPDTPI) was designed as an inhibitor of P-selectin. The suitable docking of THPDTPI towards the active site of P-selectin, the significant down-regulation of THPDTPI to P-selectin expression, and the direct action of THPDTPI on P-selectin suggest that P-selectin could be a target of THPDTPI. In vivo THPDTPI possesses the anti-tumor activity, the anti-thrombotic activity and the anti-inflammatory activity. This implies that targeting P-selectin is of essential importance for this triple activity. The minimal effective doses of THPDTPI inhibiting the tumor growth, the rat arterial thrombosis and the mouse ear edema are 0.01 μmol/kg, 0.1 μmol/kg and 0.001 μmol/kg, respectively. Atomic force microscopy images and FT-MS spectra showed that the adhesion of THPDTPI onto the surfaces of the platelets may be the first step of P-selectin targeting. Besides, the dependence of the triple action of THPDTPI inhibiting the tumor growth, the thrombosis and the inflammation on the decrease of the soluble P-selectin led to the correlation of the soluble P-selectin with the serum TNF-α and serum IL-8.

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IQCA-TASS: a nano-scaled P-selectin inhibitor capable of targeting thrombus and releasing IQCA/TARGD(S)S in vivo

Cited by 12 publications

References 41 publications

<p>RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine</p>

<p>RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine</p>

<p>Nano-scaled MTCA-KKV: for targeting thrombus, releasing pharmacophores, inhibiting thrombosis and dissolving blood clots in vivo</p>

Docking of THPDTPI: to explore P-selectin as a common target of anti-tumor, anti-thrombotic and anti-inflammatory agent

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