DHDMIQK(KAP): a novel nano-delivery system of dihydroxyl-tetrahydro-isoquinoline-3-carboxylic acid and KPAK towards the thrombus

Wang

Song³

et al. 2017

Oncotarget

Self Cite

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.

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Wang

Song³

et al. 2017

Oncotarget

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“…For instance, targeting Arg-Gly-Asp-Ser, thymopentin and Lys(Pro-Ala-Lys) were used to carry dexamethasone, 1,2 VEGF-siRNA/nanodiamond, 3,4 1,1-dimethyl tetrahydro-βcarboline-3-carboxylic acid, 5 and 6,7-dihydroxy-1,1-dimethy l-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (IQCA), 6 respectively. For instance, targeting Arg-Gly-Asp-Ser, thymopentin and Lys(Pro-Ala-Lys) were used to carry dexamethasone, 1,2 VEGF-siRNA/nanodiamond, 3,4 1,1-dimethyl tetrahydro-βcarboline-3-carboxylic acid, 5 and 6,7-dihydroxy-1,1-dimethy l-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (IQCA), 6 respectively.…”

Section: Introductionmentioning

confidence: 99%

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

Zhao

et al. 2017

J. Mater. Chem. B

Self Cite

Thrombosis seriously threatens human health worldwide. Tetrahydroisoquinoline-3-carboxylic acid (IQCA) is an antithrombotic agent, while Thr-Ala-Arg-Gly-Asp(Ser)-Ser (TASS) can target thrombus. In the discovery of nano-delivery system for targeting thrombus tetrahydroisoquinoline-3-carbonyl-Thr-Ala-Arg-Gly-Asp(Ser)-Ser (IQCA-TASS) was designed here. In vitro IQCA-TASS acted on P-selectin and down-regulated P-selectin expression. The IC 50 values of IQCA-TASS against the platelet aggregation induced by four aggregators were less than 0.45 nM.In vivo IQCA-TASS targeted thrombus, released IQCA and TASS inside thrombus, showed dose-dependent anti-thrombotic action, of which the minimal effective dose was 1 nmol/kg, and showed anti-inflammatory action. Even the dose been up to 1 μmol/kg, a dose of 1000 times of the minimal effective dose, IQCA-TASS still induced no toxic reaction. In rat plasma IQCA-TASS forms the nanoparticles of less than 41 nm in diameter. The interactions of the nanoparticles with both resting and activated platelets were imaged. In conclusion, IQCA-TASS should be a safe nano-medicine capable of targeting thrombus and releasing the anti-thrombotic/anti-inflammatory pharmacophores in the disease site.

“…However there still is no compound to associate the impact of down-regulating P-selectin, GPIIb/IIIa, IL-2, IL-6 and IL-8 on DVT therapy. In this context this paper analyzed the structural characteristics such as Arg-Gly-Asp-Val of anti-platelet aggregation agent aspirin-Arg-Gly-Asp-Val [ 34 ], dihydroxyl-tetrahydroisoquinoline-3-carboxylic acid of a P-selectin down-regulator dihydroxyl-tetrahydroisoquinoline-3-carbonyl-Lys-Pro-Ala-Lys [ 35 ], Thr-Ala-Arg-Gly-Asp(Ser)-Ser of a GPIIb/IIIa down-regulator N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-Thr-Ala-Arg-Gly-Asp(Ser)-Ser [ 36 ], and tetrahydro-β-carboline-3-carboxylic acid of an anti-inflammatory agent tetrahydro-β-carboline-3-carboxyl-thymopentin [ 37 ] to design N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-Thr-Ala-Arg-Gly-Asp(Val)-Val (IQCA-TAVV) as a novel inhibitor for essential evaluations and thereby to associate the contribution of the down- regulation of P-selectin, GPIIb/IIIa, IL-2, IL-6 and IL-8 to DVT inhibition.…”

Section: Introductionmentioning

confidence: 99%

IQCA-TAVV: To explore the effect of P-selectin, GPIIb/IIIa, IL-2, IL-6 and IL-8 on deep venous thrombosis

Yang

et al. 2017

Oncotarget

Self Cite

Deep vein thrombosis (DVT) associates with considerable morbidity, functional disability and mortality. Due to the lack of suitable inhibitor the correlation of various factors in DVT onset remains unknown. In this context we analyzed the structure of anti-platelet aggregation agent, P-selectin down-regulator, GPIIb/ IIIa down-regulator and anti-inflammatory agent, thereby designed N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-Thr-Ala-Arg-Gly-Asp(Val)-Val (IQCA-TAVV) as an inhibitor of DVT to receive evaluations. The docking predicted that IQCA-TAVV can target P-selectin and GPIIb/IIIa. The UV showed that IQCA-TAVV can act on P-selectin and GPIIb/IIIa. ELISA indicated that IQCA-TAVV concentration dependently inhibited activated platelets to express P-selectin and GPIIb/IIIa, and the minimal effective concentration was 1 nM. IC 50 of IQCA-TAVV against platelet aggregation induced by arachidonic acid, adenosine diphosphate and platelet activating factor fell within a range of 0.13 nM to 0.30 nM. In vivo IQCA-TAVV dose-dependently inhibited venous thrombosis and the minimal effective dose was 1 nmol/kg. On ear edema model the anti-inflammation activity of 10 nmol/kg IQCA-TAVV equaled that of 1.1mmol/kg aspirin. The concentration of IL-2, IL-6 and IL-8 in the serum of the ear edema mice were also significantly decreased by 10 nmol/kg IQCA-TAVV. Even at 1 μmol/kg of dose IQCA-TAVV still did not injure the kidney, the liver, and the nerves of healthy mice. Thereby IQCA-TAVV depicts a relationship of three levels (inhibiting platelet activation, targeting externalized membrane receptor, decreasing serum inflammatory factor) for the down-regulation of P-selectin, GPIIb/IIIa, IL-2, IL-6 and IL-8 in DVT.