In Vitro Anticancer Effect of Combretastatin A4 Liposomes in Destruction of Vascular Mimicry in Triple- Negative Breast Cancer Cells / 中国药学杂志

OBJECTIVE: To investigate the potential anticancer effect of combretastatin A4 liposomes (SSL-CA4) in destruction of vascular mimicry (VM) in MDA-MB-231 breast cancer cells in vitro. METHODS: The in vitro inhibitory effect and blocking woundhealing effect of SSL-CA4 were investigated. The VM destruction of SSL-CA4 was evaluated in three dimensional matrigel culture model in MDA-MB-231 cells. The in vitro inhibitory test showed that the maxium inhibition ratio of SSL-CA4 on MDA-MB-231 cells was close to 50%. SSL-CA4 blocked the wound-healing of MDA-MB-231 cells, which was similar to free CA4. RESULTS: SSL-CA4 could inhibit the formation of VM in vitro via inhibition on the VM channel indicators including hypoxia-inducible factor (HIF-α), vascular endothelial- cadherin (VE-Cad), and matrix metallopeptidases (MMP-2). The inhibition on indicators of SSL-CA4 was significantly higher than CA4 treatment groups (P <0.05). CONCLUSION: SSL-CA4 has significant anticancer activity via inhibition of VM in MDA-MB-231 cell line.

Simultaneously determining the contents of combretastatin A4 myristate and its active metabolite combretastatin A4 by HPLC / 国际药学研究杂志

Objective To develop a high performance liquid chromatography(HPLC)method for simultaneously determining the contents of combretastatin A4 myristate(CA4-14)and its active metabolite combretastatin A4(CA4)in rat plasma. Methods 1-Naphthol was used as internal standard. The analysis was performed on a Agilent Eclipse plus C18(4.6 mm × 250 mm,5μm )with gra?dient elution by using the mobile phase of acetonitrile(A)-0.4%formic acid solution(B). The column temperature was 30° C and the flow rate was 1.0 ml/min. The detection wavelength was 295 nm and the injection volume was 20μl. Results The calibration curves were linear within the range of 0.2-100μg/ml(r2=0.9980)for CA4-14,and 0.05-50μg/ml(r2=0.9999)for CA4,while the quantifica?tion limits of CA4-14 and CA4 were 0.2μg/ml and 0.01μg/ml,respectively. The recoveries of CA4-14 and CA4 were 93.79%(RSD=1.94%)and 96.81%(RSD=3.11%). Conclusion The method is convenient,fast,sensitive,with good precision,and can be used to determine the contents of CA4-14 and C A4 in rat plasma.

Nanoformulations of the vascular inhibitors: Combretastatin A4 and combretastatin A4 phosphate / 国际药学研究杂志

Combretastatin A4 (CA4), a vascular inhibitor, can target tubulin and inhibit tubulin polymerization, thus it can inhibit the tumor blood vessels and has antitumor effect. But it is insoluble in water and has low bioavailability. CA4 phosphate (CA4P), the derivative of CA4, can improve the solubility of CA4 and convert into CA4. CA4P is undergoing phase II/III clinical trials abroad. However, CA4P has several undesirable side effects and relative short half-life in vivo. Nanoformulations can increase the dissolution and absorption of the drug and obtain controlled release and targeting, prolong the efficacy and reduce side effects. Working on the physical and chemical characteristics and biological pharmacy defects of CA4 and CA4P nanoformulations may change the dissolution, absorption and distribution of the drug. This paper reviews the current nanoformulations of CA4 and CA4P, including den-drimer, polymeric micelle (PM), nanoparticles (NP), long-circulating liposome (LCL), and discusses the prospects of their nanoformulations.

Simultaneously determining the contents of combretastatin A4 myristate and its active metabolite combretastatin A4 by HPLC / 国际药学研究杂志

Objective To develop a high performance liquid chromatography (HPLC)method for simultaneously determining the contents of combretastatin A4 myristate(CA4-14)and its active metabolite combretastatin A4 (CA4) in rat plasma. Methods 1- Naphthol was used as internal standard. The analysis was performed on a Agilent Eclipse plus C18(4.6 mm × 250 mm, 5 μm) with gradient elution by using the mobile phase of acetonitrile (A)-0.4% formic acid solution(B). The column temperature was 30°C and the flow rate was 1.0 ml/min. The detection wavelength was 295 nm and the injection volume was 20 μl. Results The calibration curves were linear within the range of 0.2-100 μg/ml (r2=0.9980) for CA4-14, and 0.05-50 μg/ml(r2=0.9999)for CA4, while the quantification limits of CA4-14 and CA4 were 0.2 μg/ml and 0.01 μg/ml, respectively. The recoveries of CA4-14 and CA4 were 93.79% (RSD= 1.94%) and 96.81% (RSD=3.11%). Conclusion The method is convenient, fast, sensitive, with good precision, and can be used to determine the contents of CA4-14 and C A4 in rat plasma.

Nanoformulations of the vascular inhibitors:combretastatin A4 and combretastatin A4 phosphate / 国际药学研究杂志

Combretastatin A4(CA4),a vascular inhibitor,can target tubulin and inhibit tubulin polymerization,thus it can inhibit the tumor blood vessels and has antitumor effect. But it is insoluble in water and has low bioavailability. CA 4 phosphate (CA4P),the derivative of CA4,can improve the solubility of CA4 and convert into CA4. CA4P is undergoing phaseⅡ/Ⅲclinical tri?als abroad. However,CA4P has several undesirable side effects and relative short half-life in vivo. Nanoformulations can increase the dissolution and absorption of the drug and obtain controlled release and targeting,prolong the efficacy and reduce side effects. Work?ing on the physical and chemical characteristics and biological pharmacy defects of CA4 and CA4P,nanoformulations may change the dissolution,absorption and distribution of the drug. This paper reviews the current nanoformulations of CA4 and CA4P,including den?drimer,polymeric micelle(PM),nanoparticles(NP),long-circulating liposome(LCL),and discusses the prospects of their nanofor?mulations.

Charge-reversal nanoparticles: novel targeted drug delivery carriers

Spurred by significant progress in materials chemistry and drug delivery, charge-reversal nanocarriers are being developed to deliver anticancer formulations in spatial-, temporal- and dosage-controlled approaches. Charge-reversal nanoparticles can release their drug payload in response to specific stimuli that alter the charge on their surface. They can elude clearance from the circulation and be activated by protonation, enzymatic cleavage, or a molecular conformational change. In this review, we discuss the physiological basis for, and recent advances in the design of charge-reversal nanoparticles that are able to control drug biodistribution in response to specific stimuli, endogenous factors (changes in pH, redox gradients, or enzyme concentration) or exogenous factors (light or thermos-stimulation).

Molecular mechanisms of combretastatin A-4 amino sugar derivative CPU-XT-008 on inhibiting proliferation of vascular endothelial cells / 中国药科大学学报

Taking human umbilical vein endothelial cells (HUVEC)as experimental model which can simulate tumor-derived vascular endothelial cells;the effects of CPU-XT-008;an amino sugar derivative of combretastatin A-4 (CA-4);on HUVEC proliferation;cell cycle distribution;tubulin polymerization and the key regulatory pro-tein of cell cycle were studied.The effect of CPU-XT-008 on the proliferation of HUVEC was determined by MTT assay.The cell cycle distribution caused by CPU-XT-008 was detected by flow cytometry.Immunofluorescence was used to detect apoptosis and tubulin polymerization.The expressions of Cyclin B1;Cdc2 and β-tubulin were detected by Western blotting.Results demonstrated that CPU-XT-008 could target tubulin and inhibit the poly-merization ofβ-tubulin;and it could lead to G2/M cell cycle arrest in HUVEC by up-regulating Cyclin B1 expres-sion and down-regulating Cdc2 and p-Cdc2 expression;which resulted in inhibiting the proliferation of HUVEC and inducing its apoptosis.