Biodegradable nanoassemblies of piperlongumine display enhanced anti-angiogenesis and anti-tumor activities

Abstract

Piperlongumine (PL) shows an inhibitory effect on tumor growth; however, lipophilicity has restricted its further applications. Nanotechnology provides an effective method to overcome the poor water solubility of lipophilic drugs. Polymeric micelles with small particle size can passively target tumors by the enhanced permeability and retention (EPR) effect, thus improving their anti-tumor effects. In this study, to improve the water solubility and anti-tumor activity of PL, PL encapsulated polymeric micelles (PL micelles) were prepared by a solid dispersion method. The prepared PL micelles showed a small particle size and high encapsulation efficiency, which could be lyophilized into powder, and the re-dissolved PL micelles are homogenous and stable in water. In addition, a sustained release behavior of PL micelles was observed in vitro. Encapsulation of PL into polymeric micelles could increase the cytotoxicity, cellular uptake, reactive oxygen species (ROS) and oxidized glutathione (GSSG), and reduce glutathione (GSH) levels in vitro. Encapsulation of PL into polymeric micelles enhanced its inhibitory effect on neovascularization both in vitro and in vivo. Compared with free PL, PL micelles showed a stronger inhibitory effect on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). Additionally, in a transgenic zebrafish model, embryonic angiogenesis was inhibited by PL micelles. Furthermore, PL micelles were more effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT-26 murine tumor model in vivo. Therefore, our data revealed that the encapsulation of PL into biodegradable polymeric micelles enhanced its anti-angiogenesis and anti-tumor activities both in vitro and in vivo.

Piperlongumine induces apoptotic and autophagic death of the primary myeloid leukemia cells from patients via activation of ROS-p38/JNK pathways

“…Piperlongumine induced ROS accumulation in primary human myeloid leukemia cells PL is considered a cancer cell-specific ROS inducer [10] , and previous studies have demonstrated that PL induced ROS accumulation in various cancer cell lines [19][20][21] . We determined the level of intracellular ROS in PL-treated BMMNCs using the fluorescent ROS indicator DCFH-DA.…”

“…The final concentration of DMSO was less than 0.1%. N-acetyl-L-cysteine (NAC, antioxidant, Sigma- [20] 45, X, -X, t(8;21)(q22;q22) [20] 46, XX, t(9;22)(q34;q11) [60] 47, XX, t(10;11)(p12;q23)+mar [7] /46, XX [3] 46, XX, t(9;11)(p12;q23) [20] 46, XX, N [20] No split phase 46, XY, t(9;22)(q34;q11) [38] 46, XX [20] 46, XX, del(2)(p11), del(3)(p12), del(3)(p26), del(3)(q13), del(4)(q31), del(6)(p23), del(7)(q22q34), -10, del(12) (p12), del(13)(q12q14), +15, -16, -21, +mar[cp10] 46, XY [12] www.nature.com/aps Xiong XX et al Acta Pharmacologica Sinica npg Aldrich, St Louis, MI, USA) was used at 3 mmol/L, whereas SB203580 (P38 pathway-specific inhibitor, Cell Signaling Technology, Danvers, MA, USA) and SP600125 (JNK pathwayspecific inhibitor, Cell Signaling Technology) were used at 10 µmol/L. NAC, SB203580, and SP600125 were added 1 h before PL-treatment.…”

Enhanced antitumor activity and mechanism of biodegradable polymeric micelles-encapsulated chetomin in both transgenic zebrafish and mouse models

“…According to Fig. 9B-D, tumor volume, length of tumor-induced blood vessels and branch points of tumor-induced blood vessels were dramatically inhibited in Che-M group (3.70 AE 1.14 Â 10 À3 mm 3 and 167.7 AE 68.2 mm, 9.2 AE 4.0, respectively) compared with those in free chetomin (7.15 AE 1.59 Â 10 À3 mm 3 , P < 0.001; 337.0 AE 72.6 mm, P < 0.001; 18.5 AE 3.9, P < 0.001, respectively), blank micelles (12.78 AE 2.14 Â 10 À3 mm 3 , P < 0.001; 895.0 AE 136.8 mm, P < 0.001; 45.8 AE 5.8, P < 0.001, respectively), or normal saline (11.77 AE 2.11 Â 10 À3 mm 3 , P < 0.001; 840.7 AE 126.8 mm, P < 0.001; 42.0 AE 7.3, P < 0.001, respectively) group. The above results suggested that Che-M could dramatically inhibit both embryonic and tumor-induced angiogenesis.…”

“…Mice were injected subcutaneously with 100 mL of CT26 cell suspension containing 5 Â 10 5 cells in the right ank. When the volume of tumors was approximately 200 mm 3 , tumor bearing mice were randomized into three groups, which were injected intravenously with 100 mL…”

“…Small molecules with activities to alter reactive oxygen species (ROS) levels and cause oxidative stress to tumor cells have been proposed as treatment of tumors. [3][4][5] Therefore, it is a promising strategy by combining anti-angiogenesis with the effect of increasing cellular ROS level to achieve better therapeutic effect on tumors.…”