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Thermo-sensitive composite hydrogels based on poloxamer 407 and alginate and their therapeutic effect in embolization in rabbit VX2 liver tumors.

ABSTRACT: Interventional embolization therapy is an effective, most widely used method for inoperable liver tumors. Blood-vessel-embolic agents were essential in transarterial embolization (TAE). In this work, thermo-sensitive composite hydrogels based on poloxamer 407, sodium alginate, hydroxymethyl cellulose and iodixanol (PSHI), together with Ca2+ (PSHI-Ca2+) were prepared as liquid embolic agents for TAE therapy to liver cancer. With increasing temperature, PSHI exhibited two phase states: a flowing sol and a shrunken gel. Rheology tests showed good fluidity and excellent viscoelastic behavior with a gelation temperature (GT) of 26.5°C. The studies of erosion indicated that PSHI had calcium ion-related erosion characteristics and showed a slow erosion rate in an aqueous environment. When incubated with L929 cells, the thermo-sensitive composite hydrogels had low cytotoxicity in vitro. The results of analyzing the digital subtraction angiography and computed tomography images obtained from in vitro and in vivo assays indicated a good embolic effect in the renal arteries of normal rabbits. Angiography and histological studies on VX2 tumor-bearing rabbits indicated that PSHI-Ca2+ successfully occluded the tumors, including the peripheral vessels. In conclusion, PSHI-Ca2+ was a promising embolic agent for transarterial embolization therapy.

SUBMITTER: Huang L

PROVIDER: S-EPMC5341979 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionHepatocellular carcinoma is currently the second leading cause of cancer-related deaths worldwide with an increasing incidence.ObjectiveThe objective of this study is to investigate the effect of vascular endothelial growth factor small interfering RNA (VEGF-siRNA) on rabbit VX2 carcinoma cell viability in vitro and the effect of transarterial embolization (TAE)-mediated VEGF-siRNA delivery on the growth of rabbit VX2 liver-transplanted model in vivo.MethodsQuantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot technologies were used to detect the expression level of VEGF. TAE and computed tomography scan were used to deliver the VEGF-siRNA and detect the tumor volume in vivo, respectively. Microvessel density was detected by immunohistochemistry with CD34 antibody. A biochemical autoanalyzer was used to evaluate the hepatic and renal toxicity.ResultsThe designed VEGF-siRNAs could effectively decrease the expression levels of VEGF mRNA and protein in vitro and in vivo. In vitro, the viability of rabbit VX2 carcinoma cells was reduced by 38.5%±7.3% (VEGF-siRNA no 1) and 30.0%±5.8% (VEGF-siRNA no 3) at 48 hours after transfection. Moreover, in rabbit VX2 liver-transplanted model, the growth ratios of tumors at 28 days after TAE-mediated siRNA delivery were 155.18%±19.42% in the control group, 79.67%±19.63% in the low-dose group, and 36.09%±15.73% in the high-dose group, with significant differences among these three groups. Microvessel density dropped to 34.22±4.01 and 22.63±4.07 in the low-dose group and high-dose group, respectively, compared with the control group (57.88±5.67), with significant differences among these three groups. Furthermore, inoculation of VX2 tumor into the liver itself at later stage induced significant increase in alanine aminotransferase and aspartate aminotransferase, indicating an obvious damage of liver functions, while treatment of VX2 tumor via TAE-mediated VEGF-siRNA had no toxicity to the livers and kidneys of rabbits, and VEGF-siRNA had the ability to protect liver damage induced by tumor growth.ConclusionThis is the first study to demonstrate that targeting VEGF via TAE-mediated siRNA delivery may become a powerful new option for effective treatment of hepatocellular carcinoma in the clinic.

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Thermo-sensitive composite hydrogels based on poloxamer 407 and alginate and their therapeutic effect in embolization in rabbit VX2 liver tumors.

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