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Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice.

ABSTRACT: Barriers presented by the tumor microenvironment including the abnormal tumor vasculature and interstitial matrix invariably lead to heterogeneous distribution of nanotherapeutics. Inspired by the close association between cyclooxygenase-2 (COX-2) and tumor-associated angiogenesis, as well as tumor matrix formation, we proposed that tumor microenvironment normalization by COX-2 inhibitors might improve the distribution and efficacy of nanotherapeutics for solid tumors. The present study represents the first time that celecoxib, a special COX-2 inhibitor widely used in clinics, was explored to normalize the tumor microenvironment and to improve tumor nanotherapeutics delivery using a human-derived A549 tumor xenograft as the solid tumor model. Immunofluorescence staining of tumor slices demonstrated that oral celecoxib treatment at a dose of 200?mg/kg for two weeks successfully normalized the tumor microenvironment, including tumor-associated fibroblast reduction, fibronectin bundle disruption, tumor vessel normalization, and tumor perfusion improvement. Furthermore, it also significantly enhanced the in vivo accumulation and deep penetration of 22-nm micelles rather than 100-nm nanoparticles in tumor tissues by in vivo imaging and distribution experiments and improved the therapeutic efficacy of paclitaxel-loaded micelles in tumor xenograft-bearing mouse models in the pharmacodynamics experiment. As celecoxib is widely and safely used in clinics, our findings may have great potential in clinics to improve solid tumor treatment.

SUBMITTER: Zhang B

PROVIDER: S-EPMC5577220 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice.

Zhang Bo B Jin Kai K Jiang Ting T Wang Lanting L Shen Shun S Luo Zimiao Z Tuo Yanyan Y Liu Xianping X Hu Yu Y Pang Zhiqing Z

Scientific reports 20170830 1

Barriers presented by the tumor microenvironment including the abnormal tumor vasculature and interstitial matrix invariably lead to heterogeneous distribution of nanotherapeutics. Inspired by the close association between cyclooxygenase-2 (COX-2) and tumor-associated angiogenesis, as well as tumor matrix formation, we proposed that tumor microenvironment normalization by COX-2 inhibitors might improve the distribution and efficacy of nanotherapeutics for solid tumors. The present study represen ...[more]

PMID: 28855534

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Project description:BackgroundLung cancer is the most prevalent and deadly tumors around the world. Here we aimed to investigate the effect of wogonoside (also called baicalin) on the invasion and migration of lung cancer A549 cells and angiogenesis in xenograft tumors in nude mice.MethodsA549 cells of lung cancer were treated with different doses of wogonoside. After 24 h, CCK8 was used to detect the survival rate of cells. The non-toxic doses of wogonoside (0, 10, 25, and 50 µM) were selected for subsequent experiments. Transwell and scratch assays were used to detect invasion and migration. The number of microtubule nodules was detected by microtubule formation experiment, and the expressions of VEGF, E-cadherin, N-cadherin, and Vimentin were detected by Western blotting. BALB/c nude mice were subcutaneously injected with lung cancer A549 cells to establish the xenograft model, followed by intraperitoneal injection of 80 mg/kg of wogonoside. After 30 days, tumor volume was measured, and the levels of VEGF and vimentin were detected with immunohistochemistry. The level of CD34 was determined by flow sorting.ResultsA549 cell survival decreased in a concentration-dependent manner, with the survival rate significantly reduced when the concentration of wogonoside exceeded 100 µM (P<0.05). A549 cell invasion and the number of microtubule nodules were significantly lower in the wogonoside 20 µM and the wogonoside 50 µM groups (P<0.05) compared with the wogonoside 0 µM group, while the rate of scratch closure and the protein levels of VEGF, N-cadherin, and Vimentin were all significantly reduced (P<0.05), and the expression level of E-cadherin was significantly increased (P<0.05). Compared with the control group, the tumor volumes of wogonoside (80 mg/kg) treated mice were significantly reduced after 30 days (P<0.05), and the levels of VEGF and vimentin positive cells were significantly reduced (P<0.05), as was the level of CD34 (P<0.05).ConclusionsWogonoside can inhibit the invasion and migration of lung cancer A549 cells and angiogenesis of xenograft tumors in nude mice.

Project description:Cancers originating from the digestive system account for 290,000 or ~20% of all new cancer cases annually in the US. We previously developed paclitaxel-loaded tumor-penetrating microparticles (TPM) for intraperitoneal (IP) treatment of peritoneal tumors (Lu et al., 2008; Tsai et al., 2007; Tsai et al., 2013). TPM is undergoing NIH-supported IND-enabling studies for clinical evaluation. The present study evaluated the hypothesis that TPM, via inducing apoptosis and expanding the interstitial space, promotes the delivery and transfection of lipid vectors containing siRNA. The in vivo model was the metastatic human Hs766T pancreatic tumor that, upon IP injection, produced widely distributed solid tumors and ascites in the peritoneal cavity in 100% of animals. The target gene was survivin, an anti-apoptotic protein induced by chemotherapy and associated with metastases and poor prognosis of patients with gastric and colorectal cancers. The siRNA carrier was pegylated liposomes comprising cationic and neutral lipids plus a fusogenic lipid (PCat). PCat-loaded with survivin siRNA (PCat-siSurvivin) was active in cultured cells (decreased survivin mRNA and protein levels, reduced cell clonogenicity, enhanced paclitaxel activity), but lost its activity in vivo; this difference is consistent with the well-known problem of inadequate delivery and transfection of siRNA in vivo. In comparison, single agent TPM prolonged animal survival and, as expected, induced survivin expression in tumors. Addition of PCat-siSurvivin reversed the TPM-induced survivin expression and enhanced the antitumor activity of TPM. The finding that in vivo survivin knockdown by PCat-siSurvivin was successful only when it was given in combination with TPM provides the proof-of-concept that tumor priming promotes the delivery and transfection of liposomal siRNA. The data further suggest the TPM/PCat-siSurvivin combination as a potentially useful chemo-gene therapy for peritoneal cancer.

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Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice.

Publications

Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice.

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