Suppression of colorectal cancer subcutaneous xenograft and experimental lung metastasis using nanoparticle-mediated drug delivery to tumor neovasculature
Suppression of colorectal cancer subcutaneous xenograft and experimental lung metastasis using nanoparticle-mediated drug delivery to tumor neovasculature
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使用纳米颗粒介导的药物递送至肿瘤新血管系统抑制结直肠癌皮下异种移植物和实验性肺转移
DOI：
10.1016/j.biomaterials.2013.08.091
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发表时间：
2014-01-01
期刊：
影响因子：
14
通讯作者：
Fang, Chao
中科院分区：
文献类型：
--
作者：
Wang, Chao;Zhao, Mei;Fang, Chao
抗血管生成治疗是一种有效的治疗结直肠癌的方法。然而，由于已批准的抗血管生成抑制剂对生理功能和体内平衡的脱靶作用，不可避免地出现各种不良反应。本研究旨在探讨一种新的肿瘤血管靶向纳米颗粒给药系统——负载长春新碱的F56肽缀合纳米颗粒（F56- vcr - np），用于有效治疗CRC皮下异种移植和实验性肺转移模型。研究了F56-VCR-NP的控释行为和体内药动学特征。研究了F56-VCR-NP在人脐静脉内皮细胞（模拟肿瘤血管EC的经典细胞模型）、免疫缺陷裸鼠皮下移植人HCT-15和免疫正常小鼠肺转移模型中的肿瘤血管靶向性和抗血管生成活性。在CT-26小鼠肺转移模型中进一步研究其治疗效果（动物存活和毒性）。F56-VCR-NP在pH 7.4的PBS中可达到30天的控释，在体内具有良好的长循环特性。F56-VCR-NP能够准确靶向结直肠癌新生血管，在肿瘤血管EC中诱导纳米颗粒内化，抗血管生成的vcr诱导结直肠癌组织EC急剧凋亡和坏死。F56-VCR-NP显著延长了CT-26肺转移小鼠模型小鼠的生存期，且无明显的毒性（体重减轻、上皮缺失），这种显著的抗肿瘤作用与转移灶微血管密度降低密切相关。目前基于纳米颗粒的靶向抗血管生成治疗可能为结直肠癌和肺转移的治疗提供了一种新的有前景的方法，值得进一步的转化研究。(C) 2013 Elsevier Ltd.版权所有。
Antiangiogenic therapy is a validated approach for colorectal cancer (CRC) treatment. However, diverse adverse effects inevitably appear due to the off-target effect of the approved antiangiogenic inhibitors on the physiological functions and homeostasis. This study was to investigate a new tumor vessel targeting nanoparticulate drug delivery system, F56 peptide conjugated nanoparticles loading vincristine (F56-VCR-NP), for the effective treatment of CRC subcutaneous xenograft and experimental lung metastasis model. The controlled release behavior and in vivo pharmacokinetic profile of F56-VCR-NP were characterized. The tumor vessel targeting and antiangiogenic activity of F56-VCR-NP was evaluated in human umbilical vein endothelial cells (HUVEC, a classical cell model mimicking tumor vascular EC), subcutaneous human HCT-15 xenograft in immunodeficient nude mice, and experimental CT-26 lung metastasis model in immunocompetent mice. The therapeutic efficacy (animal survival and toxicity) was further investigated in the model of CT-26 lung metastasis in mice. F56-VCR-NP could achieve 30-day controlled drug release in PBS (pH 7.4) and exhibited favorable long-circulating feature in vivo. F56-VCR-NP could accurately target the CRC neovasculature and elicit nanoparticle internalization in the tumor vascular EC, where the antiangiogenic VCR-induced dramatic EC apoptosis and necrosis of CRC tissue. F56-VCR-NP significantly prolonged the mouse survival with no obvious toxicity (weight loss and anepithymia) in the CT-26 lung metastasis mice model, and this pronounced antitumor effect was closely related with the decreased microvessel density in the metastases. The present nanoparticle-based targeted antiangiogenic therapy may provide a new promising approach for the therapy of CRC and lung metastasis, which deserves further translational research. (C) 2013 Elsevier Ltd. All rights reserved.