The use of nanoparticulate delivery systems in metronomic chemotherapy.
The use of nanoparticulate delivery systems in metronomic chemotherapy.
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DOI：
10.1016/j.biomaterials.2013.02.017
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发表时间：
2013-05
期刊：
影响因子：
14
通讯作者：
De-Hong Yu;F. Ban;Mei Zhao;Q. Lu;J. Lovell;F. Bai;Chao Wang;Ying‐Yun Guan;Xin Luan;Yarong Liu;Chao Fang;Hong-Zhuan Chen
中科院分区：
文献类型：
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作者：
De-Hong Yu;F. Ban;Mei Zhao;Q. Lu;J. Lovell;F. Bai;Chao Wang;Ying‐Yun Guan;Xin Luan;Yarong Liu;Chao Fang;Hong-Zhuan Chen
节律化疗与常规化疗药物一样，以抑制肿瘤血管生成为目的，是一种很有前途的抗血管生成肿瘤治疗策略。然而，目前的节律化疗主要集中在游离小分子药物上，没有任何努力实现肿瘤的特异性生物分布，这可能会导致长期的毒性问题。采用纳米微粒药物传递系统(DDS)的节拍化疗在减少靶外副作用、减少累积剂量、提高肿瘤血管靶向疗效的同时不影响抗肿瘤疗效方面具有显著的优势，但缺乏全面的实验数据来描述靶向节律化疗。在这里，我们开发了一种新的纳米DDS，SP5.2肽结合，Flt-1(VEGFR-1)靶向多西紫杉醇纳米粒(SP5.2-DTX-NP)，作为研究靶向节律化疗的抗肿瘤疗效和毒性的模型。结果表明，节律性SP5.2-DTX-NP主要通过多西紫杉醇的抗血管生成作用发挥抗肿瘤作用，多西紫杉醇通过SP5.2与肿瘤血管上过表达的Flt-1受体相互作用介导的纳米颗粒内化而特异性地进入肿瘤血管内皮细胞。此外，靶向节律化疗的抗肿瘤效果优于最大耐受剂量(MTD)方案中DDS的治疗效果，其显著延长了小鼠的存活时间，且药物相关毒性(骨髓抑制、血液毒性和小肠粘膜损伤)最小。本研究揭示并强调了纳米DDS靶向节律治疗在抗血管生成肿瘤治疗中的重要性。
Metronomic chemotherapy aiming at inhibiting tumor angiogenesis with conventional chemotherapeutics is a promising strategy for antiangiogenic cancer therapy. However, current metronomic chemotherapy mainly focuses on free small-molecule drugs, without any effort to achieve tumor-specific biodistribution, which may lead to long-term toxicity concerns. Metronomic chemotherapy using nanoparticulate drug delivery system (DDS) offers significant upside to reduce off-target side effects, decrease accumulated dose, and enhance the efficacy of tumor vessel targeting without compromising antitumor efficacy; but there has been a lack of thorough experimental data describing the targeted metronomic chemotherapy. Here, we develop a new nanoparticulate DDS, SP5.2 peptide conjugated, Flt-1 (VEGFR-1) targeted nanoparticles for docetaxel (SP5.2-DTX-NP), as a model for the investigation of targeted metronomic chemotherapy with respect to both antitumor efficacy and toxicity. The results demonstrate that metronomic SP5.2-DTX-NP exerts antitumor activity mainly through the antiangiogenic effect of docetaxel, which is specifically delivered into the tumor vascular endothelial cells through the nanoparticle internalization mediated by the interaction of SP5.2 and over-expressed Flt-1 receptors on tumor vessels. Moreover, the antitumor efficacy of targeted metronomic chemotherapy is better than that of the treatment with the DDS given in the maximum tolerated dose (MTD) regimen, which is shown in significantly prolonged mice survival and minimal drug-associated toxicity (bone marrow suppression, hematological toxicity, and mucosal injury of small intestine). The present research reveals and highlights the significance of targeted metronomic therapy with nanoparticulate DDS in antiangiogenic cancer therapy.