Paclitaxel-loaded solid lipid nanoparticles modified with Tyr-3-octreotide for enhanced anti-angiogenic and anti-glioma therapy
Paclitaxel-loaded solid lipid nanoparticles modified with Tyr-3-octreotide for enhanced anti-angiogenic and anti-glioma therapy
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DOI：
10.1016/j.actbio.2016.04.026
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发表时间：
2016-07-01
影响因子：
9.7
通讯作者：
Misra, Mridula
中科院分区：
文献类型：
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作者：
Banerjee, Indranil;De, Kakali;Misra, Mridula
生长抑制素受体（SSTR），尤其是亚型2（SSTR 2）在胶质瘤中过表达。利用SSTR 2在胶质瘤新生血管内皮细胞和胶质瘤细胞上的特异性表达，我们构建了Tyr-3-octreotide（TOC）修饰的紫杉醇（PTX）固体脂质纳米粒（SLN），实现肿瘤新生血管和肿瘤细胞的双靶向化疗。在这项工作中，TOC-聚乙二醇-脂质（TOC-PEG-lipid）被成功地合成并用作靶向分子，以增强载紫杉醇空间稳定的脂质纳米粒的抗癌功效。通过标准方法表征所制备的用TOC（PSM）改性的负载PTX的SLN。在大鼠C6胶质瘤细胞中，PSM可增强PTX诱导的细胞凋亡。管形成试验和治疗原位胶质瘤组织的CD 31染色证实PSM显著提高PTX在体外和体内的抗血管生成能力。放射性标记的PSM在胶质瘤内实现了更高的特异性蓄积，这与生物分布和成像研究所表明的一致。此外，PSM在皮下和原位肿瘤模型中均表现出比未修饰的纳米颗粒和紫杉醇更好的抗神经胶质瘤功效。生长抑素受体（Somatostatin receptor，SSTR），尤其是SSTR 2亚型在多种哺乳动物肿瘤细胞中过表达。新生血管的血管内皮细胞也表达SSTR 2。Tyr-3-奥曲肽（TOC）是SSTR 2的已知配体。我们成功制备了粒径小于100 nm的紫杉醇TOC修饰固体脂质纳米粒（PSM）。我们发现PSM提高了紫杉醇对SSTR 2阳性大鼠胶质瘤的抗癌疗效。PSM的这种改善的抗胶质瘤效率可以归因于PSM的双重靶向（即肿瘤细胞和新血管系统靶向）效率，并且由于固体脂质纳米颗粒的TOC修饰而促进抗癌药物在肿瘤部位的积累。本研究旨在通过探索PSM的双靶向潜力来拓宽奥曲肽衍生物修饰纳米载体的范围。(C)2016 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Somatostatin receptors (SSTRs) especially subtype 2 (SSTR2) are overexpressed in glioma. By taking advantage of the specific expression of SSTR2 on both glioma neovasculature endothelial cells and glioma cells, we constructed Tyr-3-octreotide (TOC)-modified solid lipid nanoparticles (SLN) loaded with paclitaxel (PTX) to enable tumor neovasculature and tumor cells dual-targeting chemotherapy. In this work, a TOC-polyethylene glycol-lipid (TOC-PEG-lipid) was successfully synthesized and used as a targeting molecule to enhance anticancer efficacy of PTX loaded sterically stabilized lipid nanoparticles. The prepared PTX-loaded SLN modified with TOC (PSM) was characterized by standard methods. In rat C6 glioma cells, PSM improved PTX induced apoptosis. Both tube formation assay and CD31 staining of treated orthotopic glioma tissues confirmed that PSM significantly improved the antiangiogenic ability of PTX in vitro and in vivo, respectively. Radiolabelled PSM achieved a much higher and specific accumulation within the glioma as suggested by the biodistribution and imaging studies. Furthermore, PSM exhibited improved anti-glioma efficacy over unmodified nanoparticles and Taxol in both subcutaneous and orthotopic tumor models. These findings collectively indicate that PSM holds great potential in improving the efficacy of anti-glioma therapy.Statement of SignificanceSomatostatin receptors (SSTRs) especially subtype 2 (SSTR2) are overexpressed in various mammalian cancer cells. Proliferating endothelial cells of neovasculature also express SSTR2. Tyr-3-octreotide (TOC) is a known ligand for SSTR2. We have successfully prepared paclitaxel-loaded solid lipid nanoparticles modified with TOC (PSM) having diameter less than 100 nm. We found that PSM improved anticancer efficacy of paclitaxel in SSTR2 positive glioma of rats. This improved anti-glioma efficiency of PSM can be attributed to dual-targeting (i.e. tumor cell and neovasculature targeting) efficiency of PSM and promoted anti-cancer drug accumulation at tumor site due to TOC modification of solid lipid nanoparticles. This particular study aims at widening the scope of octreotide-derivative modified nanocarrier by exploring dual-targeting potential of PSM. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.