Folate-targeted supramolecular vesicular aggregates based on polyaspartyl-hydrazide copolymers for the selective delivery of antitumoral drugs
Folate-targeted supramolecular vesicular aggregates based on polyaspartyl-hydrazide copolymers for the selective delivery of antitumoral drugs
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DOI：
10.1016/j.biomaterials.2010.05.060
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发表时间：
2010-10-01
期刊：
影响因子：
14
通讯作者：
Fresto, Massimo
中科院分区：
文献类型：
--
作者：
Licciardi, Mariano;Paolino, Donatella;Fresto, Massimo
超分子囊泡聚集体（SVA）具有将基于磷脂的胶体囊泡载体的安全性和生物相容性与聚合物材料（即聚乙酰肼（PAHy）共聚物）的安全性和生物相容性相结合的优点。为了提供具有一定肿瘤选择性的SVA，将叶酸部分化学缀合至PAHy共聚物。评价了负载有吉西他滨的叶酸靶向SVA（FT-SVA）的理化性质（平均尺寸、多分散指数和ζ电位）。针对两种癌细胞系，即过表达叶酸受体的MCF-7细胞和不过表达该受体的BxPC-3细胞，评价了负载吉西他滨的FT-SVA的抗增殖和抗癌活性。与游离药物和载药的常规脂质体或非靶向SVA相比，载吉西他滨的FT-SVA显示出显著（p < 0.001）更大和更特异的体外抗癌活性。共聚焦显微镜、流式细胞术分析和β-闪烁强调了FT-SVA能够在仅仅3小时后与MCF-7细胞相互作用，并增加过表达叶酸受体的细胞中的内化量。体内生物分布和药代动力学实验表明，吉西他滨负载的SVA和FT-SVA从循环系统中清除的速率低于天然药物，并且观察到吉西他滨血浆浓度延长长达16小时。SVAs主要在肺、脾和肾中蓄积，而FT-SVAs也被脑摄取。这些有趣和刺激的结果表明，存在一个可能的体内应用的SVA和鼓励使用叶酸作为靶向剂在抗癌治疗。(C)2010爱思唯尔有限公司版权所有。
Supramolecular vesicular aggregates (SVAs) have the advantage of combining the safe and biocompatible properties of colloidal vesicular carriers based on phospholipids with those of polymeric materials, i.e. polyaspartyl-hydrazide (PAHy) copolymers. To provide SVAs with a certain tumour selectivity, folate moieties were chemically conjugated to PAHy copolymers. Physicochemical properties (mean sizes, poly-dispersity index and zeta potential) of folate-targeted SVAs (FT-SVAs) loaded with gemcitabine were evaluated. The antiproliferative and anticancer activity of gemcitabine-loaded FT-SVAs was evaluated against two cancer cell lines, i.e. MCF-7 cells which over-express the folate receptor and the BxPC-3 cells, which do not over-express this receptor. Gemcitabine-loaded FT-SVAs showed a significantly (p < 0.001) greater and more specific in vitro anticancer activity with respect to both the free drug and the drug-loaded conventional liposomes or untargeted SVAs. Confocal microscopy, flow cytometry analysis and beta-scintillation highlighted that FT-SVAs were able to interact with MCF-7 cells after just 3 h and to increase the amount internalization in cells over-expressing the folate receptor. The in vivo biodistribution and pharmacokinetic experiments showed that gemcitabine-loaded SVAs and FT-SVAs were removed from the circulatory system at a slower rate than the native drug and a prolonged gemcitabine plasma concentration was observed for up to 16 h. SVAs were accumulated mainly in the lungs, spleen and kidneys, while FT-SVAs were also up taken by brain. These interesting and stimulating results suggest the existence of a possible in vivo application of SVAs and encourage the use of folate as a targeting agent in anticancer therapy. (C) 2010 Elsevier Ltd. All rights reserved.