Design and synthesis of targeted star-shaped micelle for guided delivery of camptothecin: In vitro and in vivo evaluation

IF 8.1 1区工程技术 Q1 MATERIALS SCIENCE, BIOMATERIALS

Materials science & engineering. C, Materials for biological applications Pub Date : 2021-12-01 DOI:10.1016/j.msec.2021.112529

Mehrdad Sahranavard , Mahsa Shahriari , Khalil Abnous , Farzin Hadizadeh , Seyed Mohammad Taghdisi , Reza Zolfaghari , Mohammad Ramezani , Mona Alibolandi

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引用次数: 9

Abstract

This study aimed to synthesize a star-shaped micelle using 3-azido-2,2-bis(azidomethyl)propan-1-ol (pentaerythritol triazide) core, as an initiator for the synthesis of three-arm polylactic acid (PLA) block. Then, the ends of the PLA arms were converted to PLA triazide followed by conjugation to the three alkyne-PEG-maleamide through click reaction. The maleamide ends were available for coupling with sulfhydryl-modified DNA aptamer against epithelial cell adhesion molecule in order to offer targeted delivery of encapsulated drug, camptothecin to the site of action. The successful synthesis of the star-shaped polymers was confirmed via ¹HNMR. Hydrophobic anti-cancer drug, camptothecin was encapsulated into the micelles core implementing solvent switching method providing loading content (LC%) and encapsulation efficiency (EE%) of 3.7 ± 0.4 and 73.7 ± 8.2, respectively. The size of both non-targeted and aptamer-targeted micelles was determined to be 154 and 192 nm, respectively with polydispersity index below 0.3. In vitro drug release evaluation at 37 °C, pH 7.4 showed a controlled release pattern for camptothecin during 72 h. In vitro cytotoxicity of the prepared non-targeted and targeted micelles was carried out on human colorectal adenocarcinoma (HT29) and mouse colon carcinoma (C26) as EpCAM positive cell lines and Chinese hamster ovary (CHO) as EpCAM negative cell line. The results verified significantly higher cytotoxicity of the targeted micelles on HT29 and C26 cell lines, while no obvious difference was observed between targeted and non-targeted formulation on CHO cell line. The in vivo therapeutic efficiency investigation on BALB/c C26 tumor-bearing mice showed superior capability of the targeted formulation on tumor suppression and survival rate of the treated mice. The developed platform exhibited excellent characteristics to diminish camptothecin drawbacks and its adverse effects while considerably increasing its therapeutic index.

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喜树碱定向给药星形胶束的设计与合成:体外和体内评价

本研究旨在以3-叠氮-2,2-双(叠氮多甲基)丙烷-1-醇(季戊四醇三叠氮化)核为引发剂合成星形胶束，用于合成三臂聚乳酸(PLA)嵌段。然后，将聚乳酸臂末端转化为聚乳酸三叠氮，然后通过咔嗒反应与三个炔-聚乙二醇-马来酰胺偶联。马来酰胺末端可与巯基修饰的DNA适体偶联，以对抗上皮细胞粘附分子，从而提供靶向递送包裹药物喜树碱到作用部位。通过1HNMR证实了星形聚合物的成功合成。采用溶剂切换法将疏水抗癌药物喜树碱包封至胶束芯，其载药量(LC%)和包封效率(EE%)分别为3.7±0.4和73.7±8.2。非靶向和适体靶向胶束的大小分别为154 nm和192 nm，多分散指数均在0.3以下。在37℃、pH 7.4条件下，喜树碱在72 h内呈控释模式。以EpCAM阳性细胞系人结直肠癌(HT29)、小鼠结肠癌(C26)和EpCAM阴性细胞系中国地鼠卵巢(CHO)为实验对象，对制备的非靶向和靶向胶束进行体外细胞毒性研究。结果证实靶向胶束对HT29和C26细胞系的细胞毒性显著提高，而对CHO细胞系的靶向和非靶向胶束的细胞毒性无明显差异。对BALB/ C26荷瘤小鼠的体内治疗效果研究表明，靶向制剂具有较强的抑瘤能力和治疗小鼠的存活率。所开发的平台在显著提高喜树碱治疗指数的同时，表现出良好的减少喜树碱缺陷和不良反应的特性。

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来源期刊

Materials science & engineering. C, Materials for biological applications MATERIALS SCIENCE, BIOMATERIALS-

CiteScore

12.60

自引率

0.00%

发文量

审稿时长

3.3 months

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