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首页> 外文期刊>Biomaterials >Multifunctional pH-Disintegrable micellar nanoparticles of asymmetrically functionalized β-cyclodextrin-Based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties
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Multifunctional pH-Disintegrable micellar nanoparticles of asymmetrically functionalized β-cyclodextrin-Based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties

机译：与阿霉素和DOTA-Gd部分共价结合的不对称功能化β-环糊精-基星形共聚物的多功能pH崩解胶束纳米颗粒

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摘要

We report on a novel type of multifunctional pH-disintegrable micellar nanoparticles fabricated from asymmetrically functionalized β-cyclodextrin (β-CD) based star copolymers covalently conjugated with doxorubicin (DOX), folic acid (FA), and DOTA-Gd moieties for integrated cancer cell-targeted drug delivery and magnetic resonance (MR) imaging contrast enhancement. Asymmetrically functionalized β-CD, (N 3) 7-CD-(Br) 14, which possesses 7 azide functionalities and 14 α-bromopropionate moieties in the upper and lower rim of rigid toroidal β-CD core, respectively, was synthesized at first. The subsequent atom transfer radical polymerization (ATRP) of N-(2-hydroxypropyl) methacrylamide (HPMA), conjugation with DOX and FA, and click reaction with alkynyl-(DOTA-Gd) complex afforded (DOTA-Gd) 7-CD-(PHPMA-FA-DOX) 14 star copolymer comprising of 7 DOTA-Gd complex moieties and 14 PHPMA arms covalently anchored with DOX and FA via acid-labile carbamate linkages and ester bonds, respectively. The covalent conjugation with ～13 DOX molecules onto PHPMA arms per star copolymer (～14wt% loading content) endows the initially hydrophilic one with amphiphilicity, leading to the self-assembly into micellar nanoparticles of several tens of nanometers in aqueous solution at pH 7.4. Invitro DOX release profile from micellar nanoparticles is highly pH-dependent, and over a time period of 42h, cumulative releases of ～10%, 53%, and 89% conjugated DOX at pH 7.4, 5.0, and 4.0, respectively, were observed. Most importantly, the pH-modulated release of conjugated DOX from micellar nanoparticles is accompanied with the micelle disintegration due to the loss of amphiphilicity of the star copolymer scaffold. Invitro cell viability assays revealed that (DOTA-Gd) 7-CD-(PHPMA 15) 14 star copolymer is almost non-cytotoxic up to a concentration of 0.5g/L, whereas DOX-conjugated micellar nanoparticles of (DOTA-Gd) 7-CD-(PHPMA-FA-DOX) 14 can effectively enter and kill HeLa cells at a concentration higher than ～80mg/L. Invitro MR imaging experiments indicated a considerably enhanced T 1 relaxivity (r 1=11.4s -1mM -1) for micellar nanoparticles compared to that for the small molecule counterpart, alkynyl-DOTA-Gd (r 1=3.1s -1mM -1). Invivo MR imaging assay in rats revealed considerable accumulation of micellar nanoparticles within rat liver and kidney and prominent positive contrast enhancement. The integrated design of diagnostic and therapeutic functions of multifunctional pH-disintegrable micellar nanoparticles augurs well for their practical applications in the field of image-guided cancer chemotherapy.
机译：我们报告了一种新型的多功能pH可崩解胶束纳米粒子，该粒子由不对称功能化的β-环糊精（β-CD）基共价结合了阿霉素（DOX），叶酸（FA）和DOTA-Gd部分的星状共聚物制成，用于整合型癌症细胞靶向药物递送和磁共振（MR）成像对比增强。首先合成了不对称官能化的β-CD（N 3）7-CD-（Br）14，该化合物在刚性环状β-CD核的上，下缘分别具有7个叠氮化物官能团和14个α-溴丙酸酯部分。 。随后进行N-（2-羟丙基）甲基丙烯酰胺（HPMA）的原子转移自由基聚合（ATRP），与DOX和FA偶联，并与炔基-（DOTA-Gd）配合物发生点击反应，得到（DOTA-Gd）7-CD- （PHPMA-FA-DOX）由7个DOTA-Gd复杂部分和14个PHPMA臂组成的14星共聚物，分别通过酸不稳定的氨基甲酸酯键和酯键与DOX和FA共价锚定。每个星型共聚物（〜14wt％的负载量）上，〜13个DOX分子与PHPMA臂共价结合，使最初的亲水性分子具有两亲性，从而导致其在pH 7.4的水溶液中自组装成几十纳米的胶束纳米颗粒。胶束纳米颗粒的体外DOX释放曲线与pH高度相关，并且在42h的时间内，在pH 7.4、5.0和4.0下，共轭DOX的累积释放分别达到〜10％，53％和89％。最重要的是，由于星形共聚物支架的两亲性丧失，胶束纳米颗粒从共轭DOX的pH调节释放伴随着胶束崩解。体外细胞活力分析表明，浓度高达0.5g / L的（DOTA-Gd）7-CD-（PHPMA 15）14星型共聚物几乎没有细胞毒性，而（DOTA-Gd）7的DOX缀合的胶束纳米颗粒-CD-（PHPMA-FA-DOX）14可以有效进入和杀死HeLa细胞，其浓度高于〜80mg / L。体外MR成像实验表明，与小分子对应物炔基-DOTA-Gd（r 1 = 3.1s -1mM -1）相比，胶束纳米颗粒的T 1弛豫性大大增强（r 1 = 11.4s -1mM -1） 。大鼠的体内MR成像分析显示，大鼠肝脏和肾脏中大量胶束纳米颗粒蓄积，并且显着增强了阳性对比度。多功能可pH崩解的胶束纳米颗粒的诊断和治疗功能的集成设计预示着它们在图像引导癌症化学疗法领域的实际应用。

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