Facile construction of stabilized, pH-sensitive micelles based on cyclic statistical copolymers of poly(oligo(ethylene glycol)methyl ether methacrylate-st-N,N-dimethylaminoethyl methacrylate) for in vitro anticancer drug delivery,Polymer Chemistry

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Facile construction of stabilized, pH-sensitive micelles based on cyclic statistical copolymers of poly(oligo(ethylene glycol)methyl ether methacrylate-st-N,N-dimethylaminoethyl methacrylate) for in vitro anticancer drug delivery
Polymer Chemistry ( IF 4.1 ) Pub Date : 2020-09-01 , DOI: 10.1039/d0py01076f
Miao Zhang _{1,

2,

3,

4,

5} , Ying Liu _{6,

7,

8,

9} , Jinlei Peng _{1,

2,

3,

4,

5} , Yuping Liu _{1,

2,

3,

4,

5} , Fangjun Liu _{1,

2,

3,

4,

5} , Wei Ma _{1,

2,

3,

4,

5} , Liwei Ma _{1,

2,

3,

4,

5} , Cui-Yun Yu _{6,

7,

8,

9} , Hua Wei _{1,

2,

3,

4,

5}

Affiliation

Cyclic polymers have outperformed their linear analogues for controlled release applications in terms of greater stability and better therapeutic efficiency due to the endless chain topology. However, to our knowledge, there have been thus far only a few examples of the fabrication of pH-sensitive cyclic polymers for drug delivery applications. To further improve the colloidal stability of the previously synthesized cyclic poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) for drug delivery applications via a facile yet efficient approach, it will be useful and straightforward to incorporate a hydrophilic monomer for copolymerization with DMAEMA. For this purpose, we reported in this study the preparation of pH-sensitive cyclic statistical copolymers, P(OEGMA-st-DMAEMA)s, with two different compositions by atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and DMAEMA and subsequent “intra-chain” click cyclization of the α-alkyne-ω-azide linear precursor. A further comparison study on the micelle stability revealed that the spherical micelles self-assembled from c-P(OEGMA₄-st-DMAEMA₃₈) (C) with both smaller hydrodynamic size than that of the micelles of the linear analogue, l-P(OEGMA₄-st-DMAEMA₃₈) (L), and greater salt stability than that of the micelles of c-P(OEGMA₈-st-DMAEMA₃₈) were screened to be the optimal micelle construct for drug delivery applications. Flow cytometry (FCM) analysis confirmed greater cellular uptake efficiency of doxorubicin (DOX)-loaded C (C@DOX) micelles than that of the L (L@DOX) ones. More importantly, the C@DOX micelles showed comparable in vitro cytotoxicity against the cancer cell line (HeLa cells) but lower in vitro cytotoxicity against the normal cell line (HUVEC cells) relative to the L@DOX formulation after 72 h of incubation. Therefore, this study not only developed a facile approach to improve the colloidal stability of a cyclic polycation, but also presented a pH-sensitive cyclic copolymer-based nanoplatform with great potential for anticancer drug delivery.

中文翻译：

基于聚（低聚（乙二醇）甲基醚甲基丙烯酸甲酯-st-N，N-N-二甲基氨基乙基甲基丙烯酸酯）的循环统计共聚物的体外抗癌药物递送的稳定的，对pH敏感的胶束的简便构建

环状聚合物由于环状链的拓扑结构而具有更高的稳定性和更好的治疗效率，因此在控释应用中，环状聚合物的性能优于其线性类似物。然而，据我们所知，到目前为止，仅有少数几个制备用于药物递送应用的pH敏感的环状聚合物的例子。为了进一步改善先前合成的环状聚（N，N-甲基丙烯酸N-二甲氨基乙酯）（PDMAEMA）的胶体稳定性，可通过作为一种简便而有效的方法，将亲水性单体与DMAEMA共聚将是有用且直接的。为此，我们在本研究中报道了通过低聚（乙二醇）单甲基醚甲基丙烯酸酯的原子转移自由基聚合（ATRP）制备具有两种不同组成的pH敏感的环状统计共聚物P（OEGMA- st -DMAEMA）（OEGMA）和DMAEMA以及随后的α-炔烃-ω-叠氮化物线性前体的“链内”点击环化。对胶束稳定性的进一步比较研究表明，球形胶束是由c -P（OEGMA ₄ - st -DMAEMA _38）自组装的）（C）具有比线性类似物l -P（OEGMA ₄ - st -DMAEMA ₃₈）（L）的胶束更小的流体力学尺寸，以及比c -P（OEGMA）的胶束更大的盐稳定性。_将8 - st- DMAEMA ₃₈）筛选为用于药物递送应用的最佳胶束构建体。流式细胞仪（FCM）分析证实，阿霉素（DOX）加载的C（C @ DOX）胶束的细胞吸收效率高于L（L @ DOX）的胶束。更重要的是，C @ DOX胶束在体外对癌细胞系（HeLa细胞）表现出可比的细胞毒性，但在体外却较低孵育72小时后，相对于L @ DOX制剂对正常细胞系（HUVEC细胞）的细胞毒性。因此，这项研究不仅开发了一种提高环状聚阳离子胶体稳定性的简便方法，而且提出了一种基于pH敏感的环状共聚物的纳米平台，具有很大的抗癌潜力。

更新日期：2020-10-06

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