Dendrimer-Based Biocompatible Zwitterionic Micelles for Efficient Cellular Internalization and Enhanced Antitumor Effects,ACS Applied Polymer Materials

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Dendrimer-Based Biocompatible Zwitterionic Micelles for Efficient Cellular Internalization and Enhanced Antitumor Effects
ACS Applied Polymer Materials ( IF 4.4 ) Pub Date : 2019-04-26 , DOI: 10.1021/acsapm.9b00026
Longgang Wang ₁ , Linlin Zhu ₁ , Matthew T. Bernards ₂ , Shengfu Chen ₃ , Haotian Sun ₃ , Xiaolei Guo ₁ , Weili Xue ₃ , Yanshuai Cui _{1,

4} , Dawei Gao ₁

Affiliation

Zwitterionic materials have been employed to achieve excellent biocompatibility and the well-suppressed nonspecific protein adsorption of nanoparticles. However, a thick and compact zwitterionic layer may prevent the modified nanoparticles from entering tumor cells, resulting in low cellular internalization efficiency. To address this problem, new biocompatible micelles (PPIMYC) with a thin zwitterionic layer were designed and prepared. Zwitterionic generation 2 polypropyleneimine dendrimers (G2 PPI) serve as the hydrophilic external shell, and N-(2-mercaptoethyl)oleamide serves as the hydrophobic internal core. Drug-loaded dendritic micelles (PPIMYC-DOX-Ce6) were also prepared by self-assembly of PPIMYC with doxorubicin (DOX) and chlorin e6 (Ce6) to demonstrate chemo-photodynamic dual therapy. As potential drug delivery systems for antitumor therapy, PPIMYC-DOX-Ce6 exhibited sustained drug release under acidic conditions and high stability in fibrinogen solution. In addition, cytotoxicity studies showed an enhanced efficiency of PPIMYC-DOX-Ce6 in killing HeLa cells as compared to free DOX with or without irradiation (660 nm laser). More importantly, both flow cytometry and fluorescence microscopy results indicated that the cellular uptake efficiency of DOX was significantly enhanced in PPIMYC-DOX-Ce6-treated cells relative to free DOX treated cells. The intracellular internalization of PPIMYC-DOX-Ce6 was more efficient under acidic pH, representing the tumor environment, as compared to normal pH. This results from the pH sensitivity of the zwitterionic layer. Temperature was the only environmental factor affecting the cellular internalization process. It is believed that the enhanced intracellular internalization efficiency is due to the thin zwitterionic layer of PPIMYC-DOX-Ce6. The preparation scheme of zwitterionic micelles would offer a new strategy to design novel antitumor drug delivery systems with enhanced cellular internalization efficiency and high stability in a complex medium.

中文翻译：

基于树状聚合物的生物相容性两性离子胶束，可有效实现细胞内在化和增强的抗肿瘤作用

两性离子材料已用于实现出色的生物相容性和抑制良好的纳米颗粒非特异性蛋白质吸附。但是，厚而致密的两性离子层可能会阻止修饰的纳米粒子进入肿瘤细胞，从而导致细胞内化效率低下。为了解决该问题，设计并制备了具有薄两性离子层的新型生物相容性胶束（PPIMYC）。两性离子第2代聚丙烯亚胺树枝状聚合物（G2 PPI）用作亲水性外壳，而N-（2-巯基乙基）油酰胺用作疏水性内芯。还通过将PPIMYC与阿霉素（DOX）和二氢卟酚e6（Ce6）自组装来制备载有药物的树突胶束（PPIMYC-DOX-Ce6），以证明化学光动力学双重疗法。作为潜在的抗肿瘤药物输送系统，PPIMYC-DOX-Ce6在酸性条件下显示出持续的药物释放，并在纤维蛋白原溶液中具有很高的稳定性。此外，细胞毒性研究表明，与有或没有辐射（660 nm激光）的游离DOX相比，PPIMYC-DOX-Ce6在杀死HeLa细胞方面具有更高的效率。更重要的是，流式细胞术和荧光显微镜检查结果均表明，相对于游离DOX处理的细胞，PPIMYC-DOX-Ce6处理的细胞中DOX的细胞摄取效率显着提高。与正常pH相比，在酸性pH（代表肿瘤环境）下，PPIMYC-DOX-Ce6的细胞内内化作用更为有效。这是由于两性离子层的pH敏感性引起的。温度是影响细胞内在化过程的唯一环境因素。相信增强的细胞内内化效率是由于PPIMYC-DOX-Ce6的两性离子薄层。两性离子胶束的制备方案将提供一种新策略，以设计具有增强的细胞内在化效率和在复杂培养基中的高稳定性的新型抗肿瘤药物递送系统。温度是影响细胞内在化过程的唯一环境因素。相信增强的细胞内内化效率是由于PPIMYC-DOX-Ce6的两性离子薄层。两性离子胶束的制备方案将提供一种新的策略，以设计具有增强的细胞内在化效率和在复杂培养基中的高稳定性的新型抗肿瘤药物递送系统。温度是影响细胞内在化过程的唯一环境因素。相信增强的细胞内内化效率是由于PPIMYC-DOX-Ce6的两性离子薄层。两性离子胶束的制备方案将提供一种新策略，以设计具有增强的细胞内在化效率和在复杂培养基中的高稳定性的新型抗肿瘤药物递送系统。

更新日期：2019-11-18

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