The effect of dual-functional hyaluronic acid-vitamin E succinate micelles on targeting delivery of doxorubicin.
The effect of dual-functional hyaluronic acid-vitamin E succinate micelles on targeting delivery of doxorubicin.
复制标题
双功能透明质酸-维生素E琥珀酸酯胶束对阿霉素靶向递送的影响
DOI：
10.2147/ijn.s113882
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发表时间：
2016
影响因子：
8
通讯作者：
Tu P
中科院分区：
文献类型：
--
作者：
Wang J;Ma W;Guo Q;Li Y;Hu Z;Zhu Z;Wang X;Zhao Y;Chai X;Tu P
肿瘤靶向递送系统已成为有效治疗肿瘤的一种有吸引力的策略。为了增强阿霉素(DOX)的抗肿瘤作用，制备了具有不同取代度(DS)的两亲性透明质酸(HA)-维生素E琥珀酸酯(VES)共聚物(HA-VES)，并将其作为高效传递DOX的纳米载体。负载DOX的HA-VES聚合物胶束(HA-VES/DOX)由双官能团HA-VES共聚物自组装而成，具有优异的负载效率和胶体稳定性。在体外实验中，与DOX相比，HA-VES/DOX具有更强的细胞毒作用和协同抗癌作用，具有较高的诱导肿瘤细胞凋亡活性和逆转多药耐药的作用。此外，体外细胞摄取和亚细胞定位研究表明，HA-VES/DOX可以更有效地内化到癌细胞中，并选择性地在溶酶体中释放DOX，从而增加DOX在细胞核中的分布，促进其与DNA的相互作用。HA-VES/DOX通过主动识别CD44受体，降低CD44mRNA的活性，提高靶向MCF-7细胞的效率。更重要的是，HA-VES/DOX在4T1荷瘤小鼠体内表现出更好的肿瘤蓄积性和靶向性，并在降低全身毒性的同时增强了抗肿瘤效果。综上所述，基于HA-VES的药物传递系统增加了肿瘤部位的药物靶向性，并表现出较好的抗癌活性，有望成为一种有效的、有前景的肿瘤治疗策略。
Tumor-targeted delivery system has been developed as an attractive strategy for effective tumor therapy. In this study, in order to enhance the antitumor effects of doxorubicin (DOX), amphiphilic hyaluronic acid (HA)-conjugated vitamin E succinate (VES) copolymers (HA-VES) with different degrees of substitution (DS) were prepared with synergistic antitumor effects and active targeting activities, and utilized as nanocarriers for the efficient delivery of DOX. DOX-loaded HA-VES polymeric micelles (HA-VES/DOX) self-assembled from dual-functional HA-VES copolymer and exhibited excellent loading efficiency and superior colloidal stability. In vitro, HA-VES/DOX displayed enhanced cytotoxicity with synergistic anticancer effects of HA-VES copolymer, high apoptosis-inducing activities of tumor cells, and reversal effects of DOX on multidrug resistance, in comparison with DOX. Also, in vitro cellular uptake and subcellular localization studies revealed that HA-VES/DOX could more efficiently internalize into cancer cells and selectively release DOX within lysosomes, thereby enhancing the distribution of DOX in nuclei and facilitating its interactions with DNA. Specifically, HA-VES/DOX decreased the activity of CD44 mRNA and improved the targeting efficiency on MCF-7 cells, based on the active recognition between HA and CD44 receptor. More importantly, HA-VES/DOX displayed better tumor accumulation and targeting, and enhanced antitumor efficacy with reduced systemic toxicity in 4T1 tumor-bearing mice. In summary, the developed HA-VES–based drug delivery system, which increased drug targeting on the tumor site and exhibited preferable anticancer activity, could hold great potential as an effective and promising strategy for efficient tumor therapy.