Combination chemotherapy of doxorubicin, all-trans retinoic acid and low molecular weight heparin based on self-assembled multi-functional polymeric nanoparticles
Combination chemotherapy of doxorubicin, all-trans retinoic acid and low molecular weight heparin based on self-assembled multi-functional polymeric nanoparticles
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DOI：
10.1088/0957-4484/26/14/145101
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发表时间：
2015-03
期刊：
影响因子：
3.5
通讯作者：
Ting-Dong Zhang;Hui Xiong;F. Dahmani;Li Sun;Yuanke Li;Li Yao;Jianping Zhou;Jing Yao
中科院分区：
文献类型：
--
作者：
Ting-Dong Zhang;Hui Xiong;F. Dahmani;Li Sun;Yuanke Li;Li Yao;Jianping Zhou;Jing Yao
基于多柔比星（DOX）、全反式维甲酸（ATRA）和低分子肝素（LMWH）的互补作用，DOX、ATRA和LMWH的联合治疗有望发挥更强的抗肿瘤作用，同时降低毒副作用。本研究合成了两亲性LMWH-ATRA偶联物，用于包封DOX。通过化学和物理两种方式将DOX、ATRA和LMWH组装成单一的纳米体系，得到一种新型的抗肿瘤靶向给药系统，可实现多种不同性质药物同时向肿瘤的递送。LMWH-ATRA纳米粒具有良好的DOX负载能力，并具有良好的理化性质、生物相容性、诱导分化活性和抗血管生成活性。载药量为18.7%，包封率为78.8%。阿霉素负载的LMWH-ATRA纳米粒（DHR nanoparticles）可被肿瘤细胞通过内吞途径有效摄取，并主要分布在细胞浆中，然后转移到细胞核中。细胞活力测定表明，DHR纳米粒保持了DOX对MCF-7细胞的细胞毒性作用。此外，体内成像分析表明，与游离DiR相比，负载DiR的LMWH-ATRA纳米颗粒可以更有效地靶向肿瘤。与游离药物溶液相比，DHR纳米粒具有更高的抗癌活性和更低的副作用。这些结果表明，DHR纳米粒可以被认为是一个有前途的联合癌症化疗的靶向给药系统，具有较低的不良反应。
Based on the complementary effects of doxorubicin (DOX), all-trans retinoic acid (ATRA) and low molecular weight heparin (LMWH), the combination therapy of DOX, ATRA and LMWH was expected to exert the enhanced anti-tumor effects and reduce the side effects. In this study, amphiphilic LMWH–ATRA conjugate was synthesized for encapsulating the DOX. In this way, DOX, ATRA and LMWH were assembled into a single nano-system by both chemical and physical modes to obtain a novel anti-tumor targeting drug delivery system that can realize the simultaneous delivery of multiple drugs with different properties to the tumor. LMWH–ATRA nanoparticles exhibited good loading capacities for DOX with excellent physico-chemical properties, good biocompatibility, and good differentiation-inducing activity and antiangiogenic activity. The drug-loading capacity was up to 18.7% with an entrapment efficiency of 78.8%. It was also found that DOX-loaded LMWH–ATRA nanoparticles (DHR nanoparticles) could be efficiently taken up by tumor cells via endocytic pathway, and mainly distributed in cytoplasm at first, then transferred into cell nucleus. Cell viability assays suggested that DHR nanoparticles maintained the cytotoxicity effect of DOX on MCF-7 cells. Moreover, the in vivo imaging analysis indicated that DiR-loaded LMWH–ATRA nanoparticles could target the tumor more effectively as compared to free DiR. Furthermore, DHR nanoparticles possessed much higher anticancer activity and reduced side effects compared to free drugs solution. These results suggested that DHR nanoparticles could be considered as a promising targeted delivery system for combination cancer chemotherapy with lower adverse effects.