Alendronate/folic acid-decorated polymeric nanoparticles for hierarchically targetable chemotherapy against bone metastatic breast cancer
Alendronate/folic acid-decorated polymeric nanoparticles for hierarchically targetable chemotherapy against bone metastatic breast cancer
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DOI：
10.1039/d0tb00046a
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发表时间：
2020-05-07
影响因子：
7
通讯作者：
Chiu, Hsin-Cheng
中科院分区：
文献类型：
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作者：
Chen, Shih-Hong;Liu, Te-, I;Chiu, Hsin-Cheng
为了通过双骨/肿瘤靶向化疗显著提高骨转移性乳腺癌的治疗效果，本研究开发了一种以聚乳酸-羟基乙酸（PLGA）为疏水性核心的纳米颗粒递送系统，该系统由阿烯膦酸修饰的d- a-生育酚基聚乙二醇琥珀酸酯（ALN-TPGS）和叶酸偶联的聚乙二醇琥珀酸酯（FA-TPGS）包裹，作为紫杉醇（PTX）的载体。ALN/ fa修饰的纳米颗粒不仅表现出ALN介导的与骨组织中丰富的羟基磷灰石的结合亲和力，而且还促进叶酸受体过表达的癌细胞对有效载荷的摄取，从而显著增强PTX的细胞毒性。值得注意的是，通过双靶标递送至骨基质和叶酸受体过表达4T1的肿瘤，ptx负载纳米颗粒在体内骨转移中大量积累，抑制4T1肿瘤的生长和肺转移，显著提高了治疗小鼠的存活率。经ALN/ fa修饰的ptx纳米颗粒处理后，明显延缓了荷瘤小鼠的骨破坏和骨丢失，减轻了对正常组织的不良影响。这些结果表明，本研究开发的ALN/ fa修饰的ptx负载递送系统在有效治疗骨转移性乳腺癌方面具有很大的前景。
To considerably enhance treatment efficacy for bone metastatic breast cancer via dual bone/tumor-targeted chemotherapy, a nanoparticle-based delivery system comprising poly(lactic-co-glycolic acid) (PLGA) as the hydrophobic core coated with alendronate-modified D-a-tocopheryl polyethylene glycol succinate (ALN-TPGS) and folic acid-conjugated TPGS (FA-TPGS) was developed as a vehicle for paclitaxel (PTX) in this work. The ALN/FA-decorated nanoparticles not only showed superior ALN-mediated binding affinity for hydroxyapatite abundant in bone tissue but also promoted uptake of payloads by folate receptor-overexpressing cancer cells to significantly augment PTX cytotoxicity. Notably, through dual-targetable delivery to the bone matrix and folate receptor-overexpressing 4T1 tumors, the PTX-loaded nanoparticles substantially accumulated in bone metastases in vivo and inhibited 4T1 tumor growth and lung metastasis, leading to significant improvement of the survival rate of treated mice. Upon treatment with the ALN/FA-decorated PTX-loaded nanoparticles, the bone destruction and bone loss of the tumorbearing mice were appreciably retarded, and the adverse effects on normal tissues were alleviated. These results demonstrate that the ALN/FA-decorated PTX-loaded delivery system developed in this study shows great promise for the effective treatment of bone metastatic breast cancer.