目的 采用透明质酸(hyaluronic acid, HA)修饰聚酰胺-胺树状大分子,并通过化学键结合抗癌药物多柔比星(doxorubicin, DOX),构建用于克服肿瘤多药耐药的纳米载药系统透明质酸修饰多柔比星聚酰胺-胺纳米载药系统(DOX-PAMAM-HA)。方法 通过核磁共振(NMR)验证透明质酸修饰多柔比星聚酰胺-胺纳米载药系统的结构,用粒度分析仪和透射电镜观察其粒径分布和外观形态,使用共聚焦显微镜观察药物的细胞内分布,采用苏木精-伊红染色法(hematoxylin-eosin staining, HE)进行组织染色和毒性评价。结果 透明质酸修饰多柔比星聚酰胺-胺纳米载药系统为平均粒径323 nm的球状粒子,其在耐药性乳腺癌细胞MCF-7/ADR中的摄取明显高于药物溶液,与溶液组相比,透明质酸修饰多柔比星聚酰胺-胺纳米载药系统可在一定程度上促进药物多柔比星的入核,并可明显降低多柔比星对心和脾的毒性。结论 透明质酸修饰多柔比星聚酰胺-胺纳米载药系统是一种具有良好的克服肿瘤耐药性应用前景的纳米载药系统。
Abstract
Chemotherapy is the primary treatment in addition to surgery and radiotherapy in cancer therapy, and drug resistance of tumor cells remains a major obstacle to successful cancer chemotherapy. In present study, we aim to develop a novel drug delivery system, ie, doxorubicin (DOX) conjugated poly (amido amine) (PAMAM) dendrimers was further decorated by hyaluronic acid (HA) (DOX-PAMAM-HA) to circumvent drug resistance in cancer cells. METHODS Nuclear magnetic resonance (NMR) was performed to confirm the synthesis of the DOX-PAMAM-HA, its average size was analyzed by a dynamic light-scattering detector, and its morphological examination was performed by transmission electron microscope (TEM). To study the ability of DOX-PAMAM-HA in overcome multi-drug resistance, the multi-drug resistant breast cancer cells (MCF-7/ADR cells) was used as model cell, and the confocal microscopy was utilized to observe the drug intracellular distribution, moreover, the hematoxylin-eosin staining (HE) studies were employed to evaluate the tissue staining and toxicity. RESULTS The drug delivery system DOX-PAMAM-HA was successfully synthesized, which is spherical particles with a average particle size of 323 nm. The uptake in MCF-7/ADR cells for DOX-PAMAM-HA is higher than that of DOX solution, and DOX-PAMAM-HA maybe distribute mainly in the lysosome of the cells, which could increase the accumulation of DOX in its action target (nucleus). In contrast, DOX solution was mainly diffused in the cytoplasm of the tumor cells. Furthermore, less toxicity in heart and spleen induced by DOX-PAMAM-HA in comparing to that of DOX solution after intravenous administration for 3 weeks. CONCLUSION DOX-PAMAM-HA is a prospect future nanodrug delivery system in overcoming drug-resistance of tumor cells.
关键词
透明质酸 /
聚酰胺-胺 /
多柔比星 /
肿瘤多药耐药 /
纳米载药系统
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Key words
hyaluronic acid /
poly (amido amine) /
doxorubicin /
cancer mult-drug resistance /
nanodrug delivery system
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中图分类号：
R944
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参考文献
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脚注
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基金
深圳市重大产业技术攻关计划项目(SW201110152)
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