Bortezomib Dendrimer Prodrug-Based Nanoparticle System
Bortezomib Dendrimer Prodrug-Based Nanoparticle System
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基于硼替佐米树枝状聚合物前药的纳米颗粒系统
DOI：
10.1002/adfm.201807941
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发表时间：
2019-04-04
影响因子：
19
通讯作者：
Lu, Weiyue
中科院分区：
文献类型：
--
作者：
Hu, Xuefeng;Chai, Zhilan;Lu, Weiyue
硼替佐米（BTZ）主要用于治疗血液肿瘤，如多发性骨髓瘤和小细胞淋巴瘤。然而，由于其在体内的稳定性差和毒性，其用于实体肿瘤治疗的有用性受到限制。本文以1，1-二羟甲基丙酸和多巴胺为原料，合成了含叠氮基功能化聚乙二醇和炔基功能化树枝状大分子，并将其与多巴胺分子进行了两亲性聚乙二醇化树枝状大分子的合成。通过超声乳化法将含有多巴胺分子的两亲性聚乙二醇化树枝状大分子与BTZ反应以构建基于BTZ前药的纳米粒。基于BTZ前药的纳米颗粒具有比单独的BTZ更大的血清稳定性，并且在酸性环境中释放原型药物。基于BTZ前药的纳米颗粒比BTZ本身更有效地对抗皮下肿瘤。此外，c（RGDyK）修饰显著提高了基于BTZ前药的纳米颗粒对皮下和颅内肿瘤的抗肿瘤功效。此外，基于BTZ前药的纳米颗粒显著降低了BTZ在体内的毒性。因此，基于PEG化BTZ树枝状大分子前药的纳米颗粒具有用于体内实体肿瘤治疗的巨大潜力。
Bortezomib (BTZ) is mainly used to treat hematologic tumors, such as multiple myeloma and small cell lymphoma. However, its usefulness for solid tumor therapy is limited owing to its poor stability and toxicity in vivo. In the present study, an amphiphilic PEGylated dendrimer with dopamine molecule is synthesized from azide group-functionalized polyethylene glycol and alkyne group-functionalized dendrimer, which is produced from 1,1-dimethylolpropionic acid and dopamine. The amphiphilic PEGylated dendrimer with dopamine molecule reacts with BTZ to construct a BTZ prodrug-based nanoparticle through a ultrasonic emulsification method. The BTZ prodrug-based nanoparticles have greater serum stability than BTZ alone and release the prototype drug in acidic environments. The BTZ prodrug-based nanoparticle is more effective against subcutaneous tumors than BTZ itself. Furthermore, c(RGDyK) modification significantly improves the antitumor efficacy of the BTZ prodrug-based nanoparticle with regard to subcutaneous and intracranial tumors. Moreover, the BTZ prodrug-based nanoparticle significantly reduces the toxicity of BTZ in vivo. Therefore, the PEGylated BTZ dendrimer prodrug-based nanopartides have great potential for the treatment of solid tumors in vivo.