Protein nanocapsules containing doxorubicin as a pH-responsive delivery system.
Protein nanocapsules containing doxorubicin as a pH-responsive delivery system.
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DOI：
10.1002/smll.201002242
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发表时间：
2011-04-18
期刊：
影响因子：
13.3
通讯作者：
Wang, Szu-Wen
中科院分区：
文献类型：
--
作者：
Ren, Dongmei;Kratz, Felix;Wang, Szu-Wen
丙酮酸脱氢酶的E2组分已被设计成一个笼状的中空十二面体蛋白组装体，我们已经研究了这种支架通过将半胱氨酸引入内腔作为药物输送系统的可行性（D381C）。荧光染料Alexa Fluor 532 （AF532M）和抗肿瘤药物阿霉素通过客体分子上的马来酰亚胺偶联到该内腔。在纳米胶囊内部的分子结合后，病毒样颗粒的结构和稳定性保持不变。在pH 5.0条件下，腙键的pH依赖性水解使D381C支架在72小时内释放90%的药物。MDA-MB-231乳腺癌细胞的荧光显微镜显示，含有AF532M和阿霉素的D381C支架被显著摄取，并提示纳米颗粒通过内吞作用被内化。我们观察到蛋白质支架不会诱导细胞死亡，但包裹在D381C中的阿霉素确实具有细胞毒性，IC50为1.3±0.3 μM。虽然大多数基于颗粒的药物递送策略将药物封装在聚合物纳米颗粒中，但我们的研究结果显示了使用大分子蛋白质组件的潜力。这种方法为设计用于治疗递送的高度定义的纳米材料提供了一个有希望的新机会。
The E2 component of pyruvate dehydrogenase has been engineered to form a caged, hollow dodecahedral protein assembly, and we have examined the feasibility of this scaffold to be used as a drug delivery system by introducing cysteines to the internal cavity (D381C). Fluorescent dye Alexa Fluor 532 (AF532M) and the antitumor drug doxorubicin were coupled to this internal cavity through maleimides on the guest molecules. The virus-like particle’s structure and stability remained intact after binding of the molecules within the interior of the nanocapsule. The pH-dependent hydrolysis of a hydrazone linkage to doxorubicin allowed 90% drug release from the D381C scaffold within 72 hrs at pH 5.0. Fluorescence microscopy of MDA-MB-231 breast cancer cells indicated significant uptake of the D381C scaffold incorporating AF532M and doxorubicin and suggested internalization of the nanoparticles through endocytosis. We observed that the protein scaffold does not induce cell death, but doxorubicin encapsulated in D381C is indeed cytotoxic, yielding an IC50 of 1.3 ± 0.3 μM. While the majority of particulate-based drug delivery strategies encapsulates drugs within polymeric nanoparticles, our results show the potential of using macromolecular protein assemblies. This approach yields a promising new opportunity for designing highly-defined nanomaterials for therapeutic delivery.
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