Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs
Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs
复制标题
设计和制造多功能丝胶纳米粒子，用于癌症化疗药物的肿瘤靶向和 pH 响应亚细胞递送
DOI：
10.1021/acsami.5b11617
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发表时间：
2016-03-16
影响因子：
9.5
通讯作者：
Wang, Lin
中科院分区：
文献类型：
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作者：
Huang, Lei;Tao, Kaixiong;Wang, Lin
肿瘤化疗药物的严重细胞毒性限制了其临床应用。为了减少药物的副作用，各种具有良好生物相容性的蛋白质纳米粒被开发出来用于化疗药物的缓释。丝胶是从蚕丝中提取的一种天然蛋白质，不具有免疫原性，具有多种生物活性，这促使了丝胶的应用研究。然而，丝胶作为一种多功能纳米载体用于癌症治疗的潜力还没有被充分开发。在这里，我们成功地制备和表征了具有肿瘤靶向能力的叶酸偶联丝胶纳米粒(这些纳米粒被称为FA-SND)，以响应阿霉素的pH响应释放。DOX与丝胶“通过对pH敏感的腙键形成pH触发的释放特性而共价连接。DOX的疏水性和丝胶的亲水性促进了丝胶-DOX(SND)纳米结合物的自组装。然后将Mate(FA)共价嫁接到SND纳米结合物上，作为结合单位，主动靶向过度表达叶酸受体的癌细胞。我们的表征研究表明，FA-SND纳米颗粒表现出表面负电荷，这将减少循环的非特异性清除。这些纳米粒子具有良好的细胞毒性和血液相容性。酸性环境(pH 5.0)触发FA-SND有效释放DOX，是中性条件(pH 7.4)的5倍。此外，FA-SND纳米颗粒专门针对富含叶酸受体的KB细胞，并内吞到溶酶体中，溶酶体是一种酸性细胞器。溶酶体的酸性微环境促进DOX快速释放到细胞核，产生癌症特异性的化学细胞毒性。因此，FA介导的肿瘤靶向和溶酶体酸性促进DOX释放，这两个由FA-SND设计的组分触发的顺序发生的细胞事件，构成了FA-SND实现其局部和细胞内化学细胞毒性的基础。综上所述，这项研究表明，这些FA-SND纳米颗粒可能是一种潜在的有效载体，特别适用于输送疏水性化疗药物，用于治疗叶酸受体高表达的癌症。
The severe cytotoxicity of cancer chemotherapy drugs limits their clinical applications. Various protein-based nanoparticles with good biocompatibility have been developed for chemotherapy drug delivery in hope of reducing drugs' side effects. Sericin, a natural protein from silk, has no immunogenicity and possesses diverse bioactivities that have prompted sericin's application studies. However, the potential of sericin as a multifunctional nanoscale vehicle for cancer therapy have not been fully explored. Here we report the successful fabrication and characterization of folate-conjugated sericin nanoparticles with cancer targeting capability for pH-responsive release of doxorubicin (these nanoparticles are termed "FA-SND"). DOX is covalently linked to sericin "through pH-sensitive hydrazone bonds that render a pH-triggered release property. The hydrophobicity of DOX and the hydrophilicity of sericin promote the self-assembly of sericin-DOX (SND) nanoconjugates. Mate (FA) is then covalently grafted to SND nanoconjugates as a binding unit for actively targeting cancer cells that overexpress folate receptors. Our characterization study shows that FA-SND nanoparticles exhibit negative surface charges that would reduce nonspecific clearance by circulation. These nanoparticles possess good cytotoxicity and hemocompatibiliy. Acidic environment (pH 5.0) triggers effective DOX release from FA-SND, 5-fold higher than does a neutral condition (pH 7.4). Further, FA-SND nanoparticles specifically target folate-receptor-rich KB cells, and endocytosed into lysosomes, an acidic organelle. The acidic microenvironment of lysosomes promotes a rapid release of DOX to nuclei, producing cancer specific chemo-cytotoxicity. Thus, FA-mediated cancer targeting and lysosomal-acidity promoting DOX release, two sequentially-occurring cellular events triggered by the designed components of FA-SND, form the basis for FA-SND to achieve its localized and intracellular chemo-cytotoxicity. Together, this study suggests that these FA-SND nanoparticles may be a potentially effective carrier particularly useful for delivering hydrophobic chemotherapeutic agents for treating cancers with high-level expression of folate receptors.