Bioengineered yeast-derived vacuoles with enhanced tissue-penetrating ability for targeted cancer therapy
Bioengineered yeast-derived vacuoles with enhanced tissue-penetrating ability for targeted cancer therapy
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DOI：
10.1073/pnas.1509371113
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发表时间：
2016-01-19
影响因子：
11.1
通讯作者：
Jon, Sangyong
中科院分区：
文献类型：
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作者：
Gujrati, Vipul;Lee, Miriam;Jon, Sangyong
尽管合成纳米材料在临床前研究中用于靶向癌症治疗取得了可观的成功，但涉及其大规模、成本效益高的生产和与材料相关的固有毒性的技术挑战，以及它们无法深入穿透肿瘤组织，限制了它们的临床转化。在这里，我们描述了从生物工程酵母菌株开发的生物衍生纳米载体，它可以克服这些障碍。对芽殖酵母酿酒酵母进行基因工程改造以产生纳米级空泡，其展示用于主动靶向的人表皮生长因子受体2（HER2）特异性抗体。这些纳米大小的空泡有效地装载抗癌药物阿霉素（Dox），并被培养的癌细胞有效地内吞。它们的癌症靶向能力，沿着其独特的内膜组成，显著增强了药物在多细胞培养物中的渗透，并改善了药物在肿瘤异种移植物中的分布。此外，装载Dox的空泡成功地阻止了肿瘤生长，而没有引发任何延长的免疫应答。目前的研究提供了一个平台技术，用于产生癌症特异性，组织穿透性，安全性和可扩展的生物纳米粒子，用于靶向癌症治疗。
Despite the appreciable success of synthetic nanomaterials for targeted cancer therapy in preclinical studies, technical challenges involving their large-scale, cost-effective production and intrinsic toxicity associated with the materials, as well as their inability to penetrate tumor tissues deeply, limit their clinical translation. Here, we describe biologically derived nanocarriers developed from a bioengineered yeast strain that may overcome such impediments. The budding yeast Saccharomyces cerevisiae was genetically engineered to produce nanosized vacuoles displaying human epidermal growth factor receptor 2 (HER2)-specific affibody for active targeting. These nanosized vacuoles efficiently loaded the anticancer drug doxorubicin (Dox) and were effectively endocytosed by cultured cancer cells. Their cancer-targeting ability, along with their unique endomembrane compositions, significantly enhanced drug penetration in multicellular cultures and improved drug distribution in a tumor xenograft. Furthermore, Dox-loaded vacuoles successfully prevented tumor growth without eliciting any prolonged immune responses. The current study provides a platform technology for generating cancer-specific, tissue-penetrating, safe, and scalable biological nanoparticles for targeted cancer therapy.