EGFR和CD44双靶多功能透明质酸纳米凝胶可促进体内和体内向卵巢癌和乳腺癌的蛋白质递送。,ACS Applied Materials & Interfaces

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EGFR和CD44双靶多功能透明质酸纳米凝胶可促进体内和体内向卵巢癌和乳腺癌的蛋白质递送。
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2017-07-10 00:00:00 , DOI: 10.1021/acsami.7b06879
Jing Chen ₁ , Jia Ouyang ₂ , Qijun Chen ₁ , Chao Deng ₁ , Fenghua Meng ₁ , Jian Zhang ₁ , Ru Cheng ₁ , Qing Lan ₂ , Zhiyuan Zhong ₁

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具有细胞内靶标的蛋白药物（例如Granzyme B（GrB））已在癌细胞中表现出极大的增殖抑制活性。然而，它们的临床翻译依赖于安全，有效和选择性的蛋白质递送载体的开发。在这里，我们报告表皮生长因子受体（EGFR）和CD44双靶向多功能透明质酸纳米凝胶（EGFR / CD44-NGs）在体外和体内增强了蛋白质向卵巢癌和乳腺癌的递送。通过透明质酸衍生物与四唑，GE11肽/四唑和甲基丙烯酸胱胺通过纳米沉淀和光点击化学获得的EGFR / CD44-NG具有几乎定量的治疗性蛋白质负载量，例如细胞色素C（CC）和GrB，大约小。165 nm，出色的血清稳定性，在还原条件下快速释放蛋白质。流式细胞仪分析表明，EGFR / CD44-NGs在CD44和EGFR阳性SKOV-3卵巢癌细胞中的摄取比CD44-NGs高出6倍以上。因此，与GrB加载的CD44-NGs（GrB-CD44-NGs）对照相比，GrB加载的EGFR / CD44-NGs（GrB-EGFR / CD44-NGs）在SKOV-3细胞中显示出增强的胱天蛋白酶活性和生长抑制。有趣的是，对裸鼠异种移植的SKOV-3人卵巢癌和MDA-MB-231人乳腺肿瘤的治疗研究表明，低剂量3.85 nmol GrB equiv / kg的GrB-EGFR / CD44-NGs几乎可以完全抑制生长这两种肿瘤均明显优于GrB-CD44-NGs，而没有引起任何不良反应。EGFR和CD44双重靶向多功能透明质酸纳米凝胶已成为癌症蛋白治疗的安全有效平台。

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EGFR and CD44 Dual-Targeted Multifunctional Hyaluronic Acid Nanogels Boost Protein Delivery to Ovarian and Breast Cancers In Vitro and In Vivo

Protein drugs with intracellular targets like Granzyme B (GrB) have demonstrated great proliferative inhibition activity in cancer cells. Their clinical translation, however, relies on the development of safe, efficient, and selective protein-delivery vehicles. Here, we report that epidermal growth factor receptor (EGFR) and CD44 dual-targeted multifunctional hyaluronic acid nanogels (EGFR/CD44-NGs) boost protein delivery to ovarian and breast cancers in vitro and in vivo. EGFR/CD44-NGs obtained via nanoprecipitation and photoclick chemistry from hyaluronic acid derivatives with tetrazole, GE11 peptide/tetrazole, and cystamine methacrylate groups had nearly quantitative loading of therapeutic proteins like cytochrome C (CC) and GrB, a small size of ca. 165 nm, excellent stability in serum, and fast protein release under a reductive condition. Flow cytometry assays showed that EGFR/CD44-NGs exhibited over 6-fold better uptake in CD44 and EGFR-positive SKOV-3 ovarian cancer cells than CD44-NGs. In accordance, GrB-loaded EGFR/CD44-NGs (GrB-EGFR/CD44-NGs) displayed enhanced caspase activity and growth inhibition in SKOV-3 cells as compared to GrB-loaded CD44-NGs (GrB-CD44-NGs) control. Intriguingly, the therapeutic studies in SKOV-3 human ovarian carcinoma and MDA-MB-231 human breast tumor xenografted in nude mice revealed that GrB-EGFR/CD44-NGs at a low dose of 3.85 nmol GrB equiv/kg induced nearly complete growth suppression of both tumors, which was obviously more effective than GrB-CD44-NGs, without causing any adverse effects. EGFR and CD44 dual-targeted multifunctional hyaluronic acid nanogels have appeared as a safe and efficacious platform for cancer protein therapy.

更新日期：2017-07-11

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