Safe and Effective Reversal of Cancer Multidrug Resistance Using Sericin-Coated Mesoporous Silica Nanoparticles for Lysosome-Targeting Delivery in Mice
Safe and Effective Reversal of Cancer Multidrug Resistance Using Sericin-Coated Mesoporous Silica Nanoparticles for Lysosome-Targeting Delivery in Mice
复制标题
使用丝胶涂覆的介孔二氧化硅纳米颗粒在小鼠中进行溶酶体靶向递送，安全有效地逆转癌症多药耐药性。
DOI：
10.1002/smll.201602567
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发表时间：
2017-03-07
期刊：
影响因子：
13.3
通讯作者：
Wang, Zheng
中科院分区：
文献类型：
--
作者：
Liu, Jia;Li, Qilin;Wang, Zheng
多药耐药（MDR）和不良反应是肿瘤化疗面临的主要挑战。本文报道了pH/蛋白酶双重响应的、用于溶酶体递送阿霉素（DOX）以克服MDR并降低全身毒性的丝氨酸涂覆的介孔二氧化硅纳米颗粒（SMSNs）。蚕丝蛋白是一种天然的蛋白质，通过pH敏感的亚胺键被包覆在MSN上作为看门人。该丝胶蛋白壳防止包封的DOX从细胞外环境中的MSN中过早泄漏。一旦到达耐药肿瘤，丝胶蛋白的细胞粘附生物活性增强细胞对SMSN的摄取，SMSN又被转运到核周溶酶体中，从而避免由膜结合泵介导的药物流出。溶酶体酸性触发切割的pH敏感性连接之间的丝胶和MSNs与溶酶体蛋白酶解构的丝胶外壳。这种pH/蛋白酶双重响应性导致DOX爆发释放到细胞核中，诱导有效的细胞死亡，从而逆转MDR。这些装载DOX的SMSN不仅在体外有效地杀死耐药细胞，而且在临床前动物模型中将DOX耐药MCF-7/ADR（乳腺癌细胞）肿瘤的生长显著减少70%，而不会引发当前临床治疗制剂中经常遇到的全身毒性。因此，双重响应的SMSN是用于对抗MDR的化学治疗剂的有效的、亲溶酶体的和生物安全的递送系统。
Multidrug resistance (MDR) and adverse side effects are the major challenges facing cancer chemotherapy. Here, pH/protease dually responsive, sericin-coated mesoporous silica nanoparticles (SMSNs) for lysosomal delivery of doxorubicin (DOX) to overcome MDR and reduce systemic toxicity are reported. Sericin, a natural protein from silkworm cocoons, is coated onto MSNs as a gatekeeper via pH sensitive imine linkages. The sericin shell prevents the premature leakage of encapsulated DOX from MSNs in extracellular environment. Once reaching drug-resistant tumors, sericin's cell-adhesive bioactivity enhances cellular uptake of SMSNs that are in turn transported into perinuclear lysosomes, thus avoiding drug efflux mediated by membrane-bound pumps. Lysosomal acidity triggers cleavage of pH sensitive linkage between sericin and MSNs concurrently with lysosomal proteases deconstructing sericin shell. This pH/protease dual responsiveness leads to DOX burst release into cell nuclei, inducing effective cell death, thus reversing MDR. These DOX-loaded SMSNs not only effectively kill drug-resistant cells in vitro, but also significantly reduce the growth of DOX-resistant MCF-7/ADR (breast cancer cells) tumor by 70% in a preclinical animal model without eliciting systemic toxicity frequently encountered in current clinical therapeutic formulations. Thus, the dually responsive SMSNs are an effective, lysosome-tropic, and bio-safe delivery system for chemotherapeutics for combating MDR.