Tumor-targeting pH/redox dual-responsive nanosystem epigenetically reverses cancer drug resistance by co-delivering doxorubicin and GCN5 siRNA.
Tumor-targeting pH/redox dual-responsive nanosystem epigenetically reverses cancer drug resistance by co-delivering doxorubicin and GCN5 siRNA.
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DOI：
10.1016/j.actbio.2021.09.002
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发表时间：
2021-09
影响因子：
9.7
通讯作者：
Ye Yuan;Jia Liu;Xiangnan Yu;Xingxin Liu;Yanni Cheng;Cheng-peng Zhou;Mingyi Li;Lin Shi;Yan Deng;Huan Liu;Guobin Wang;Lin Wang;Zheng Wang
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文献类型：
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作者：
Ye Yuan;Jia Liu;Xiangnan Yu;Xingxin Liu;Yanni Cheng;Cheng-peng Zhou;Mingyi Li;Lin Shi;Yan Deng;Huan Liu;Guobin Wang;Lin Wang;Zheng Wang
多药耐药是恶性肿瘤化疗失败和复发的主要原因。耐多药的一个重要机制是p -糖蛋白（P-gp，一种药物外排泵）的过度表达。通过下调P-gp来提高靶向肿瘤的药物传递效率，同时抑制药物外排，是增强细胞内药物积累对抗耐多药肿瘤的有效策略。通用控制非抑制5 （GCN5）是一种组蛋白乙酰转移酶，作为多药耐药蛋白1 （MDR1）的表观遗传调节剂，在耐药癌细胞中正调控P-gp水平。本文制备了一种透明质酸包被的pH/氧化还原双响应纳米系统（HPMSNs），用于共同递送阿霉素（DOX）和GCN5 siRNA （siGCN5）。这种纳米系统可以有效地封装DOX和siRNA，防止过早泄漏，并通过pH/氧化还原双重反应在细胞内释放这些治疗药物。DOX/siGCN5@HPMSNs通过cd44介导的靶向作用，增加cd44过表达癌细胞的药物内化，并通过沉默GCN5下调耐药癌症中P-gp的表达，显著促进DOX保留。值得注意的是，在耐多药乳腺肿瘤模型中，DOX和siGCN5共同递送的hpmsn抑制耐多药肿瘤生长77%，消除p- gp介导的耐药，并消除DOX的全身毒性。因此，肿瘤靶向、刺激反应的纳米系统是共同递送抗癌药物和siRNA对抗癌症耐药的有效载体。我们设计了一种肿瘤靶向、pH/氧化还原双响应纳米系统（HPMSNs），用于化学药物和siRNA共递送。该纳米系统有效地将DOX和siGCN5共递送到耐药癌细胞中，并通过以下途径显著抑制肿瘤生长：(1)HA壳通过cd44介导的靶向作用增强了负载DOX和siGCN5的细胞内化；(2) pH/氧化还原双响应纳米系统对胞内环境的释放；(3)释放的siGCN5在表观遗传上下调P-gp。在MDR乳腺肿瘤模型（MCF7/ADR）中，DOX和siGCN5负载HPMSNs显著抑制肿瘤生长，几乎完全消除P-gp表达，并将DOX的全身毒性降至最低。
Multidrug resistance (MDR) is a major cause accounting for chemotherapy failure and recurrence of malignant tumors. A prominent mechanism underlying MDR is overexpression of P-glycoprotein (P-gp, a drug efflux pump). Promoting drug delivery efficacy by targeting tumor and concurrently suppressing drug efflux through down-regulating P-gp emerges as an effective strategy to enhance intracellular drug accumulation for combating MDR tumor. General Control Non-repressed 5 (GCN5), a histone acetyltransferase acting as an epigenetic regulator of multidrug resistance protein 1 (MDR1), positively regulates P-gp levels in drug-resistant cancer cells. Herein, a hyaluronic acid-coated, pH/redox dual-responsive nanosystem (HPMSNs) is fabricated for co-delivering doxorubicin (DOX) and GCN5 siRNA (siGCN5). This nanosystem can effectively encapsulate DOX and siRNA preventing premature leakage and releasing these therapeutics intracellularly via its pH/redox dual responsiveness. Through CD44-mediated targeting, DOX/siGCN5@HPMSNs increases drug internalization in CD44-overexpressing cancer cells, and markedly promotes DOX retention by down-regulating P-gp expression in drug-resistant cancers through silencing GCN5. Of note, in an MDR breast tumor model, DOX and siGCN5 co-delivered HPMSNs inhibits MDR tumor growth by 77%, abolishes P-gp-mediated drug resistance, and eliminates DOX's systemic toxicity. Thus, the tumor-targeting, stimuli-responsive nanosystem is an effective carrier for co-delivering anticancer drug and siRNA for combating cancer drug resistance.Statement of significanceWe designed a tumor-targeting, pH/redox dual-responsive nanosystem (HPMSNs) for chemo-drug and siRNA co-delivery. This nanosystem efficiently co-delivered DOX and siGCN5 into drug-resistant cancer cells and significantly inhibited the tumor growth through: (1) HA shell enhanced the cellular internalization of loaded DOX and siGCN5 via CD44-mediated targeting; (2) the pH/redox dual-responsive nanosystem released the cargos in response to the intracellular environment; (3) the released siGCN5 downregulated P-gp epigenetically. In an MDR breast tumor model (MCF7/ADR), DOX and siGCN5 loaded HPMSNs markedly inhibited tumor growth, almost completely abolished P-gp expression, and minimized systemic toxicity of DOX.