Redox-Responsive Dual Drug Delivery Nanosystem Suppresses Cancer Repopulation by Abrogating Doxorubicin-Promoted Cancer Stemness, Metastasis, and Drug Resistance
Redox-Responsive Dual Drug Delivery Nanosystem Suppresses Cancer Repopulation by Abrogating Doxorubicin-Promoted Cancer Stemness, Metastasis, and Drug Resistance
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氧化还原响应双重药物递送纳米系统通过消除阿霉素促进的癌症干性、转移和耐药性来抑制癌症增殖
DOI：
10.1002/advs.201801987
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发表时间：
2019-04-03
期刊：
影响因子：
15.1
通讯作者：
Wang, Lin
中科院分区：
文献类型：
--
作者：
Liu, Jia;Chang, Bingcheng;Wang, Lin
化疗是癌症患者的主要治疗选择。然而，其有效性受到化学药物与残留癌细胞的内在病理相互作用的挑战。在诱导癌细胞死亡的同时，化疗药物通过上调环氧合酶-2/前列腺素E2（考克斯-2/PGE（2））信号传导增强癌症的干性、侵袭性和剩余癌细胞的耐药性，从而促进癌症再增殖和复发。为了根除肿瘤，有必要通过消除这些化疗诱导的效应来改善化疗。在此，氧化还原响应，塞来昔布修饰的介孔二氧化硅纳米粒子与聚（β-环糊精）包裹（MSCPs）的密封阿霉素（DOX）的合成。塞来昔布是FDA批准的考克斯-2抑制剂，被用作结构和功能元件，赋予MSCPs氧化还原反应性和考克斯-2/PGE（2）抑制活性。MSCPs有效地将DOX和塞来昔布共同递送到肿瘤位置，最大限度地减少全身毒性。更重要的是，MSCPs通过阻断化疗激活的考克斯-2/PGE（2）信号通路，显著增强DOX的抗肿瘤活性，抑制肿瘤的干性、侵袭性以及由DOX化疗诱导的耐药性。这在三种临床前体内肿瘤模型中也显著实现。载DOX的MSCPs通过阻断考克斯-2/PGE（2）信号传导，有效抑制肿瘤再增殖，从而消除DOX诱导的肿瘤干细胞样细胞扩增、远处转移和获得性耐药。因此，这种药物递送纳米系统能够有效地抑制肿瘤再增殖，并且具有潜在的临床转化价值。
Chemotherapy is a major therapeutic option for cancer patients. However, its effectiveness is challenged by chemodrugs' intrinsic pathological interactions with residual cancer cells. While inducing cancer cell death, chemodrugs enhance cancer stemness, invasiveness, and drug resistance of remaining cancer cells through upregulating cyclooxygenase-2/prostaglandin-E2 (COX-2/PGE(2)) signaling, therefore facilitating cancer repopulation and relapse. Toward tumor eradication, it is necessary to improve chemotherapy by abrogating these chemotherapy-induced effects. Herein, redox-responsive, celecoxib-modified mesoporous silica nanoparticles with poly(-cyclodextrin) wrapping (MSCPs) for sealing doxorubicin (DOX) are synthesized. Celecoxib, an FDA-approved COX-2 inhibitor, is employed as a structural and functional element to confer MSCPs with redox-responsiveness and COX-2/PGE(2) inhibitory activity. MSCPs efficiently codeliver DOX and celecoxib into the tumor location, minimizing systemic toxicity. Importantly, through blocking chemotherapy-activated COX-2/PGE(2) signaling, MSCPs drastically enhance DOX's antitumor activity by suppressing enhancement of cancer stemness and invasiveness as well as drug resistance induced by DOX-based chemotherapy in vitro. This is also remarkably achieved in three preclinical tumor models in vivo. DOX-loaded MSCPs effectively inhibit tumor repopulation by blocking COX-2/PGE(2) signaling, which eliminates DOX-induced expansion of cancer stem-like cells, distant metastasis, and acquired drug resistance. Thus, this drug delivery nanosystem is capable of effectively suppressing tumor repopulation and has potential clinical translational value.