Self-activated arsenic manganite nanohybrids for visible and synergistic thermo/immuno-arsenotherapy
Self-activated arsenic manganite nanohybrids for visible and synergistic thermo/immuno-arsenotherapy
复制标题
用于可见和协同热/免疫砷疗法的自激活砷锰纳米杂化物
DOI：
10.1016/j.jconrel.2022.08.054
复制
发表时间：
2022
影响因子：
10.8
通讯作者：
Chen Huabing
中科院分区：
文献类型：
--
作者：
Zhai Yanhua;Liu ming;Yang Tao;Luo Jie;Wei Chaogang;Shen Junkang;Song Xue;Ke Hengte;Sun Peng;Guo Miao;Deng Yibing;Chen Huabing
尽管使用三氧化二砷（arsenic trioxide，ATO）治疗急性早幼粒细胞白血病（acute promyelocytic leukemia，AL），但是由于缺乏有效和可生物降解的载体，ATO不能充分递送到实体瘤中，从而阻碍了砷疗法的临床应用。因此，有效砷治疗的亚细胞ATO递送的精确时空控制仍然具有挑战性。在此，我们报告了用于高对比度磁共振成像（MRI）和砷化三阴乳腺癌（TNBC）协同作用的自激活砷锰氧化物纳米杂化物。由白蛋白纳米笼（As/Mn-NHs）内的砷锰共生物矿化纳米颗粒组成的纳米杂化物，将信号沉默背景转换为高质子弛豫率，同时在酸性和谷胱甘肽环境中提供显着的亚细胞ATO水平，以及降低ATO对肿瘤细胞的抗性。然后，纳米混合物在各种肿瘤模型中实现活体高对比度T1加权MRI信号，用于描绘肿瘤边界，同时通过多种凋亡途径产生有效的砷化物功效，用于有效抑制皮下和原位乳腺模型。As/Mn-NHs在皮下4 T1肿瘤中表现出最大肿瘤与正常组织（T/N）对比度（205%）和肿瘤生长抑制率（88%）。这些纳米杂化物在与同时热疗法组合时进一步产生针对原发性和转移性乳腺肿瘤的优选协同抗肿瘤功效。更重要的是，As/Mn-NH显著诱导免疫原性细胞死亡（ICD）效应，以将免疫原性“冷”肿瘤微环境激活为“热”微环境，从而与免疫检查点阻断协同作用，以产生最强的肿瘤抑制和可忽略的肺转移灶。我们的研究提供了对临床潜在的砷化物纳米药物有效治疗实体瘤的见解。
Arsenotherapy has been clinically exploited to treat a few types of solid tumors despite of acute promyelocytic leukemia using arsenic trioxide (ATO), however, its efficacy is hampered by inadequate delivery of ATO into solid tumors owing to the absence of efficient and biodegradable vehicles. Precise spatiotemporal control of subcellular ATO delivery for potent arsenotherapy thus remains challengeable. Herein, we report the self-activated arsenic manganite nanohybrids for high-contrast magnetic resonance imaging (MRI) and arsenotherapeutic synergy on triple-negative breast cancer (TNBC). The nanohybrids, composed of arsenic‑manganese-co-biomineralized nanoparticles inside albumin nanocages (As/Mn-NHs), switch signal-silent background to high proton relaxivity, and simultaneously afford remarkable subcellular ATO level in acidic and glutathione environments, together with reduced ATO resistance against tumor cells. Then, the nanohybrids enablein vivohigh-contrastT1-weighted MRI signals in various tumor models for delineating tumor boundary, and simultaneously yield efficient arsenotherapeutic efficacy through multiple apoptotic pathways for potently suppressing subcutaneous and orthotopic breast models. As/Mn-NHs exhibited the maximum tumor-to-normal tissue (T/N) contrast ratio of 205% and tumor growth inhibition rate of 88% at subcutaneous 4T1 tumors. These nanohybrids further yield preferable synergistic antitumor efficacy against both primary and metastatic breast tumors upon combination with concurrent thermotherapy. More importantly, As/Mn-NHs considerably induce immunogenic cell death (ICD) effect to activate the immunogenically “cold” tumor microenvironment into “hot” one, thus synergizing with immune checkpoint blockade to yield the strongest tumor inhibition and negligible metastatic foci in the lung. Our study offers the insight into clinically potential arsenotherapeutic nanomedicine for potent therapy against solid tumors.