Acetazolamide-Loaded pH-Responsive Nanoparticles Alleviating Tumor Acidosis to Enhance Chemotherapy Effects
Acetazolamide-Loaded pH-Responsive Nanoparticles Alleviating Tumor Acidosis to Enhance Chemotherapy Effects
复制标题
负载乙酰唑胺的 pH 响应纳米颗粒减轻肿瘤酸中毒以增强化疗效果
DOI：
10.1002/mabi.201800366
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发表时间：
2019-02-01
影响因子：
4.6
通讯作者：
Hu, Yong
中科院分区：
文献类型：
--
作者：
Liu, Sen;Luo, Xingyu;Hu, Yong
碳酸酐酶IX（CA IX）在癌细胞上过表达，催化CO2转化为碳酸氢盐和质子，有助于酸性细胞外pH（pHe），这增强了肿瘤细胞的多药耐药性。因此，减轻肿瘤酸中毒将大大改善化疗的结果。本工作制备了乙酰唑胺（ACE）负载的pH响应性纳米颗粒（ACE-NPs），其在酸性溶液（pH 6.8）中快速崩解，导致ACE从这些NPs中快速释放，以抑制CA IX的表达，从而上调pH值。这些ACE-NPs在体外没有明显的细胞毒性，体内研究证实ACE-NPs在肿瘤组织中积累。此外，用ACE和紫杉醇（PTX）共负载的NP处理的小鼠与用ACE-或PTX-负载的NP处理的小鼠相比显示出更小的肿瘤尺寸和更高的存活率。本工作揭示了ACE和化疗药物同时递送至肿瘤组织可上调酸性pH值，从而增强化疗药物的抗肿瘤能力。这些发现为临床上增强传统化疗的抗肿瘤能力打开了新的窗口。
Carbonic anhydrase IX (CA IX), over-expressed on cancer cells, catalyzes CO2 to bicarbonate and protons, contributing to the acidic extracellular pH (pHe), which enhances the multidrug resistance of tumor cells. Therefore, alleviating tumor acidosis would greatly improve the outcome of chemotherapy. This work fabricates acetazolamide (ACE)-loaded pH-responsive nanoparticles (ACE-NPs), which are quickly disintegrated in an acidic solution (pH 6.8), resulting in a quick release of ACE from these NPs to inhibit the expression of CA IX, thus up-regulating the pHe value. These ACE-NPs have no obvious in vitro cytotoxicity and in vivo studies confirm the accumulation of ACE-NPs in tumor tissue. In addition, mice treated with ACE and paclitaxel (PTX) co-loaded NPs show a smaller tumor size and a higher survival rate when compared to that of mice treated with ACE- or PTX-loaded NPs. This work reveals that simultaneous delivery of ACE and chemotherapy agents to tumor tissue can up-regulate the acidic pHe value, consequently enhancing the anti-tumor ability of chemotherapy medicine. These findings open a new window for enhancing the anti-tumor ability of traditional chemotherapy in clinic.