pH-Sensitive Multiligand Gold Nanoplatform Targeting Carbonic Anhydrase IX Enhances the Delivery of Doxorubicin to Hypoxic Tumor Spheroids and Overcomes the Hypoxia-Induced Chemoresistance.
pH-Sensitive Multiligand Gold Nanoplatform Targeting Carbonic Anhydrase IX Enhances the Delivery of Doxorubicin to Hypoxic Tumor Spheroids and Overcomes the Hypoxia-Induced Chemoresistance.
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DOI：
10.1021/acsami.8b05607
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发表时间：
2018-05-30
影响因子：
9.5
通讯作者：
Ilies MA
中科院分区：
文献类型：
--
作者：
Shabana AM;Mondal UK;Alam MR;Spoon T;Ross CA;Madesh M;Supuran CT;Ilies MA
缺氧是实体瘤的一个共同特征，导致对化疗产生抵抗。选择性地将化疗药物输送到缺氧的肿瘤壁龛仍然是一个悬而未决的问题。为此，我们构建了针对碳酸酐酶IX(CAIX)表位的金纳米平台，该表位在缺氧性肿瘤细胞中比正常组织中过表达。我们设计了兼容的小分子碳酸酐酶抑制剂配体(CAI)和阿霉素(Dox)配体，并优化了AuNPs的高效修饰方案，以实现良好的靶向配体密度和最佳的载药量，同时保持胶体稳定性。与非靶向纳米平台相比，优化的Dox-HZN-DTDP@Au NPs-LA-PEG2000-CaI(THZN)纳米平台被证明对HT-29肿瘤细胞具有非常有效的杀伤作用，特别是在缺氧条件下。共聚焦显微镜显示，它还介导了阿霉素内化后在溶酶体中的有效释放。此外，使用肿瘤球体作为缺氧实体肿瘤的代表性模型，我们的THZN纳米平台增强了阿霉素选择性输送的2.5倍，并将化疗耐药性降至最低，与免费药物治疗相比，显示出更好的肿瘤药物渗透性。我们的技术是第一个以CA IX为靶标的金纳米平台，以受控的方式将阿霉素有效地输送到缺氧肿瘤，旨在改善实体肿瘤的治疗并将化疗耐药性降至最低。
Hypoxia is a common feature of solid tumors contributing to resistance to chemotherapy. Selective delivery of chemotherapeutic drugs to hypoxic tumor niche remains an unsolved issue. For this purpose, we constructed a gold nanoplatform targeting carbonic anhydrase IX (CA IX) epitope, which is overexpressed in hypoxic tumor cells versus normal tissues. We designed compatible small MW carbonic anhydrase inhibitor ligands (CAI)- and doxorubicin (Dox)-ligands, and optimized protocols for AuNPs efficient decoration to achieve both good targeting ligand density and optimum drug loading, while preserving colloidal stability. The optimized Dox-HZN-DTDP @ Au NPs-LA-PEG2000-CAI (THZN) nanoplatform proved to be very efficient towards killing HT-29 tumor cells, especially under hypoxic conditions as compared to the non-targeted nanoplatform. It also mediated the effective release of doxorubicin in the lysosomes following internalization, as revealed by confocal microscopy. Furthermore, using tumor spheroids as a representative model for hypoxic solid tumors, our THZN nanoplatform enhanced up to 2.5 times the selective delivery of doxorubicin and minimized chemoresistance, showing better tumor drug penetration as compared to free drug treatment. Our technology is the first CA IX-targeted gold nanoplatform for efficient delivery of doxorubicin to hypoxic tumors in a controlled fashion, with the perspective to improve the therapy of solid tumors and minimize chemoresistance.
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影响因子：
7.3
作者：
Akocak, Suleyman;Alam, M. Raqibul;Hies, Marc A.
通讯作者：
Hies, Marc A.
影响因子：
7.3
作者：
Cecchi, A;Hulikova, A;Supuran, CT
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作者：
Kizewski, Adrian;Ilies, Marc A.
通讯作者：
Ilies, Marc A.
影响因子：
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作者：
Lv PC;Roy J;Putt KS;Low PS
通讯作者：
Low PS