Efficient overcoming of drug resistance to anticancer nucleoside analogs by nanodelivery of active phosphorylated drugs.
Efficient overcoming of drug resistance to anticancer nucleoside analogs by nanodelivery of active phosphorylated drugs.
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DOI：
10.1016/j.ijpharm.2010.05.028
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发表时间：
2010-08-16
影响因子：
5.8
通讯作者：
Vinogradov, Serguei V.
中科院分区：
文献类型：
--
作者：
Galmarini, Carlos M.;Warren, Galya;Senanayake, Madapathage T.;Vinogradov, Serguei V.
关键词：
癌症化疗中的主要问题之一是对大多数抗癌疗法的耐药性的快速发展。因此，细胞毒性核苷类似物临床疗效最终下降的一个重要原因是选择了核苷转运蛋白或核苷活化激酶表达缺陷的耐药癌细胞。在这里，我们提出了一种有效的策略，克服这种类型的耐药性的肿瘤特异性递送纳米凝胶封装的活性三磷酸核苷类似物（NATP）。装载有阴离子NATP的可生物降解的阳离子纳米凝胶的小颗粒有效地与癌细胞相互作用，并将活性药物化合物释放到细胞质中。在核苷转运缺陷型（CEM/araC/C8）或核苷活化缺陷型（RL 7/G）淋巴源性癌细胞中评价了新型药物制剂的潜力。与核苷类似物相比，负载NATP的纳米凝胶表现出增加的细胞毒性，在CEM/araC/C8细胞中将耐药性指数降低250至900倍，在RL 7/G细胞中降低70至100倍。纳米制剂的强细胞毒性作用伴随着特征性细胞周期扰动，通常在药物处理的敏感细胞中观察到，并导致在所有研究的耐药细胞中诱导细胞凋亡。发现纳米凝胶的有效细胞积累和随后的NATP细胞内水平的增加是决定纳米制剂的细胞毒性功效的主要因素。用多分子肿瘤特异性肽（LyP 1）修饰纳米凝胶增强了纳米载体与淋巴癌细胞的结合效力。当在皮下RL 7/G异种移植肿瘤模型中注射时，活化的吉西他滨（LyP 1-NG-dFdCTP）的靶向纳米制剂显示出比吉西他滨在更高剂量下更有效两倍的肿瘤生长抑制。纳米凝胶药物制剂在治疗过程中没有表现出全身毒性，因此扩展了核苷类似物在治疗耐药淋巴源性肿瘤中的多功能性。
One of the major problems in cancer chemotherapy is the fast development of drug resistance to most anticancer therapeutics. Thus, an important cause of the eventual decline in clinical efficacy of cytotoxic nucleoside analogs was the selection of resistant cancer cells with deficiencies in the expression of nucleoside transporters or nucleoside-activating kinases. Here, we present an efficient strategy of overcoming this type of drug resistance by tumor-specific delivery of nanogel-encapsulated active triphosphates of nucleoside analogs (NATP). The small particles of biodegradable cationic nanogels loaded with anionic NATP efficiently interacted with cancer cells and released active drug compounds into the cytoplasm. The potential of novel drug formulations was evaluated in the nucleoside transport-deficient (CEM/araC/C8) or nucleoside activation-deficient (RL7/G) lymphogenic cancer cells. Compared to nucleoside analogs, NATP-loaded nanogels demonstrated increased cytotoxicity, reducing the drug resistance index 250 to 900-fold in CEM/araC/C8 cells and 70 to 100-fold in RL7/G cells. The strong cytotoxic effect of nanoformulations was accompanied by characteristic cell cycle perturbations, usually observed in drug-treated sensitive cells, and resulted in the induction of apoptosis in all studied drug-resistant cells. Efficient cellular accumulation of nanogels and the consequent increase in intracellular levels of NATP were found to be the major factors determining cytotoxic efficacy of nanoformulations. Decoration of nanogels with multiple molecules of tumor lymphatic-specific peptide (LyP1) enhanced the binding efficacy of nanocarriers with lymphogenic cancer cells. The targeted nanoformulation of activated gemcitabine (LyP1-NG-dFdCTP), when injected in subcutaneous RL7/G xenograft tumor model, demonstrated two-fold more efficient tumor growth inhibition than gemcitabine at a higher dose. Nanogel-drug formulations exhibited no systemic toxicity during the treatment, hence extending the versatility of nucleoside analogs in the treatment of drug-resistant lymphogenic tumors.
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影响因子：
11.2
作者：
Fogal V;Zhang L;Krajewski S;Ruoslahti E
通讯作者：
Ruoslahti E
影响因子：
10.8
作者：
Hillaireau, Herve;Le Doan, Trung;Couvreur, Patrick
通讯作者：
Couvreur, Patrick
影响因子：
5.8
作者：
Hillaireau, H.;Le Doan, T.;Couvreur, P.
通讯作者：
Couvreur, P.
影响因子：
10.8
作者：
Kohli, Ekta;Han, Huai-Yun;Vinogradov, Serguel V.
通讯作者：
Vinogradov, Serguel V.
影响因子：
5.7
作者：
Galmarini CM;Warren G;Kohli E;Zeman A;Mitin A;Vinogradov SV
通讯作者：
Vinogradov SV