Formulations of biodegradable Nanogel carriers with 5'-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity
Formulations of biodegradable Nanogel carriers with 5'-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity
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DOI：
10.1016/j.jconrel.2007.04.007
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发表时间：
2007-08-16
影响因子：
10.8
通讯作者：
Vinogradov, Serguel V.
中科院分区：
文献类型：
--
作者：
Kohli, Ekta;Han, Huai-Yun;Vinogradov, Serguel V.
包括核苷类似物在内的治疗与严重的毒副作用和获得耐药性有关。我们之前报道过5'-三磷酸盐（NTP）包裹在聚乙烯亚胺（PEI）和PEG/Pluronic（(R)）聚合物（纳米凝胶）交联阳离子网络中的药物递送形式。本研究合成了含有可生物降解PEI的纳米凝胶，该纳米凝胶在还原胞质环境中容易解离，形成的产物毒性很小，具有低细胞毒性。纳米凝胶的毒性明显取决于载体的总正电荷，并且负载NTP的载体的毒性降低了5-6倍。虽然细胞内ATP水平在纳米凝胶处理后立即降低了约50%，但随后基本恢复。纳米凝胶对细胞的各种呼吸成分的影响也是可逆的，因此，导致细胞的低立即死亡。纳米凝胶和AZT- tp制剂的线粒体毒性比AZT低得多。作为低毒纳米凝胶载体潜在抗病毒应用的一个例子，制备了一种5'-三磷酸化利巴韦林纳米凝胶制剂，在感染甲型流感病毒的MDCK细胞中，与单独使用该药物相比，有效药物浓度（EC90）降低了30倍，选择性指数增加了10倍。(C) 2007 Elsevier B.V.版权所有
Therapies including nucleoside analogs are associated with severe toxic side effects and acquirement of drug resistance. We have previously reported the drug delivery in the form of 5'-triphosphates (NTP) encapsulated in cross-linked cationic networks of polyethylenimine (PEI) and PEG/Pluronic((R)) polymers (Nanogels). In this study, Nanogels, containing biodegradable PEI that could easily dissociate in reducing cytosolic environment and form products with minimal toxicity, were synthesized and displayed low cytotoxicity. Toxicity of Nanogels was clearly dependent on the total positive charge of carriers and was 5-6 fold lower for carriers loaded with NTP. Though intracellular ATP level was immediately reduced by ca. 50% following the treatment with Nanogels, it was largely restored 24 It later. Effect of Nanogels on various respiratory components of cells was reversible too, and, therefore, resulted in low immediate cell death. Nanogel alone and formulations with AZT-TP demonstrated a much lower mitochondrial toxicity than AZT. As an example of potential antiviral applications of low-toxic Nanogel carriers, a 5'-triphosphorylated Ribavirin-Nanogel formulation was prepared that demonstrated a 30-fold decrease in effective drug concentration (EC90) and, totally, a 10-fold increase in selectivity index compared to the drug alone in MDCK cells infected with influenza A virus. (C) 2007 Elsevier B.V. All rights reserved.