期刊
JOURNAL OF CONTROLLED RELEASE
卷 121, 期 1-2, 页码 19-27出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2007.04.007
关键词
delivery vehicle; nanogel polymer network; nucleoside analogs 5'-triphosphates; mitochondrial toxicity; influenza a virus
资金
- NCI NIH HHS [R01 CA102791, R01 CA102791-03, CA102791] Funding Source: Medline
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.
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