Synthesis, characterization and evaluation of in vitro toxicity in hepatocytes of linear polyesters with varied aromatic and aliphatic co-monomers.
Synthesis, characterization and evaluation of in vitro toxicity in hepatocytes of linear polyesters with varied aromatic and aliphatic co-monomers.
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DOI：
10.1016/j.jconrel.2016.08.003
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发表时间：
2016-12
期刊：
影响因子：
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通讯作者：
Deepak D Kakde;Leagh G. Powell;K. Bansal;S. Howdle;D. Irvine;G. Mantovani;G. Millar;L. Dailey;V. Stone;Helinor J Johnston;C. Alexander
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文献类型：
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作者：
Deepak D Kakde;Leagh G. Powell;K. Bansal;S. Howdle;D. Irvine;G. Mantovani;G. Millar;L. Dailey;V. Stone;Helinor J Johnston;C. Alexander
聚酯由于其可控的生物降解特性和良好的细胞相容性而广泛应用于药物输送。然而，新的酯基材料正在不断被寻找，这些材料可以从容易获得的单体中生产出来，可以被调整为药物包封，并保持良好的细胞相容性。本研究以1,10-癸二醇与不同比例的琥珀酸/苯基琥珀酸反应，合成了5种摩尔质量相近的聚酯，并考察了苯基侧链基团加成对与药物传递相关的聚合物性能的影响。选择琥珀酸和苯琥珀酸比例为70/30的聚合物是基于其在纳米颗粒（NP）配方中封装模型染料的能力，并且发现在磷酸盐缓冲盐水（PBS）中可缓慢降解，但在脂肪酶存在下降解得更快。该聚合物的NP配方与Pluronic F68稳定涂层的相容性在体外使用C3A肝细胞系进行了评估。使用Alamar蓝、CDFA和中性红测定暴露后- 124小时NP浓度范围为4.68-300 μ mL的细胞活力。C3A细胞内化包被和未包被聚酯NPs的程度相似，随着时间的推移（10-1440分钟），摄取量增加。虽然在测试浓度下细胞存活率为80%，但在所有试验中，发现Pluronic F68包被的聚（decanediol-phenylsuccinate-co-succinate）在氧化机制下刺激了显著的DNA损伤，而未包被的聚酯类似物和Pluronic F68单独没有影响。所得结果表明，从材料的角度来看，可以合成具有理想性能的新型聚酯，但添加其他赋形剂的配方需要仔细评估以用于药物传递应用。
Polyesters are extensively used in drug delivery because of their controllable biodegradation properties and perceived favorable cytocompatibility. However, new ester-based materials are continually being sought which can be produced from readily accessible monomers, which can be tuned for drug encapsulation and which retain good cellular compatibilities. In this study, 5 polyesters of similar molar mass were synthesized by reacting 1,10-decanediol with different ratios of succinic acid/phenylsuccinic acid and the effect of the phenyl side-chain group addition on polymer properties relevant to drug delivery was investigated. A polymer with a 70/30 ratio of succinic acid and phenylsuccinic acid was selected based on its ability to encapsulate a model dye in nanoparticle (NP) formulations, and was found to be slowly degradable in phosphate buffered saline (PBS) but more rapidly degraded in the presence of a lipase. The compatibility of NP formulations of this polymer either with or without a Pluronic F68 stabilizing coating was assessed in vitro using the C3A hepatocyte cell line. Cell viability was assessed, at NP concentrations ranging from 4.68–300 μg mL− 124 h post-exposure, using the Alamar Blue, CDFA and Neutral Red assays. C3A cells internalized both coated and uncoated polyester NPs to a similar extent, with uptake observed to increase over time (10–1440 min). Although cell viability was > 80% at the concentrations tested, in all assays, it was found that a Pluronic F68 coated poly (decanediol-phenylsuccinate-co-succinate) stimulated significant DNA damage driven by an oxidant mechanism, whereas the non-coated polyester analogue and the Pluronic F68 alone had no effect. The results obtained suggest that new polyesters can be synthesized with desirable properties from the materials perspective but formulation with additional excipients requires careful evaluation for drug delivery applications.