Functional properties and biodistribution of poly(triethylenetetramine/cystamine bisacrylamide) and poly(triethylenetetramine/cystamine bisacrylamide)- poly (ethylene glycol) mixtures formed with nucleic acid
Functional properties and biodistribution of poly(triethylenetetramine/cystamine bisacrylamide) and poly(triethylenetetramine/cystamine bisacrylamide)- poly (ethylene glycol) mixtures formed with nucleic acid
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DOI：
10.1016/j.jconrel.2012.01.010
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发表时间：
2012-04-10
影响因子：
10.8
通讯作者：
Yockman, James W.
中科院分区：
文献类型：
--
作者：
Brumbach, Jonathan H.;Lee, Yong Won;Yockman, James W.
非病毒基因递送试剂的临床成功受到其低效的细胞转基因递送的阻碍，这在很大程度上受到目前未定义和误解的载体性质的影响。为了进一步定义和理解安全有效的非病毒基因递送试剂的要求，研究实验室经常设计和评估许多具有细微理化差异的推定产品，以描述改善体外和体内成功的要求。许多推定试剂的合成通常是耗时、费力和昂贵的。在我们实验室发表的先前手稿中，将不同量的聚（三亚乙基四胺/胱胺双丙烯酰胺）（p（TETA/CBA））及其聚乙二醇化对应物聚（三亚乙基四胺/胱胺双丙烯酰胺）-聚（乙二醇）（p（TETA/CBA）-g-PEG）混合在一起，以容易地在体外鉴定最佳试剂性质和候选物，同时避免合成许多推定的候选物用于研究。本报告使用上述简易方法来评估通过一锅合成获得的产物的试剂性质，这提高了合成的容易性。因此，合成时间从6天减少到3天，并且与以前的工作相比具有相当或改善的转染和活力。此外，该合成产生了比先前研究中使用的更高分子量的产物，并且允许用于络合的聚合物剂量更低，这对于本文使用的全身递送是有用的。在研究其在小鼠结肠腺癌模型中的体内生物分布特征之前，研究了使用这些新型试剂衍生的制剂的理化性质。有趣的是，带负电荷的复合物与带正电荷的复合物相比，在全身给药后表现出更大的被动肿瘤蓄积。这些研究保证了对使用带负电荷的药物和基因递送试剂进行被动肿瘤靶向的进一步研究，并且它们证实了使用聚阳离子/PEG-聚阳离子混合物进行简易产品评价，以阐明非病毒基因递送制剂临床成功的设计和制剂要求。(C)2012 Elsevier B. V.保留所有权利。
The clinical success of non-viral gene delivery reagents is hampered by their inefficient cellular transgene delivery, which is largely influenced by carrier properties that are currently undefined and misunderstood. In an attempt to further define and understand the requirements for a safe and efficient non-viral gene delivery reagent, research labs often engineer and evaluate many putative products with subtle physiochemical differences in order to delineate requirements for improved in vitro and in vivo success. The synthesis of many putative reagents is often time-intensive, laborious and costly. In a previous manuscript published by our lab, different amounts of poly(triethylenetetramine/cystamine bisacrylamide) (p(TETA/CBA) and its pegylated counterpart, poly(triethylenetetramine/cystamine bisacrylamide)-poly(ethylene glycol) (p(TETA/CBA)-g- PEG) were mixed together to easily identify optimal reagent properties and candidates in vitro, while avoiding the synthesis of many putative candidates for study. This report uses the aforementioned facile approach to evaluate reagent properties of products that were obtained via one-pot synthesis, which improved synthetic ease. As such, synthesis time was reduced from 6 days to 3 days and had comparable or improved transfection and viability compared to previous works. Moreover, this synthesis resulted in higher molecular weight products than were used in the previous study and allow for lower polymer doses to be used for complexation, which is useful for systemic delivery that is used herein. The physiochemical properties of the formulations derived using these novel reagents was studied prior to investigating their in vivo biodistribution profiles in a murine colon adenocarcinoma model. Interestingly, negatively charged complexes exhibited greater passive tumor accumulation compared to positively charged complexes following their systemic administration. These studies warrant further investigation for the use of negatively charged drug and gene delivery reagents for passive tumor targeting, and they substantiate the use of polycation/PEG-polycation mixtures for facile product evaluation in order to elucidate design and formulation mandates for the clinical success of nonviral gene delivery formulations. (C) 2012 Elsevier B.V. All rights reserved.