One-Pot Synthesis of an Acid-Labile Amphiphilic Triblock Copolymer and its pH-Responsive Vesicular Assembly
One-Pot Synthesis of an Acid-Labile Amphiphilic Triblock Copolymer and its pH-Responsive Vesicular Assembly
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DOI：
10.1002/anie.201302722
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发表时间：
2013-07-08
影响因子：
16.6
通讯作者：
Ghosh, Suhrit
中科院分区：
文献类型：
--
作者：
Dan, Krishna;Ghosh, Suhrit
在过去的十年中，各种“点击”反应[1]在聚合物合成[2]中产生了巨大的影响。由于硫醇基团与许多官能团如异氰酸酯、烯烃、马来酰亚胺、炔、丙烯酸酯、二硫化物、卤代烷等的高保真反应，该领域已通过包括多功能巯基化学而显著扩展。[3]如果得到的连接体对外部刺激敏感，特别是生物学相关刺激，则这些极其有效的点击反应在丰富大分子结构多样性方面的效用在功能聚合物的研究领域中将更有吸引力。[4]在这种情况下，硫醇-丙烯酸酯迈克尔加成反应是非常有吸引力的，因为它产生β-硫代丙酸酯连接基，其可以在温和的酸性条件（pH% 5.5）下以非常慢的速率选择性地水解[5]，不像其他酸不稳定的官能团，如缩醛、缩酮和腙基团，其显示出快得多的降解动力学。[6]β-硫代丙酸酯基团的这种特征与药物分子在肿瘤细胞中选择性持续释放高度相关，肿瘤细胞具有比健康细胞更酸性的环境。[7]聚合物囊泡[8]在这种情况下进行了研究，因为它们能够螯合疏水性和亲水性客体分子、高动力学稳定性和适当的粒度，以利用增强的渗透性和保留（EPR）效应。[9]聚合物囊泡主要由两亲性三嵌段或二嵌段共聚物形成，其通过各种受控聚合技术以逐步方式合成。在这种优雅的大分子支架的结构多样性已被探索到很大程度上通过产生游离的硫醇基团以及各种硫醇反应性官能团，无论是在链端或作为侧基。[10]相比之下，对于逐步增长聚合[11]很少报道类似的策略，其中，与链聚合不同，聚合物主链中的结构工程机会很多。在此，我们揭示了一种非常简单的合成方法（方案1），用于通过在一锅中使用连续的硫醇-丙烯酸酯迈克尔加成反应来合成ABA型两亲性三嵌段共聚物（P1）。[12]为了合成该聚合物，将二硫醇（M1）和二丙烯酸酯（M2）以化学计量不平衡的方式混合（M1/M2= 1.2：1.0）并在催化量的Me 2 PPh存在下缩合以产生遥爪疏水性聚合物P1 a，其被酸不稳定的β-硫代丙酸酯官能团周期性地分段，并且应该在两端含有游离巯基，因为M1过量使用。
Various “click” reactions [1] have made tremendous impact in polymer synthesis [2] during the last decade. This area has been expanded significantly by including versatile sulfhydryl chemistry owing to high-fidelity reactions of the thiol group with many functional groups such as isocyanates, alkenes, maleimides, alkynes, acrylates, disulfides, halogenated alkanes and so forth.[3] The utility of these extremely efficient click reactions in enriching the structural diversity of macromolecules will be more appealing in the research area of functional polymers, if the resulting linker is sensitive to an external stimulus, particularly a biologically relevant one.[4] In this context the thiol–acrylate Michael addition reaction is highly attractive, because it produces a β-thiopropionate linker, which can be hydrolyzed selectively under mild acidic conditions (pH% 5.5) at a very slow rate [5] unlike other acid-labile functional groups, such as acetal, ketal, and hydrazone groups, which show much faster degradation kinetics.[6] This feature of the β-thiopropionate group is highly relevant in the sustained release of drug molecules selectively in tumor cells, which have a more acidic environment than healthy cells.[7] Polymersomes [8] have been studied in this context because of their ability to sequester both hydrophobic and hydrophilic guest molecules, high kinetic stability, and appropriate particle size to utilize the enhanced permeability and retention (EPR) effect.[9] Polymersomes are formed mainly by amphiphilic triblock or diblock copolymers, which are synthesized in a stepwise manner by various controlled polymerization techniques. The structural diversity in such elegant macromolecular scaffolds has been explored to a great extent by generating free thiol groups as well as various thiol-reactive functional groups either in the chain end or as pendant.[10] In contrast similar strategies have been rarely reported for step-growth polymerizations [11] in which, unlike in chain polymerizations, opportunities are galore for structural engineering in the polymer backbone. Herein we have revealed an extremely simple synthetic approach (Scheme 1) for the synthesis of an ABA-type amphiphilic triblock copolymer (P1) by using a sequential thiol–acrylate Michael addition reaction in one pot.[12] Further we show its vesicular assembly, guest encapsulation, and pH-specific sustained-release properties.For synthesizing the polymer, a dithiol (M1) and diacrylate (M2) monomer were mixed with stoichiometric imbalance (M1/M2= 1.2: 1.0) and condensed in the presence of a catalytic amount of Me2PPh to generate a telechelic hydrophobic polymer P1a, which is periodically segmented by an acid-labile β-thiopropionate functional group and should contain free sulfhydryl groups at both ends, since M1 was used in excess.