Preparation of ideal PEG analogues with a tunable thermosensitivity by controlled radical copolymerization of 2-(2-methoxyethoxy)ethyl methacrylate and oligo(ethylene glycol) methacrylate
Preparation of ideal PEG analogues with a tunable thermosensitivity by controlled radical copolymerization of 2-(2-methoxyethoxy)ethyl methacrylate and oligo(ethylene glycol) methacrylate
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DOI：
10.1021/ma0517042
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发表时间：
2006-01-24
期刊：
影响因子：
5.5
通讯作者：
Hoth, A
中科院分区：
文献类型：
--
作者：
Lutz, JF;Hoth, A
聚（乙二醇）（PEG）（根据合成条件也称为聚（环氧乙烷）（PEO））是一种廉价、中性、水溶性、生物相容性、FDA批准的聚合物，因此可能是生物技术和医学中应用最广泛的合成聚合物。1例如，PEG是用于体内递送各种生物活性化合物的优良屏蔽剂。事实上，PEG允许在生理介质中具有良好的溶解性，并防止可引发免疫应答的血浆蛋白的吸附。2，3因此，PEG广泛用于递送低分子量药物、活性肽、蛋白质或遗传物质。4-7存在不同的合成策略用于构建基于PEG的递送载体。第一种方法依赖于活性物质与PEG的直接共价缀合（通常称为PEG化的合成途径）。两者之间的共价键可以是稳定的（永久聚乙二醇化）或不稳定的（前药策略）。另一种方法依赖于活性物质在人工纳米载体（例如，纳米球、胶束、囊泡或复合物）的受保护的内部区域（核心、内层、中空）中的物理截留。例如，通过三嵌段共聚物PEO-b-聚（环氧丙烷）-b-PEO 8（商业上称为Pluronic）或二嵌段共聚物PEO-b-多肽6，9的水性自组装获得的纳米载体已广泛应用于生命科学中。这些经典的基于PEO的结构单元通常通过阴离子开环聚合制备。然而，在过去的几年中，受控自由基聚合（CRP）技术如原子转移自由基聚合（ATRP）、氮氧自由基介导聚合（NMP）和可逆加成-断裂转移聚合（RAFT）已越来越被认为是制备用于生命科学的明确结构单元的直接替代方法。11-19特别地，ATRP被证明是制备基于PEG的两亲物的非常通用的途径。13，20-24然而，“PE-糖基化”的可能性在ATRP中仍然非常有限。在ATRP中已经使用了两种合成路线来将PEG掺入大分子结构中（方案1）。第一种是大分子引发剂方法，其中通过阴离子聚合制备的ω-羟基-PEG片段转化为ATRP引发剂（方案1a）。后者可以通过将PEG的羟基末端官能团与2-溴-2-甲基丙酰溴23，25，26或2-溴异丁酸偶联来获得。20，22这种方法并不简单，因为它需要在阴离子聚合和CRP之间的界面处工作。26实际上，商业R-甲氧基-ω-羟基-PEG聚合物可用于此类合成，20，22，23但在这种情况下，PEG片段的分子结构仅限于市售化合物（即，可以购买有限范围的分子量和R-官能度）。这种方法的另一个主要缺点是在PEG链段和ATRP引发剂之间（因此，在PEG链段和通过ATRP生长的连续嵌段之间）形成可水解的酯键，这在大多数情况下对于在水性介质中的应用是有问题的。Haddleton及其同事以及Armes及其同事的开创性工作优雅地说明，这种策略是将PEG纳入由CRP构建的大分子结构中的非常方便的替代方案。17，27，28然而，PEG...
Poly (ethylene glycol)(PEG)(also known as poly (ethylene oxide)(PEO) depending on the synthetic conditions) is a cheap, neutral, water-soluble, biocompatible, FDA-approved polymer and thus is probably the most widely applied synthetic polymer in biotechnology and medicine. 1 For instance, PEG is an excellent shielding agent for in vivo delivery of various bioactive compounds. Indeed, PEG allows a good solubility in physiological media and prevents the adsorption of plasma proteins, which can trigger immune response. 2, 3 Thus, PEG was extensively used in delivery of either low molecular weight drugs, active peptides, proteins, or genetic material. 4-7 Different synthetic strategies exist for constructing PEG-based delivery vehicles. A first approach relies on the direct covalent conjugation of an active substance with PEG (a synthetic route commonly known as PEGylation). The covalent linkage between both can be either stable (permanent PEGylation) or labile (prodrug strategy). Another approach relies on the physical entrapment of active substances in the protected internal regions (core, internal layer, hollow) of artificial nanocarriers (eg, nanospheres, micelles, vesicles or polyplexes). For example, nanocarriers obtained via the aqueous self-assembly of triblock copolymers PEO-b-poly (propylene oxide)-b-PEO8 (known commercially as Pluronic) or diblock copolymers PEO-b-polypeptide6, 9 have been extensively applied in life science. These classic PEO-based building blocks are typically prepared by anionic ring-opening polymerization. However in the past few years, controlled radical polymerization (CRP) techniques such as atom transfer radical polymerization (ATRP), 10 nitroxide-mediated polymerization (NMP), 10 and reversible addition-fragmentation transfer polymerization (RAFT) 10 have been more and more considered as a straightforward alternative for preparing welldefined building blocks for life science. 11-19 In particular, ATRP was proven to be a very versatile pathway for preparing PEG-based amphiphiles. 13, 20-24 However, the possibilities of “PE-Gylation” are still very limited in ATRP. Two synthetic routes have been used in ATRP for incorporating PEG in macromolecular constructions (Scheme 1). The first one is a macroinitiator approach, in which an ω-hydroxy-PEG segment prepared by anionic polymerization is transformed into an ATRP initiator (Scheme 1a). The latter can be obtained by coupling the hydroxy terminal functionality of PEG with either 2-bromo-2-methylpropionyl bromide23, 25, 26 or 2-bromoisobutyric acid. 20, 22 Such an approach is not straightforward since it requires to work at the interface between anionic polymerization and CRP. 26 Indeed, commercial R-methoxy-ω-hydroxy-PEG polymers can be used for such synthesis, 20, 22, 23 but in this case the molecular structure of the PEG segment is only limited to commercially available compounds (ie, a limited range of molecular weight and R-functionalities can be bought). Another major disadvantage of such approach is the formation of a hydrolyzable ester linkage between the PEG segment and the ATRP initiator (thus, between the PEG segment and the successive block grown by ATRP), which is in most cases problematic for applications in aqueous media.The second approach directly polymerizes of a radically polymerizable PEG macromonomer such as oligo (ethylene glycol) methacrylate (OEGMA). The pioneering works of Haddleton and co-workers and Armes and co-workers elegantly illustrate that such strategy is a very convenient alternative for incorporating PEG in macromolecular architectures built by CRP. 17, 27, 28 However, the PEG …