Synthesis of Well-Defined Polymer Nanoparticles
Synthesis of Well-Defined Polymer Nanoparticles
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明确聚合物纳米颗粒的合成
DOI：
10.14264/166443
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发表时间：
2008
期刊：
影响因子：
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通讯作者：
Carl N. Urbani
中科院分区：
文献类型：
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作者：
Carl N. Urbani
明确的聚合物纳米颗粒的合成将立即在生物医学行业中得到应用，作为用于控制递送和释放水不溶性药物的纳米容器。控制分子量、颗粒形态和化学官能度以及获得具有窄分子量和粒度分布的聚合物纳米颗粒的能力对于其特定应用的设计至关重要。研究了两种合成方法来合成明确的聚合物纳米颗粒：乳液聚合和自组装。在乳液聚合中成功实施可逆加成-断裂链转移（RAFT）是控制纳米颗粒分子量和尺寸时面临的第一个挑战。最初，我们证明可以使用非离子表面活性剂成功地进行苯乙烯的“活性”乳液聚合。在制备低分子量聚合物（5 和 9 K 目标 Mn，多分散性 (PDI) 低于 1.2）时取得了成功。当 Mn 的目标值大于 20 K（100% 转化率）时，就会出现与理想“生活”行为的偏差。然后研究了“脱气技术”，作为在不添加表面活性剂的情况下通过乳液聚合生成稳定的聚苯乙烯纳米颗粒的途径（残留的表面活性剂会对产品质量产生不利影响）。这种乳液体系在低反应性 RAFT 试剂存在下的聚合本质上是“活的”。在高反应性 RAFT 剂存在下，乳液体系表现出“活性”性质，然而，发生二次成核，从而导致宽分子量分布 (MWD)。因此，制备明确的聚合物纳米颗粒的乳液聚合方法给出的结果不太理想。制备具有受控化学组成和形态的聚合物纳米粒子的另一种方法是在水中自组装预合成的嵌段共聚物。与乳液体系相比，这种方法具有几个显着的优点：（i）所有聚合物链的链长和化学组成接近均匀，（ii）疏水性和亲水性聚合物之间的比例可以轻松控制，（iii）化学官能团可以位于不同的形态区域，（iv）可以制备除球体之外的各种3维结构（即棒和囊泡），以及（v）不使用通常在乳液聚合后发现的添加剂，例如表面活性剂，稳定剂和残留单体。自组装方法中需要。这些优势证明了我们战略转变的合理性。自组装过程的唯一缺点是不能达到水中聚合物的高重量分数，并且通常限制在2重量％以下，而乳液聚合可以允许聚合物的重量分数接近50重量％。通过RAFT溶液聚合制备的结构明确的两亲性4臂星形聚丙烯酸-嵌段-聚苯乙烯(PAA-b-PSTY)共聚物分散在水中形成核-壳胶束，其中壳由束缚的PAA环组成。与相同臂长的线性二嵌段共聚物相比，具有此类环的熵损失导致 PSTY 核的堆积密度较低。由于束缚点，壳的表面是不规则的，但当 PAA 链断裂时，它会延伸形成规则且相对均匀的冠。控制聚合物结构能够合成具有束缚 PAA 环的聚合物胶束，需要时可以打开形成均匀的电晕。然后，结合原子转移自由基聚合 (ATRP) 和 Huisgen 1,3-偶极环加成“点击”反应，合成了由 PSTY、聚丙烯酸叔丁酯 (PtBA)、聚丙烯酸甲酯 (PMA) 和 PAA 组成的三分子臂星形和树枝状聚合物。在所有反应中，星形和树枝状大分子的轮廓清晰，PDI 低于 1.09。这是合成明确的高度有序聚合物结构的第一步。这种结构的合成在每个合成步骤都需要高纯度，以消除副反应的可能性，从而降低产物收率。采用反应性固体支持物的合成和使用来去除过量的线性聚合物，以增加聚合三臂星形聚合物和树枝状聚合物的产率。这些载体是一种清除具有叠氮基或炔基官能团的聚合物物质的廉价方法，之后可以将固体载体从产品中过滤掉。这些载体有助于合成第三代聚合树枝状分子和树枝状聚合物，其由均聚物 PSTY 与外围的醇缩酮或醇、二嵌段 PSTY 和 PtBA 以及两亲性二嵌段组成。用于构建这些结构的方法是结合 ATRP 来生产具有遥爪功能的线性聚合物，随后使用该功能通过“点击”反应将聚合物连接在一起。水中两亲结构的胶束化产生尺寸均匀的聚合物纳米粒子。树枝状聚合物纳米颗粒直径为 18 nm，由 19 个单独的树枝状聚合物组成。树枝状聚合物很可能没有相互渗透，因此均匀堆积形成胶束。树突纳米粒子的直径为 21 nm，每个胶束聚集了 43 个树突，这表明它们形成锥状结构并自组装形成平头胶束。使用聚合方法，使用铜线作为“点击”催化剂，合成由 PSTY、PMA、PtBA 和 PAA 组成的高纯度聚合物结构，该结构具有前所未有的化学多样性（疏水性或两亲性）和复杂性（具有可降解核心的 G2 miktoarm 树枝状聚合物）。
The synthesis of well-defined polymer nanoparticles will have immediate applications in the biomedical industry as nanocontainers for the controlled delivery and release of water insoluble drugs. The ability to control molecular weight, particle morphology and chemical functionality and to obtain polymeric nanoparticles with narrow molecular weight and particle size distributions is paramount for their application-specific design. Two synthetic approaches were investigated in the synthesis of well-defined polymer nanoparticles, emulsion polymerization and self assembly. The successful implementation of Reversible Addition-Fragmentation Chain Transfer (RAFT) in emulsion polymerization was the first challenge faced when controlling nanoparticle molecular weight and size. Initially we showed that successful ‘living’ emulsion polymerizations of styrene could be carried out using a non-ionic surfactant. The success was achieved when preparing polymers of low molecular weight (5 and 9 K targeted Mn’s with polydispersities (PDIs) below 1.2). Deviation from ideal ‘living’ behavior occurred when targeting Mn’s greater than 20 K (at 100 % conversion). The ‘degassing technique’ was then investigated as an avenue to generate stable polystyrene nanoparticles by emulsion polymerization without the addition of surfactant (residual surfactant can result in detrimental effects on product quality). The polymerization of this emulsion system in the presence of a low reactive RAFT agent was ‘living’ in nature. In the presence of a high reactive RAFT agent the emulsion system showed ‘living’ nature, however, secondary nucleation occurred, which resulted in broad molecular weight distribution (MWD). Thus, the emulsion polymerization approach to preparing well-defined polymer nanoparticles was giving less than desirable results. An alternative method to prepare polymer nanoparticles with controlled chemical composition and morphology is to self assemble pre-synthesized block copolymers in water. This approach has several significant advantages over the emulsion systems: (i) all polymer chains are of near uniform chain length and chemical composition, (ii) the ratio between the hydrophobic and hydrophilic polymers can easily be controlled, (iii) chemical functionality can be located in different morphological regions, (iv) a wide range of 3-dimensional structures apart from spheres can be prepared (i.e. rods and vesicles), and (v) additives such as surfactant, stabilizers and residual monomer usually found after an emulsion polymerization are not required in the self assembly methodology. These advantages justify our shift in strategy. The only disadvantage of the self assembly process is that one cannot reach high weight fractions of polymer in water and is usually limited to below 2 wt-%, where as emulsion polymerizations can allow weight fractions of polymer close to 50 wt-%. Well-defined amphiphilic 4-arm star polyacrylic acid-block-polystyrene (PAA-b-PSTY) copolymers, prepared by RAFT solution polymerization, were dispersed in water to form core-shell micelles, in which the shell consisted of tethered PAA loops. The entropic penalty for having such loops resulted in a less densely packed PSTY core when compared to linear diblock copolymers of the same arm length. The surface of the shell was irregular due to the tethering points, but when cleaved the PAA chains extended to form a regular and relatively uniform corona. Controlling the polymer architecture enabled the synthesis of polymer micelles with tethered PAA loops, which could be opened to form uniform corona when desired. Three-miktoarm star and dendrimers with miktoarms consisting of PSTY, polytert-butyl acrylate (PtBA), polymethyl acrylate (PMA) and PAA were then synthesized using a combination of Atom Transfer Radical Polymerization (ATRP) and Huisgen 1,3-dipolar cycloaddition ‘click’ reactions. In all reactions, the stars and dendrimers were well-defined with PDIs lower than 1.09. This was the first step in the synthesis of well-defined highly ordered polymer structures. The synthesis of such structures demands high level of purity at each synthetic step eliminating the possibility of side reactions, which as of consequence lowers product yields. The synthesis and use of reactive solid supports to remove excess linear polymer to increase the yields of polymeric 3-arm stars and dendrimers was employed. These supports are a cheap approach to scavenge polymeric species with either azido or alkynyl functionality, after which the solid support can be filtered away from the product. These supports aided the synthesis of 3rd generation polymeric dendrons and dendrimers consisting of homopolymer PSTY with either solketals or alcohols at the periphery, diblock PSTY and PtBA, and amphiphilic diblock. The methodology used to construct these structures was a combination of ATRP to produce linear polymers with telechelic functionality, with the subsequent use of this functionality to join the polymers together via ‘click’ reactions. Micellization of the amphiphilic structures in water produced polymer nanoparticles of uniform size. The dendrimer nanoparticles were 18 nm in diameter, consisting of 19 individual dendrimers. The dendrimers most probably have no mutual interpenetration and thus pack uniformly to form the micelles. The dendron nanoparticles were 21 nm with an aggregation number of 43 dendrons per micelle, which suggests they form cone-like structures and self-assemble to form crew-cut micelles. Using a convergent approach polymer structures with unprecedented chemical diversity (hydrophobic or amphiphilic) and complexity (G2 miktoarm dendrimers with a degradable core) consisting of PSTY, PMA, PtBA and PAA were then synthesized with high purity using copper wire as the ‘click’ catalyst.