摘要
树形分子因其具有独特的树枝状分子结构以及多价协同作用等特性在生物医学领域具有广阔的应用前景。然而树形分子合成繁琐费时、纯化困难,使得大规模制备高代无缺陷的树形分子困难重重。为了克服这一困难,研究人员提出了一种基于自组装的方法构建树形分子的策略,即利用低代的两亲性树形分子自组装构建非共价超分子树形分子,用以模拟高代共价树形分子。本文介绍超分子树形分子的研究及其在生物医学领域的应用,例如输送小分子抗肿瘤药物、核酸治疗试剂和分子造影剂等,并通过一些代表性的实例展现超分子树形分子的应用前景与挑战。
1978年,Buhleier
树形分子是一类具有独特的树枝状结构的合成高分子(

Figure 1 Illustration of the structure of a dendrimer composed of a central core, the repetitive branching units which form the generations, and the terminal groups on the dendrimer surface. The central core itself is generation 0 (G0); generation 1 (G1), generation 2 (G2) and generation 3 (G3) refer to dendrimers with the first, second and third levels of branching, respectively
由于树形分子特殊的分子结构和多价协同作用,它们在生物医学领域有着广泛的应用前景,例如诊断、药物和药物递送以及基因递
不同于传统高分子“一锅煮”的制备方法,树形分子是通过逐步合成法来构建的,这一方法使树形分子具有精确的结构和优异的单分散性。树形分子的合成策略一般可分为发散法、收敛法或发散/收敛组合法(

Figure 2 Cartoon presentation of the different approaches for dendrimer synthesis
A:Divergent approach; B:Convergent approach; C:Combined divergent and convergent approach
通过发散法可以制备高达10代的树形分子,但高代树形分子常伴有结构缺陷。随着树形分子代数的增长,空间位阻的增加会不可避免地引起反应不完全以及各种副反应,从而产生结构缺
发散/收敛组合法集发散法和收敛法的优势于一身。这一策略首先通过发散法合成树形分子所需的各种结构单元,然后通过收敛法将结构单元组合成目标树形分
不同于传统树形分子合成方法,Peng课题组提出了自组装的方法构建非共价自组装超分子树形分子的策略,即利用低代的两亲性树形分子组装成超分子树形分子来模拟的高代共价树形分子(

Figure 3 Illustration of the self-assembly approach for constructing the non-covalent self-assembling dendrimer to mimic the covalent dendrimer of high-generatio
聚酰胺-胺类(PAMAM)树形分子是迄今为止研究得最为广泛和深入的一类树形分子。PAMAM树形分子具有与多肽相似的化学结构和组成:其内部有大量的酰胺骨架和叔胺结构,表面有众多的伯胺结构,因此有“人造蛋白质”的美
Tomalia

Figure 4 Synthesis of PAMAM dendrimers via the iterative two-reaction sequences consisting of Michael addition and subsequent amidatio
尽管PAMAM树形分子也可以使用收敛法和固相合成法来制

Figure 5 Chemical structure of a 4th generation of poly(amido)amine (PAMAM) dendrimer bearing a triethanolamine-cor
虽然树形分子在生物医学领域的学术研究中有着广泛的应用,但其临床转化方面仍然面临着巨大的挑战,究其原因主要是无法大规模生产高质量且无缺陷的高代树形分子。在此背景下,研究人员提出了利用自组装的方法将低代的两亲性树形分子组装成超分子树形分子的这一个全新的树形分子合成策略(
与共价构建的树形分子不同,由低代两亲性树形分子自组装构建的超分子树形分子在其核心中具有较大的疏水性空腔,可用于装载疏水性药物以进行药物递送。因此,Wei

Figure 6 Self-assembling supramolecular PAMAM dendrimers for drug delivery by physical encapsulation of drug molecules within the interio
此外,两亲树形分子的末端也可用于共价缀合多个生物活性分子,随后其自组装形成超分子树形分子进行药物递送。基于此设想,Zhou

Figure 7 Enzyme-responsive amphiphilic dendrimer 3 bearing bioactive nucleoside analogues at the terminals for drug deliver

Figure 8 Supramolecular dendrimers constructed via self-assembly of small amphiphilic dendrimer 4 bearing a hydrophobic C18 alkyl chain and a hydrophilic PAMAM dendron with 8 amine-terminals for siRNA deliver
为了进一步提高载体的递送能力,Liu

Figure 9 Chemical structure of the small amphiphilic dendrimer 5 bearing a hydrophobic C18 alkyl chain and a hydrophilic PAMAM dendron with 8 arginine-terminals for siRNA deliver
两亲性树形分子的树枝状末端也可以与造影剂偶联,然后自组装成为超分子树形分子用于生物成像。例如,基于两亲性树形分子6,Garrigue

Figure 10 Supramolecular dendrimers constructed via self-assembly of small amphiphilic dendrimer 6 bearing a hydrophobic alkyl chain and a hydrophilic PAMAM dendron with 4 terminals carrying the radioactive G
在此基础上,Ding

Figure 11 Chemical structure of the small amphiphilic dendrimer 7 bearing a hydrophobic alkyl chain and a hydrophilic PAMAM dendron with 4 terminals carrying the radioactive I
本文介绍了构建树形分子的不同策略,特别是基于自组装的方法构建超分子树形分子的策略。研究者们提出了利用低代的且易于合成的两亲树形分子自组装构筑超分子树形分子这一全新的树形分子合成理念,并用此策略成功地构建了一系列超分子树形分
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