"Cascade-release dendrimers" liberate all end groups upon a single triggering event in the dendritic core
"Cascade-release dendrimers" liberate all end groups upon a single triggering event in the dendritic core
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DOI：
10.1002/anie.200351942
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发表时间：
2003-01-01
影响因子：
16.6
通讯作者：
Scheeren, HW
中科院分区：
文献类型：
--
作者：
de Groot, FMH;Albrecht, C;Scheeren, HW
树枝状聚合物是具有多个末端基团的明确定义的支化树状分子。[1，2]已经探索了这些星形结构的许多应用。[3，4]它们可以用于磁共振成像（MRI），基因治疗，[5]液晶，传感器和催化等领域。树枝状聚合物在药物传递中的应用目前受到科学界的广泛关注。[6-9]迄今为止报道的大多数树枝状聚合物已被构建为共价或非共价结合功能分子的分支骨架。附着在树枝状结构末端的生物活性物质[10]可以通过化学或生物学方法释放。[11]已经报道了几种含有共价连接的阿霉素分子作为端基的分支结构。[12-14]然而，在迄今为止报道的所有分支结构或树枝状聚合物中，每个单一药物必须独立地裂解才能释放。在这里，我们报告的树枝状聚合物已建成完全和迅速解离成单独的积木后，一个单一的触发事件在树突状核心。该过程诱导连接到树突末端的所有端基分子的同时释放。我们将这些多次释放的树枝状系统称为“级联释放树枝状聚合物”。这种树枝状聚合物在单一（化学或生物）活化步骤后坍缩成它们单独的单体结构单元，该活化步骤引发级联的自消除反应，从而从“爆炸”级联释放树枝状聚合物的外围释放所有端基（参见支持信息）。一个特定的领域是（靶向）药物递送，其中级联释放树枝状聚合物具有优于常规树枝状聚合物的两个主要优点：1）多个共价结合的药物分子可以通过单个切割步骤从靶向部分位点特异性地释放;和2）它们被选择性地以及完全地降解。因此，与常规树枝状聚合物相比，它们可以容易地从体内排出。大分子从体内的清除可能是当前大分子药物递送系统的限制因素，[15]因为一些合成大分子在胃肠外药物中的长期作用尚不完全清楚。[16个]
Dendrimers are well-defined, branched treelike molecules with multiple end groups.[1, 2] Numerous applications of these starlike structures have been explored.[3, 4] They can be utilized in areas such as magnetic resonance imaging (MRI), gene therapy,[5] liquid crystals, sensors, and catalysis. The application of dendrimers in drug delivery is currently receiving much scientific attention.[6–9] Most dendrimers reported so far have been constructed as a branched skeleton that incorporates functional molecules either covalently or noncovalently. Biologically active substances that are attached to the termini of dendritic structures [10] can be liberated by chemical or biological methods.[11] Several branched constructs have been reported which contain covalently linked doxorubicin molecules as end groups.[12–14] However, in all the branched structures or dendrimers reported so far, each single drug has to be independently cleaved to be released. Here, we report dendrimers that have been built to completely and rapidly dissociate into separate building blocks upon a single triggering event in the dendritic core. This process induces simultaneous release of all end-group molecules connected to the dendritic termini. We term these multiple-release dendritic systems “cascade-release dendrimers”. Such dendrimers collapse into their separate monomeric building blocks after a single (chemical or biological) activation step that triggers a cascade of self-elimination reactions, thereby releasing all the end groups from the periphery of the “exploding” cascade-release dendrimer (see Supporting Information).Functional dendrimers of this kind may find application in several fields. One particular area is (targeted) drug delivery, where cascade-release dendrimers possess two major advantages over conventional dendrimers: 1) multiple covalently bound drug molecules can be site-specifically released from the targeting moiety by a single cleaving step; and 2) they are selectively as well as completely degraded. Thus, in contrast to conventional dendrimers, they can be easily drained from the body. Clearance of macromolecules from the body may be a limiting factor in current macromolecular drug-delivery systems,[15] as the long-term effects of some synthetic macromolecules in parenteral medicine are not completely known.[16]