School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
J Pept Sci. 2011 Jun;17(6):470-8. doi: 10.1002/psc.1347. Epub 2011 Feb 24.
Conventional dendrimers are spherical symmetrically branched polymers ending with active surface functional groups. Polyamidoamine (PAMAM) dendrimers have been widely studied as gene delivery vectors and have proven effective at delivering DNA to cells in vitro. However, higher-generation (G4-G8) PAMAM dendrimers exhibit toxicity due to their high cationic charge density and this has limited their application in vitro and in vivo. Another limitation arises when attempts are made to functionalize spherical dendrimers as targeting moieties cannot be site-specifically attached. Therefore, we propose that lower-generation asymmetric dendrimers, which are likely devoid of toxicity and to which site-specific attachment of targeting ligands can be achieved, would be a viable alternative to currently available dendrimers. We synthesized and characterized a series of peptide-based asymmetric dendrimers and compared their toxicity profile and ability to condense DNA to spherical PAMAM G1 dendrimers. We show that asymmetric dendrimers are minimally toxic and condense DNA into stable toroids which have been reported necessary for efficient cell transfection. This paves the way for these systems to be conjugated with targeting ligands for gene delivery in vitro and in vivo.
传统树状聚合物呈球形对称分支，末端带有活性表面官能团。聚酰胺-胺（PAMAM）树状聚合物已被广泛研究作为基因传递载体，并已被证明可有效将 DNA 递送至体外细胞。然而，由于较高代数（G4-G8）的 PAMAM 树状聚合物具有较高的正电荷密度，因此表现出毒性，这限制了它们在体外和体内的应用。另一个限制是，当尝试将球形树状聚合物官能化作为靶向部分时，由于不能进行特异性附着，因此无法实现。因此，我们提出，低代数不对称树状聚合物可能没有毒性，并且可以实现靶向配体的特异性附着，将成为目前可用树状聚合物的可行替代品。我们合成并表征了一系列基于肽的不对称树状聚合物，并比较了它们的毒性特征和将 DNA 凝聚成球形 PAMAM G1 树状聚合物的能力。我们表明，不对称树状聚合物的毒性最小，并将 DNA 凝聚成稳定的环，据报道，这对于有效细胞转染是必需的。这为这些系统与靶向配体进行基因传递的体外和体内共轭铺平了道路。
