Design of novel nanocapsules with target-specificity using dendrimers

我们设计并合成了新型纳米胶囊，使用树枝状大分子将抗癌药物和生物活性分子输送到人体的特定部位。合成了链端含有聚乙二醇的聚酰胺胺树枝状大分子，并考察了其对阿霉素、甲氨蝶呤等抗癌药物的包封性。我们发现，聚乙二醇改性的树枝状大分子可以将这些药物包裹在其内部。为了提高其包封性，下一步，我们制备了由疏水氨基酸残基组成壳层的聚乙二醇化树枝状大分子。这些具有疏水外壳的树枝状大分子显示出增强的保留小客体分子Rose Bengal的能力，Rose Bengal被用作光动力疗法的光敏剂。我们还制备了带有半胱氨酸残基的聚乙二醇改性的树状大分子，其侧链上含有硫醇基团。含半胱氨酸的树状大分子在还原环境中对孟加拉玫瑰的吸附比在氧化环境中更强，因为链的交联端通过半胱氨酸残基之间的二硫键产生了一个外壳，减少了孟加拉玫瑰分子进入树枝状大分子内部的途径。这种树状大分子可以用作纳米胶囊，在细胞内部释放药物，因为细胞内部是已知的还原环境。此外，我们还合成了由聚酰胺胺树枝和两个长链烷基链组成的两亲性树枝状大分子作为基因的载体。我们发现，两亲性树枝状大分子可以通过静电相互作用与质粒DNA形成复合物，并将其输送到哺乳动物细胞中。由于它们的转染活性高于广泛使用的阳离子脂质体，这些树枝状大分子可能作为一种非病毒载体用于基因治疗。

We designed and synthesized novel nanocapsules, which deliver anticancer drugs and bioactive molecules to a specific site of the body, using dendrimers. Polyamidoamine dendrimers having poly(ethylene glycol) (PEG) at every chain end were prepared and their ability to encapsulate anticancer drugs, such as adriamycin and methotrexate. We found that the PEG-modified dendrimers could encapsulate these drugs in their interior. To improve their encapsulation ability, next, we prepared PEG-modified dendrimers with a shell consisting of hydrophobic amino acid residues. These dendrimers having a hydrophobic shell showed enhanced ability for the retention of a small guest molecule rose bengal, which is used as photosensitizer for photodynamic therapy. We also prepared PEG-modified dendrimers having cysteine residues, which have thiol groups on their side chains. The cysteine-bearing dendrimer adsorbed rose bengal more strongly in a reductive environment than in an oxidative environment, because crosslink of chain ends via disulfide bond between the cysteine residues generates a shell which reduces access of rose bengal molecules into the interior of the dendrimer. This dendrimer can be used as a nanocapsule, which releases drugs in the interior of a cell, since the inside of a cell is known to be a reductive environment. In addition, we synthesized amphiphilic dendrimers which consist of the polyamidoamine dendron and two long alkyl chains as a carrier for genes. We found that the amphiphilic dendrimer could form a complex with plasmid DNA through electrostatic interaction and deliver it into mammalian cells. Because their transfection activity was higher than a widely-used cationic liposomes for this purpose, these dendrimers may be useful as a nonviral vector for gene therapy.