Reversibly Stabilized Multifunctional Dextran Nanoparticles Efficiently Deliver Doxorubicin into the Nuclei of Cancer Cells
Reversibly Stabilized Multifunctional Dextran Nanoparticles Efficiently Deliver Doxorubicin into the Nuclei of Cancer Cells
复制标题
可逆稳定的多功能右旋糖酐纳米颗粒有效地将阿霉素输送到癌细胞的细胞核中
DOI：
10.1002/anie.200904260
复制
发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Zhong, Zhiyuan
中科院分区：
文献类型：
--
作者：
Li, Yu-Ling;Zhu, Li;Zhong, Zhiyuan
药物递送被认为是许多药物临床成功的关键。[1-3]在过去的十年中，为了改善化疗，已经做出了巨大的努力来开发用于抗癌药物（包括多柔比星（DOX）和紫杉醇（PTX））的受控递送的聚合物纳米颗粒。[4-12]这些纳米载体提供了几个独特的功能，例如增强药物的水溶性和生物利用度，延长循环时间，通过增强的渗透性和保留（EPR）效应在肿瘤部位优先蓄积，并减少全身副作用。[13然而，纳米颗粒的一个实际挑战是它们的低体内稳定性，因为大的稀释体积和/或与血液中存在的细胞和生物分子的相互作用，这通常导致药物过早释放、聚集和药物到达其靶标的能力降低。[15]在过去的几年中，已经采用了不同的交联方法来提高其稳定性，[16，17]例如，通过亲水壳的交联，[18]在疏水核内，[19-21]或在核-壳界面。[22]另一方面，应该注意的是，过度稳定的纳米颗粒对于药物递送应用也远不是最佳的，因为药物功效被禁止从纳米颗粒释放而显著降低，即使它们到达靶位点。[23最后但并非最不重要的是，迄今报道的交联纳米颗粒中很少有生物相容性和可降解的，[19，20]这仍然是生物医学应用的基本先决条件。在温和氧化的细胞外环境和还原的细胞内流体（例如细胞质和细胞核）之间存在氧化还原电位的巨大差异，[25]这使得还原敏感性聚合物对于生物医学应用特别有吸引力。[26]例如，还原敏感性聚合物/DNA复合物，[27]聚离子复合物胶束，[28，29]胶束，[30]聚合物囊泡，[31]交联聚合物囊泡，[32]和可降解纳米凝胶[33，34]已被报道实现DNA，siRNA或药物的快速细胞内释放。
Drug delivery has been considered as the key to the clinical success of numerous drugs.[1–3] In the past decade, with an aim to improve chemotherapy, tremendous effort has been directed to the development of polymer nanoparticles for the controlled delivery of anticancer drugs, including doxorubicin (DOX) and paclitaxel (PTX).[4–12] These nanovehicles offer several unique features, such as enhancing the aqueous solubility and bioavailability of the drug, prolonging the circulation time, preferential accumulation at the tumor sites by the enhanced permeability and retention (EPR) effect, and reducing systemic side effects.[13, 14] However, one practical challenge with nanoparticles is their low stability invivo because of the large dilution volume and/or interactions with cells and biomolecules present in the blood, which often lead to premature drug release, aggregation, and a diminished ability of the drug to reach its target.[15] In the past few years, different cross-linking approaches have been adopted to improve their stability,[16, 17] for example, through cross-linking of the hydrophilic shell,[18] within the hydrophobic core,[19–21] or at the core–shell interface.[22] It should be noted, on the other hand, that overly stable nanoparticles are also far from optimal for drug-delivery applications, because drug efficacy is significantly reduced by the prohibited release of drugs from the nanoparticles even though they reach the target sites.[23, 24] Last but not least, few of the cross-linked nanoparticles so far reported are biocompatible and degradable,[19, 20] which are nevertheless fundamental prerequisites for biomedical applications.There exists a large difference in the redox potential between the mildly oxidizing extracellular milieu and the reducing intracellular fluids, such as the cytoplasm and the cell nucleus,[25] which renders reduction-sensitive polymers particularly appealing for biomedical applications.[26] For example, reduction-sensitive polymer/DNA complexes,[27] polyion complex micelles,[28, 29] micelles,[30] polymersomes,[31] cross-linked polymersomes,[32] and degradable nanogels [33, 34] have been reported to achieve fast intracellular release of DNA, siRNA, or drugs.