A Tumor-Acidity-Activated Charge-Conversional Nanogel as an Intelligent Vehicle for Promoted Tumoral-Cell Uptake and Drug Delivery
A Tumor-Acidity-Activated Charge-Conversional Nanogel as an Intelligent Vehicle for Promoted Tumoral-Cell Uptake and Drug Delivery
复制标题
肿瘤酸激活电荷转换纳米凝胶作为促进肿瘤细胞摄取和药物输送的智能载体
DOI：
10.1002/anie.200907210
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Du, Jin-Zhi;Sun, Tian-Meng;Wang, Jun
在过去的十年中，人们一直在努力开发用于药物控释的刺激响应性药物递送系统。用于触发药物释放的典型生物刺激包括pH [1-4]和温差，[3]氧化还原反应，[5，6]和酶。[7，8]在这些刺激中，pH响应性是最常用的刺激之一，因为不同组织和细胞区室的pH值不同。例如，肿瘤细胞外环境比血液（pH% 7.4）酸性更强（pH % 6.5），内体和溶酶体的pH值甚至更低（约6.5）。5.0-5.5）。[9]通过利用pH值的变化，已经开发了许多pH响应性递送载体，包括聚合物胶束[2，3]纳米凝胶[10-12]和聚合物-药物缀合物[13，14]，用于pH触发的药物递送。然而，它们中的大多数对显著酸性的内/溶酶体条件比对微酸性的肿瘤细胞外环境更敏感。对可被肿瘤细胞外pH值激活的纳米载体的追求形成了肿瘤靶向药物递送的新策略的基础。[15]该策略旨在创建在循环过程中保持其隐形特性的纳米载体，然后转化为更具细胞相互作用的形式，以显示响应性药物释放或以肿瘤特异性方式增强纳米载体与靶细胞之间的相互作用。典型的例子是由Bae及其同事开发的基于pH响应性含聚（L-组氨酸）嵌段共聚物的胶束系统。这些系统在pHe值下将生物素或达特肽暴露在胶束表面上，这导致肿瘤细胞的细胞摄取增强。[16-18]对于基于TAT-肽的脂质体系统也描述了类似的策略。[19]最近，pH依赖性电荷转换被用于药物递送的纳米载体开发。Kataoka及其同事设计了几种纳米载体，它们在中性条件下带负电荷，在内体pH值下带正电荷。这些智能载体已被用于内体溶解和溶酶体溶解pH响应蛋白和基因递送。[20-22] Shen及其同事还使用电荷反转聚合物胶束[23]和缀合物[24]用于核药物递送，其中用叶酸修饰的后一种载体显示出上级细胞杀伤效率。然而，用于增强细胞摄取的具有肿瘤激活的电荷转换特征的纳米载体仍然很少被研究。据报道，纳米颗粒的表面电荷在其体内和体外的命运中起着重要作用。[25]带正电的纳米颗粒对带负电的细胞膜显示出更高的亲和力，因此可以容易地被细胞内化，如许多研究所证明的。[26然而，带正电荷的纳米颗粒总是与血清组分强烈相互作用，这导致严重的聚集和从循环中快速清除，并限制了它们的体内应用。[28]相反，带负电荷的载体显示出蛋白质抗性的潜力。[21]一些已经表现出延长的循环时间用于体内应用。[26在这项研究中，我们设计了一种由pHe值触发的电荷转换纳米凝胶，用于增强体外和体内的细胞内化。我们用2，3-二甲基马来酸酐（DMMA）修饰氨基官能化的纳米凝胶，其与氨基反应产生酰胺键和羧酸基团。生成的酰胺键在中性和碱性pH值下相对稳定，但在微酸性条件下迅速降解为...
Within the last decade, persistent efforts have been made in the development of stimuli-responsive drug-delivery systems for controlled drug release. Typical biological stimuli exploited for triggered drug release include pH [1–4] and temperature differences,[3] redox reactions,[5, 6] and enzymes.[7, 8] Of these stimuli, pH-responsiveness is one of the most frequently used, as pH values in different tissues and cellular compartments vary. For example, the tumor extracellular environment is more acidic (pHe% 6.5) than blood (pH% 7.4), and the pH values of endosomes and lysosomes are even lower (ca. 5.0–5.5).[9] By utilizing variations in pHvalues, a number of pH-responsive delivery vehicles, including polymeric micelles,[2, 3] nanogels,[10–12] and polymer–drug conjugates,[13, 14] have been developed for pH-triggered drug delivery. However, most of them are more sensitive to the significantly acidic endo-/lysosomal conditions than to the slightly acidic tumor extracellular environment. The pursuit of nanocarriers that can be activated by tumor extracellular pHvalues forms the basis of a new strategy for tumortargeted drug delivery.[15] The strategy aims to create nanocarriers that maintain their stealth character during circulation and then transform into a more cell-interactive form to display responsive drug release or enhanced interaction between nanocarriers and target cells in a tumor-specific manner. Typical examples are the micellar systems developed by Bae and co-workers that are based on pHe-responsive poly (L-histidine)-containing block copolymers. These systems expose biotin or TAT peptide on the micelle surface at pHe values, which leads to enhanced cellular uptake by tumor cells.[16–18] A similar strategy was also described for a TAT-peptide-based liposome system.[19] Recently, pH-dependent charge conversion was utilized for nanocarrier development for drug delivery. Kataoka and co-workers designed several nanocarriers that were negatively charged under neutral conditions and positively charged at endosomal pH values. Those smart carriers have been used for endosomolytic and lysosomolytic pH-responsive protein and gene delivery.[20–22] Shen and co-workers have also used charge-reversal polymeric micelles [23] and conjugates [24] for nuclear drug delivery, whereby the latter carriers, which were decorated with folic acid, displayed superior cellkilling efficiency. However, nanocarriers with tumor-activated charge-conversional features for enhanced cellular uptake remain scarcely investigated. It has been reported that the surface charge of the nanoparticles plays an important role in their fate, both in vitro and in vivo.[25] Positively charged nanoparticles show higher affinity for negatively charged cell membranes and thus can be readily internalized by the cells, as proved by many investigations.[26, 27] However, positively charged nanoparticles always interact strongly with serum components, which causes severe aggregation and rapid clearance from circulation and limits their in vivo application.[28] In contrast, negatively charged carriers have shown potential for protein resistance.[21] Some have exhibited prolonged circulation time for in vivo applications.[26, 27]In this study, we designed a charge-conversional nanogel triggered by pHe values for enhanced cellular internalization both in vitro and in vivo. We modified an amino-functionalized nanogel with 2, 3-dimethylmaleic anhydride (DMMA), which reacted with the amino group to produce an amide bond and a carboxylic acid group. The resultant amide bond is relatively stable at neutral and alkali pH values, but degrades promptly under slightly acidic conditions to …