"SMART" drug delivery systems: Double-targeted pH-responsive pharmaceutical nanocarriers
"SMART" drug delivery systems: Double-targeted pH-responsive pharmaceutical nanocarriers
复制标题
DOI：
10.1021/bc060080h
复制
发表时间：
2006-07-19
影响因子：
4.7
通讯作者：
Torchilin, V. P.
中科院分区：
文献类型：
--
作者：
Sawant, R. M.;Hurley, J. P.;Torchilin, V. P.
为了开发能够对某些局部刺激(如肿瘤或脑梗塞的pH值降低)做出反应的靶向药物载体，已制备了具有多种功能的靶向长循环聚乙二醇化脂质体和聚乙二醇磷脂酰乙醇胺(PEGPE)胶束。首先，它们能够通过PNP-PEG-PE部分将抗肌球蛋白单抗2G4连接到它们的表面，从而靶向特定的细胞或器官。其次，通过生物素-PE或TATP-PE或TATP-Short PEG-PE衍生物将生物素或TAT多肽(TATP)部分附加到纳米载体表面，对这些脂质体和胶束进行修饰。通过在聚乙二醇缩乙二醇酮和聚乙烯之间插入pH敏感的联键(PEGHZ-PE)，使用于脂质体表面修饰或胶束制备的聚乙二醇化聚乙烯可被降解。在正常pH值下，纳米载体表面的生物素和TATP功能被长链保护的聚乙二醇链(pH可降解的聚乙二醇(2000)-PE或聚乙二醇(5000)-PE)或用于将抗体附着到纳米载体上的更长的PNP-PEG-PE部分(非pH可降解的聚乙二醇(3400)-PE或聚乙二醇(5000)-PE)“屏蔽”。在pH 7.4-8.0范围内，脂质体和胶束与2G4抗体底物肌球蛋白显示出高度的特异性结合，但与亲和素柱(含生物素的纳米载体)或NIH/3T3或U-87细胞(含TATP的纳米载体)的结合非常有限。然而，在较低的pH值(pH 5.0-6.0)下短暂孵育(15-30分钟)后，纳米载体由于聚乙二醇-赫兹-PE的酸性水解而失去其保护的聚乙二醇壳，并能够强烈地保留在亲和素柱上(含生物素的纳米载体)或通过TATP部分(含TATP的纳米载体)有效地被细胞内化。我们认为这一结果是开发多功能刺激敏感型药物纳米载体的第一步。
To develop targeted pharmaceutical carriers additionally capable of responding to certain local stimuli, such as decreased pH values in tumors or infarcts, targeted long-circulating PEGylated liposomes and PEG-phosphatidylethanolamine (PEG-PE)-based micelles have been prepared with several functions. First, they are capable of targeting a specific cell or organ by attaching the monoclonal antimyosin antibody 2G4 to their surface via pNP-PEG-PE moieties. Second, these liposomes and micelles were additionally modified with biotin or TAT peptide (TATp) moieties attached to the surface of the nanocarrier by using biotin-PE or TATp-PE or TATp-short PEG-PE derivatives. PEG-PE used for liposome surface modification or for micelle preparation was made degradable by inserting the pH-sensitive hydrazone bond between PEG and PE (PEG-Hz-PE). Under normal pH values, biotin and TATp functions on the surface of nanocarriers were "shielded" by long protecting PEG chains (pH-degradable PEG(2000)-PE or PEG(5000)-PE) or by even longer pNP-PEG-PE moieties used to attach antibodies to the nanocarrier (non-pH-degradable PEG(3400)-PE or PEG(5000)-PE). At pH 7.4-8.0, both liposomes and micelles demonstrated high specific binding with 2G4 antibody substrate, myosin, but very limited binding on an avidin column (biotin-containing nanocarriers) or internalization by NIH/3T3 or U-87 cells (TATp-containing nanocarriers). However, upon brief incubation (15-30 min) at lower pH values (pH 5.0-6.0), nanocarriers lost their protective PEG shell because of acidic hydrolysis of PEG-Hz-PE and acquired the ability to become strongly retained on an avidin column (biotin-containing nanocarriers) or effectively internalized by cells via TATp moieties (TATp-containing nanocarriers). We consider this result as the first step in the development of multifunctional stimuli-sensitive pharmaceutical nanocarriers.