Camptothecin in sterically stabilized phospholipid nano-micelles: A novel solvent pH change solubilization method
Camptothecin in sterically stabilized phospholipid nano-micelles: A novel solvent pH change solubilization method
复制标题
DOI：
10.1166/jnn.2006.460
复制
发表时间：
2006-09-01
影响因子：
--
通讯作者：
Onyuksel, Hayat
中科院分区：
文献类型：
--
作者：
Koo, Otilia M. Y.;Rubinstein, Israel;Onyuksel, Hayat
喜树碱（CPT）是一种拓扑异构酶I抑制剂，对多种癌症起作用。不幸的是，CPT的临床应用受到不溶性、不稳定性和毒性问题的限制。为了避免CPT的这些递送问题，我们提出了生物相容性的靶向立体稳定胶束（SSM）作为CPT的纳米载体（CPT-SSM）。由聚乙二醇（聚乙二醇化）磷脂组成的SSM是CPT递送的有吸引力的纳米载体，因为它们足够小，可以通过肿瘤和炎症组织的渗漏微血管外渗，进行被动靶向。本研究的目的是开发一种基于pH依赖性、可逆羧酸-内酯转化化学的CPT-SSM制备新方法。在pH为5的条件下，将CPT羧酸盐加入到SSM中，有利于形成活性但疏水的CPT内酯，与SSM自发结合。考察了CPT转化和CPT- ssm形成的动力学，以及不同的CPT- peg磷脂摩尔比对CPT- ssm性能和CPT增溶的影响。CPT逐渐由羧酸酯形式转化为内酯形式，孵育12 h后形成CPT- ssm。CPT-SSM的平均尺寸为14 nm。与之前报道的共沉淀/重构技术不同，CPT的增溶性（类似于12 μ g/ml）和其他CPT- ssm胶束性质没有随着CPT与聚乙二醇化磷脂摩尔比的增加而显著改变。这种可重复的CPT在SSM中的增溶是由于这种方法避免了药物聚集的形成。我们的溶剂pH变化法制备CPT- ssm的优势支持进一步研究该方法在化学上与CPT相似的其他疏水药物以及CPT在其他纳米载体上的分子增溶作用。
Camptothecin (CPT) is a topoisomerase I inhibitor that acts against a broad spectrum of cancers. Unfortunately clinical application of CPT is limited by insolubility, instability, and toxicity problems. To circumvent these delivery problems of CPT, we propose biocompatible, targeted sterically stabilized micelles (SSM) as nanocarriers for CPT (CPT-SSM). SSM composed of polyethylene glycol (PEGylated) phospholipids are attractive nanocarriers for CPT delivery because they are sufficiently small to extravasate through the leaky microvasculature of tumor and inflamed tissues for passive targeting. The purpose of this study was to develop a novel method of preparing CPT-SSM based on its pH dependent, reversible carboxylate-lactone conversion chemistry. CPT carboxylate was added to SSM at pH 5 that favored the formation of active but hydrophobic CPT lactone for spontaneous association with SSM. The kinetics of CPT conversion and CPT-SSM formation, and the effect of varying CPT-PEGylated phospholipid molar ratio on CPT-SSM properties and CPT solubilization were evaluated. CPT converted gradually from the carboxylate form to lactone, and CPT-SSM were formed after 12 h incubation. The mean size of CPT-SSM was similar to 14 nm. CPT solubilization (similar to 12 mu g/ml) and other CPT-SSM micelle properties did not change significantly with increasing CPT to PEGylated phospholipid molar ratios using this novel method, unlike the coprecipitation/reconstitution technique previously reported. This reproducible CPT solubilization in SSM was attributed to avoidance of drug aggregate formation by this method. The advantages of our solvent pH change method to prepare CPT-SSM support further investigations of this approach to other hydrophobic drugs similar to CPT in chemistry and also CPT molecular solubilization in other nanocarriers.