PDF(Pubmed)
Abstract：
Gemcitabine is a widely used antimetabolite drug of pyrimidine structure, which can exist as a free-base molecular form (Gem). The encapsulated forms of medicinal drugs are of interest for delayed and local drug release. We utilized, for the first time, a novel approach of mechano-chemistry by liquid-assisted grinding (LAG) to encapsulate Gem on a \"matrix\" of porphyrin aluminum metal-organic framework Al-MOF-TCPPH2 (compound 2). The chemical bonding of Gem to compound 2 was studied by ATR-FTIR spectroscopy and powder XRD. The interaction involves the C=O group of Gem molecules, which indicates the formation of the encapsulation complex in the obtained composite. Further, the delayed release of Gem from the composite was studied to phosphate buffered saline (PBS) at 37 °C using an automated drug dissolution apparatus equipped with an autosampler. The concentration of the released drug was determined by HPLC-UV analysis. The composite shows delayed release of Gem due to the bonded form and constant concentration thereafter, while pure Gem shows quick dissolution in less than 45 min. Delayed release of Gem drug from the composite follows the kinetic pseudo-first-order rate law. Further, for the first time, the mechanism of delayed release of Gem was assessed by the variable stirring speed of drug release media, and kinetic rate constant k was found to decrease when stirring speed is decreased (diffusion control). Finally, the prolonged time scale of toxicity of Gem to pancreatic cancer PANC-1 cells was studied by continuous measurements of proliferation (growth) for 6 days, using the xCELLigence real-time cell analyzer (RTCA), for the composite vs. pure drug, and their differences indicate delayed drug release. Aluminum metal-organic frameworks are new and promising materials for the encapsulation of gemcitabine and related small-molecule antimetabolites for controlled delayed drug release and potential use in drug-eluting implants.
摘要：
吉西他滨是一种广泛使用的嘧啶结构的抗代谢药物，它可以作为游离碱分子形式（Gem）存在。药物的包封形式对于延迟和局部药物释放是令人感兴趣的。我们利用,第一次,一种通过液体辅助研磨（LAG）将宝石封装在卟啉铝金属有机骨架Al-MOF-TCPPH2（化合物2）的“基质”上的机械化学新方法。通过ATR-FTIR光谱和粉末XRD研究了宝石与化合物2的化学键合。这种相互作用涉及宝石分子的C=O基团，这表明在获得的复合物中形成了包封复合物。Further,使用配备有自动进样器的自动药物溶解装置,在37°C下研究Gem在磷酸盐缓冲盐水(PBS)中的延迟释放。通过HPLC-UV分析确定释放的药物的浓度。由于结合形式和此后的恒定浓度，该复合材料显示出Gem的延迟释放，而纯Gem显示在小于45分钟内快速溶解。Gem药物从复合材料中的延迟释放遵循动力学假一级速率定律。Further,第一次,通过药物释放介质的可变搅拌速度来评估Gem的延迟释放机理，当搅拌速度降低（扩散控制）时，发现动力学速率常数k降低。最后,通过连续测量增殖（生长）6天，研究了Gem对胰腺癌PANC-1细胞毒性的延长时间尺度，使用xCELLigence实时细胞分析仪(RTCA)，对于复合材料与纯药物，它们的差异表明药物释放延迟。铝金属-有机骨架是用于封装吉西他滨和相关小分子抗代谢物的新的有前途的材料，用于控制药物延迟释放和在药物洗脱植入物中的潜在用途。
