Umar Sheriff, Catazaro Jonathan, Wachira James, Samokhvalov Alexander
Department of Chemistry, Morgan State University, 1700 East Cold Spring Lane, Baltimore, MD, 21251, USA.
Department of Chemistry, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.
J Drug Deliv Sci Technol. 2025 Sep;111. doi: 10.1016/j.jddst.2025.107195. Epub 2025 Jun 18.
Gemcitabine is a powerful anticancer antimetabolite drug which is usually administered as hydrochloride salt (GemHCl), but its systemic administration is accompanied by the undesirable "burst" phenomenon and its adverse side effects. To avoid the "burst", drugs can be encapsulated on suitable matrices to yield a local and delayed release. Here, GemHCl was encapsulated on aluminum metal-organic framework MOF-253 by liquid-assisted grinding (LAG) to form a new pharmaceutical composite. In the composite, the bonding was determined by the complementary ATR-FTIR spectroscopy, solid-state NMR (SS-NMR) spectroscopy and powder XRD. The interactions "drug-matrix" proceed by the C-N group of GemHCl drug and the bipyridyl unit of linker in MOF-253 matrix. Next, a powder of the composite was processed to obtain a mechanically pressed robust pharmaceutical pellet. The pellet was further tested for the delayed release of gemcitabine to phosphate buffered saline (PBS) at 37 ℃ using an automated drug dissolution system (ADDS). The pellet of the composite is found to be stable in PBS, and it shows delayed drug release up to 5 days without the "burst", in contrast to the pellet of GemHCl which quickly dissolves. Next, in the viability tests of pancreatic cancer cells PANC-1 by the Alamar Blue fluorescence assay in the 72 h. timescale, the composite is found to be more toxic than GemHCl. Finally, the prolonged toxicity of the released gemcitabine to PANC-1 cells was investigated by continuous measurements of proliferation (growth) for 6 days, using xCELLigence Real Time Cell Analyzer (RTCA). At higher concentrations and longer times, the composite is more effective than pure GemHCl, consistently with delayed drug release from the former. The encapsulation of GemHCl on MOFs by the means of mechano-chemistry constitutes a new and promising approach for the preparation of advanced functional composites for controlled, delayed and local drug release, and their potential use in the anticancer drug-eluting implants.
吉西他滨是一种强效的抗癌抗代谢药物，通常以盐酸盐（GemHCl）的形式给药，但其全身给药伴随着不良的“突释”现象及其副作用。为了避免“突释”，可将药物封装在合适的基质上以实现局部和延迟释放。在此，通过液相助磨法（LAG）将GemHCl封装在金属有机框架MOF-253上，形成一种新型药物复合物。在该复合物中，通过互补的衰减全反射傅里叶变换红外光谱（ATR-FTIR）、固态核磁共振（SS-NMR）光谱和粉末X射线衍射（XRD）确定键合情况。“药物-基质”之间的相互作用通过GemHCl药物的C-N基团与MOF-253基质中连接体的联吡啶单元进行。接下来，将复合物粉末加工成机械压制的坚固药物微丸。使用自动药物溶出系统（ADDS）进一步测试该微丸在37℃下向磷酸盐缓冲盐水（PBS）中吉西他滨的延迟释放情况。发现该复合物微丸在PBS中稳定，与迅速溶解的GemHCl微丸相比，它显示出长达5天的延迟药物释放且无“突释”现象。接下来，在72小时时间范围内通过阿拉玛蓝荧光测定法对胰腺癌细胞PANC-1进行活力测试，发现该复合物比GemHCl毒性更大。最后，使用xCELLigence实时细胞分析仪（RTCA）通过连续测量6天的增殖（生长）情况，研究释放的吉西他滨对PANC-1细胞的延长毒性。在较高浓度和较长时间下，该复合物比纯GemHCl更有效，这与前者的延迟药物释放一致。通过机械化学方法将GemHCl封装在金属有机框架上，为制备用于可控、延迟和局部药物释放的先进功能复合材料及其在抗癌药物洗脱植入物中的潜在应用构成了一种新的且有前景的方法。
