Mechano-chemical encapsulation of gemcitabine hydrochloride on metal-organic framework, preparation of shaped pellets, delayed drug release, and time-dependent toxicity to PANC-1 cancer cells.

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.