Gemcitabine is major chemotherapy drug from antimetabolites group and pyrimidine subgroup. It is approved by FDA for treatment of pancreatic cancer and as part of combined chemotherapy regimes. It is also extensively investigated in the laboratory and clinical practice. Gemcitabine exists in two molecular forms: free base (Gem) and hydrochloride salt (Gemzar). Gemzar is administered systemically via intravenous route and it exhibits the significant undesirable “burst” effect. The “burst” is a quick increase of drug concentration in the body, followed by decrease of concentration; this leads to severe systemic side effects and decreased efficiency of chemotherapy. The alternative pathway is to utilize drug-eluting formulations “Matrix/Drug” which allow time-delayed release avoiding the “burst”, plus offer site-targeted local release. The reported drug encapsulation matrices include biopolymers, synthetic polymers, vesicles, nanoparticles. There are only few studies of delayed release of gemcitabine. Metal-organic frameworks MOFs are advanced nanostructured porous coordination polymers, which consist of metal cations and organic “linkers”. The latter serve as binding groups for encapsulated drug molecules.<br/>We investigated encapsulation of gemcitabine on aluminum metal-organic frameworks Al-MOF with few archetypal linkers of simple structure. Facile mechano-chemical procedure was utilized via liquid-assisted grinding (LAG). First, we tested encapsulation of gemcitabine in each of its forms. The other major variables in the encapsulation are molar ratios “Al-MOF/Drug”, grinding fluid, and grinding time. Second, the molecular mechanism of binding gemcitabine to complexes with Al-MOFs (Al-MOF/Gem) was investigated by ATR-FTIR spectroscopy. Third, the timescale of delayed release of gemcitabine from complexes in the form of powder to phosphate buffered saline (PBS) was systematically investigated at pH 7.4 and 37 C. Analysis of liquid phase was conducted by facile HPLC-UV method with reversed phase column. Complexes Al-MOF/Gem show time delayed release of the drug within several days. Temporal profiles of drug release show two regimes, corresponding to its physisorbed and chemisorbed forms. In the reference experiments, gemcitabine is found stable in PBS under the same conditions. Research is in progress to determine specific kinetic rate laws of delayed release, and relationships between the rate constants and molecular structure of linker as binding site.

Encapsulation and time delayed release of major antimetabolite drug gemcitabine from aluminum metal-organic frameworks

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