Pharmaceutical Binary and Ternary Complexes of Gemcitabine with Aluminum Metal–Organic Framework: Mechano-Chemical Encapsulation, Delayed Drug Release, and Toxicity to Pancreatic Cells

TL;DR

This study explores using metal-organic frameworks to encapsulate gemcitabine, a cancer drug, to delay its release and reduce side effects in pancreatic cancer treatment.

Contribution

The study introduces a mechano-chemical method to create binary and ternary drug complexes with delayed release and evaluates their toxicity to cancer cells.

Findings

lag(CYCU-3)(Gem) shows delayed gemcitabine release for 6000 minutes and retains crystal structure.

The ternary complex lag(CYCU-3)1(Gem)1(CIT)2 also demonstrates delayed drug release and bonding via O-H groups.

lag(CYCU-3)(Gem) suppresses PANC−1 cancer cells in a time-dependent manner.

Abstract

Background: gemcitabine is a cytidine analog and major anticancer drug functioning as an antimetabolite. However, its administration by systemic route is accompanied by “burst” and side effects. To limit this, drugs are encapsulated in matrices; metal–organic frameworks (MOFs) are coordination polymers with strong potential for drug encapsulation and delayed release. Methods: mechano-chemical synthesis of solid-state binary complex lag(CYCU-3)(Gem) is described from aluminum MOF (Al-MOF) CYCU-3 and gemcitabine free base (Gem). Synthesis is conducted by liquid-assisted grinding (LAG) with dimethyl sulfoxide (DMSO) followed by its outgassing. The alternative “dry” synthesis results in dry(CYCU-3)(Gem). Materials were characterized by FTIR spectroscopy and XRD, and delayed Gem release was tested to phosphate buffered saline (PBS) at 37 °C. The in vitro toxicity to pancreatic cancer PANC−1 and healthy cells hTERT−HPNE E6/E7/K−RasG12D was assessed by fluorometric assay. Results: in lag(CYCU-3)(Gem) interactions MOF-drug are via non-covalent bonds at O-H and COO− groups of CYCU-3 as found by FTIR marker peak shifts and crystal structure is retained, while dry(CYCU-3)(Gem) shows significant amorphization and loss of functional groups. The lag(CYCU-3)(Gem) but not dry(CYCU-3)(Gem) shows delayed Gem release for 6000 min. The suppression of PANC−1 cells by lag(CYCU-3)(Gem) is time-dependent and it correlates with delayed Gem release. For the first time, a concept of ternary stoichiometric complex lag(CYCU-3)1(Gem)1(CIT)2 is tested that also contains natural organic compound citronellol (CIT), and its structure, bonding and release of Gem are compared to those of binary complex. Bonding is at the O-H groups of CYCU-3 and this complex shows delayed Gem release. Conclusions: binary and ternary complexes of Gem with CYCU-3 yield delayed release and cytotoxicity. LAG is promising for synthesis of solid-state complexes of gemcitabine for delayed release and time-dependent suppression of cancer cells.

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