Investigations of potent biocompatible metal-organic framework for efficient encapsulation and delivery of Gemcitabine: Biodistribution, pharmacokinetic and cytotoxicity study

Abstract

Gemcitabine (GEM), a nucleoside analogue, is used for the treatment of various cancers. However, this drug possesses several limitations such as poor pharmacokinetics, metabolic degradation by cytidine deaminase, development of drug resistance, and schedule dependent toxicity. To circumvent these drawbacks, it can be entrapped in a suitable formulation for protection against metabolic degradation or urinary excretion. To this end, we have synthesized and investigated different iron (Fe-III)-based biocompatible metal-organic frameworks (MOFs), namely, MIL-101-NH2 (rigid), MIL-88A, and MIL-53 (flexible). All these MOFs have different topologies, connectivity, and chemical composition. MIL-53 was identified as a promising carrier for GEM delivery, with enhanced encapsulation and progressive release in relation to other candidates. The release of GEM from MIL-53 followed zero order kinetics, leading to an effective plasma concentration within the therapeutic range. Furthermore, in- vitro cytotoxicity study by using pancreatic cancer cell lines (MIAPaCa-2 and PANC1) stipulated that GEM loaded in MIL-53 (MIL53-GEM) had an increased cytotoxic effect relative to native GEM. Additionally, the slow release of GEM in a controlled manner could protect the drug from enzymatic degradation to increase its efficacy, half-life, and bioavailability without toxicity to organs as evidenced by in-vivo studies. This study demonstrates the potential of MIL53-GEM in upgrading the clinical outcome of GEM-based chemotherapy against cancer.