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Biodistribution and Pharmacokinetic Study of Gemcitabine Hydrochloride Loaded Biocompatible Iron-Based Metal Organic Framework

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Abstract

This study was designed to improve bioavailability and therapeutic efficacy of Gemcitabine (GEM) with reduced side effects using MOF MIL-100 as cargo. MIL-100 was synthesized, and characterized by microscopic and spectroscopic techniques. Impregnation approach was used for encapsulation of GEM inside the MIL-100 (i.e., MIL100-GEM). In-vitro release studies of MIL100-GEM was carried out in different media (PBS, deionized water and Tris buffer, pH = 7.4, 9.5 mM) to find out the drug release mechanism. Cytotoxicity and apoptosis assays were evaluated using MTT and fluorescence-activated cell sorting (FACS) assay in MiaPaCa-2 pancreatic cancer cell lines. Biocompatibility, pharmacokinetic and biodistribution studies of MIL100-GEM were assessed in Wistar rats. MIL100-GEM exhibited high encapsulation efficiency (78.6 ± 0.5%) and maximum payload (23.6 ± 1%). PXRD confirmed crystallinity of MIL-100, and did not show any effect on its structural integrity after encapsulation of GEM. In-vitro release studies revealed a biphasic release pattern in PBS buffer which followed Higuchi diffusion kinetics. In-vitro cytotoxicity studies showed low IC50 value for MIL100-GEM (3.50 ± 1.33 µg/ml) compared to GEM (6.22 ± 1.55 µg/ml), ensuring adequate cell proliferation after 72 h. Hemolysis study showed that MIL100-GEM (14.54 ± 1.3%) had better biocompatibility than the native GEM (30.52 ± 1.67%). Furthermore, pharmacokinetic and biodistribution studies exhibited ∼17-fold increased bioavailability, ∼20-fold increased distribution half-life and ∼15-folds elimination half-life of GEM with less accumulation of drug in the kidneys. MIL-100 MOF was synthesized and characterized to address the metabolic degradation issue of GEM. Biocompatible, MIL100-GEM demonstrated efficient drug (GEM) loading and enhanced cytotoxic activity in pancreatic cancer cell line with augmented bioavailability, providing MIL-100 a promising drug cargo.

Graphic Abstract

MIL-100 was synthesized using a microwave-assisted method. The anticancer drug Gemcitabine Hydrochloride (GEM) was loaded into the MIL-100 using the impregnation method. Encapsulation protected the drug from its metabolic inactivation to enhance bioavailability in target organs and reduce side effects.

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Acknowledgements

Ms. Preeti Kush, Jitender Madan, and Upendra Kumar Jain acknowledge the management of the Chandigarh group of colleges, Mohali (Punjab), India & IKG Punjab Technical University, Kapurthala (Punjab), India for providing the necessary infrastructure and laboratory facilities. Akash Deep and Parveen Kumar thank the Director, CSIR-CSIO, Chandigarh for providing the necessary infrastructure and the Department of Science and Technology, India for providing a research grant under the INSPIRE Faculty award. KHK also acknowledges the support of the R&D Center for Green Patrol Technologies through the R&D for Global Top Environmental Technologies funded by the Ministry of Environment (Grant No: 2018001850001) as well as a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, & Future Planning (Grant No. 2016R1E1A1A01940995).

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Authors and Affiliations

  1. I.K. Gujral Punjab Technical University, Jalandhar, Punjab, India

    Preeti Kush

  2. Chandigarh College of Pharmacy, Mohali, Punjab, India

    Preeti Kush, Tania Bajaj, Manjot Kaur, Jitender Madan & Upendra Kumar Jain

  3. Nanotechnology Division, CSIR-Central Scientific Instruments Organization, Chandigarh, 160030, India

    Parveen Kumar & Akash Deep

  4. Department of Civil & Environmental Engineering, Hanyang University, 222 Wangsimni-Ro, Seoul, 04763, Republic of Korea

    Ki-Hyun Kim

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  1. Preeti Kush
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Kush, P., Bajaj, T., Kaur, M. et al. Biodistribution and Pharmacokinetic Study of Gemcitabine Hydrochloride Loaded Biocompatible Iron-Based Metal Organic Framework. J Inorg Organomet Polym 30, 2827–2841 (2020). https://doi.org/10.1007/s10904-019-01417-4

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