Physicochemical and in vitro cytotoxicity studies of inclusion complex between gemcitabine and cucurbit[7]uril host

Adam Buczkowski; Michał Gorzkiewicz; Artur Stepniak; Małgorzata Malinowska-Michalak; Paweł Tokarz; Paweł Urbaniak; Maksim Ionov; Barbara Klajnert-Maculewicz; Bartlomiej Palecz

doi:10.1016/j.bioorg.2020.103843

Physicochemical and in vitro cytotoxicity studies of inclusion complex between gemcitabine and cucurbit[7]uril host

Bioorg Chem. 2020 Jun:99:103843. doi: 10.1016/j.bioorg.2020.103843. Epub 2020 Apr 13.

Authors

Adam Buczkowski¹, Michał Gorzkiewicz², Artur Stepniak³, Małgorzata Malinowska-Michalak³, Paweł Tokarz⁴, Paweł Urbaniak⁵, Maksim Ionov², Barbara Klajnert-Maculewicz², Bartlomiej Palecz³

Affiliations

¹ Unit of Biophysical Chemistry, Department of Physical Chemistry, Faculty of Chemistry, University of Lodz, 165 Pomorska St., 90-236 Lodz, Poland. Electronic address: adam.buczkowski@chemia.uni.lodz.pl.
² Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236 Lodz, Poland.
³ Unit of Biophysical Chemistry, Department of Physical Chemistry, Faculty of Chemistry, University of Lodz, 165 Pomorska St., 90-236 Lodz, Poland.
⁴ Molecular Spectroscopy Laboratory, Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, Lodz 91-403, Poland.
⁵ Department of Inorganic and Analytical Chemistry, Faculty of Chemistry, University of Lodz, 12 Tamka St., 91-403 Lodz, Poland.

PMID: 32305692
DOI: 10.1016/j.bioorg.2020.103843

Abstract

Gemcitabine, a cytostatic drug from the pyrimidine antimetabolite group, exhibits limited storage stability and numerous side effects during therapy. One of the strategies to improve the effectiveness of therapy with such drugs is the use of supramolecular nano-containers, including dendrimers and macrocyclic compounds. The ability of gemcitabine to attach a proton in an aqueous environment necessitates the search for a carrier that is well-tolerated by an organism and capable of supramolecular binding of a ligand (drug) in a cationic form. In the current study a promising strategy was tested for using cucurbituril Q7 to bind gemcitabine cations for its efficient intracellular delivery on three selected cancer cell lines (MOLT4, THP-1 and U937). Based on physicochemical studies (equilibrium dialysis, UV and ¹H NMR titrations, DOSY ¹H NMR measurements, DSC calorimetry) and cytotoxicity tests on cells with a free and blocked hENT1 transporter, the conclusion was drawn about the binding and penetration of the cucurbituril-drug complex into cancer cells.

Keywords: Cytotoxicity; DOSY (1)H NMR; DSC; Equilibrium dialysis; Intracellular drug transport; Nucleoside analogues; hENT1 inhibition.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Bridged-Ring Compounds / chemistry
Bridged-Ring Compounds / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Deoxycytidine / analogs & derivatives*
Deoxycytidine / chemistry
Deoxycytidine / pharmacology
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Gemcitabine
Humans
Imidazoles / chemistry
Imidazoles / pharmacology*
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Bridged-Ring Compounds
Imidazoles
cucurbit(7)uril
Deoxycytidine
Gemcitabine