LogP of N-acyl-gemcitabine and lectin-corona emerge as key parameters in nanoparticulate intravesical cancer therapy.

Autor: Anzengruber M; University of Vienna, Faculty of Life Sciences, Division of Pharmaceutical Technology and Biopharmaceutics, Josef-Holaubek-Platz 2, 1090 Vienna, Austria., Wimmer L; University of Vienna, Faculty of Life Sciences, Division of Pharmaceutical Technology and Biopharmaceutics, Josef-Holaubek-Platz 2, 1090 Vienna, Austria., Szuchar R; University of Vienna, Faculty of Life Sciences, Division of Pharmaceutical Technology and Biopharmaceutics, Josef-Holaubek-Platz 2, 1090 Vienna, Austria., Skoll K; University of Vienna, Faculty of Life Sciences, Division of Pharmaceutical Technology and Biopharmaceutics, Josef-Holaubek-Platz 2, 1090 Vienna, Austria., Wirth M; University of Vienna, Faculty of Life Sciences, Division of Pharmaceutical Technology and Biopharmaceutics, Josef-Holaubek-Platz 2, 1090 Vienna, Austria., Gabor F; University of Vienna, Faculty of Life Sciences, Division of Pharmaceutical Technology and Biopharmaceutics, Josef-Holaubek-Platz 2, 1090 Vienna, Austria. Electronic address: franz.gabor@univie.ac.at.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2023 Jan 01; Vol. 180, pp. 106330. Date of Electronic Publication: 2022 Nov 12.
DOI: 10.1016/j.ejps.2022.106330
Abstrakt: After surgical removal of the tumour tissue, bladder cancer is treated by intravesical instillation of cytotoxic drugs such as gemcitabine. Gemcitabine, however, is highly hydrophilic and possesses a short half-life due to fast enzymatic deamination. Additionally, continuous dilution by urine, a hardly permeable urothelial barrier and rapid excretion by urination make therapy difficult. To modify lipophilicity of the drug, N-acyl-gemcitabine derivatives with quite different solubility and logP were synthesized, purified and characterized. The loading of PLGA nanoparticles with the N-acyl-gemcitabine derivatives followed by release in artificial urine, revealed that the drug content increases but the subsequent release decreases with lipophilicity. Additionally, acylation increased cytotoxicity and opened passive diffusion as an additional pathway into cancer cells. To address physiological constraints, the surface of the monodisperse nanoparticles was grafted with bioadhesive wheat germ agglutinin. Cytoadhesion to artificial bladder cancer tissue and even uptake into the cells as indicated by microscopic imaging are expected to prolong the retention time in the bladder cavity as well as to promote uptake into the cells. By using N-caprylic-gemcitabine as most appropriate gemcitabine-derivative for drug loading and making use of the bioadhesive characteristics of wheat germ agglutinin for grafting the corona of PLGA-nanoparticles, an innovative strategy towards smart drug delivery for instillative therapy of bladder cancer is proposed.
Competing Interests: Declaration of Competing Interest There is no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
(Copyright © 2022. Published by Elsevier B.V.)
Databáze: MEDLINE
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