Open Access
International Journal of Pharmaceutics, volume 559, pages 138-146
Type of pH sensitive linker reveals different time-dependent intracellular localization, in vitro and in vivo efficiency in alpha-fetoprotein receptor targeted doxorubicin conjugate
Mollaev Murad D
1, 2
,
Gorokhovets N.
3
,
Faustova M
5
,
Zabolotsky A
5
,
Zhunina O
2
,
Sokol M
5
,
Zamulaeva Irina
4
,
Severin E.
2
,
2
JSC Russian Research Center for Molecular Diagnostics and Therapy, 117149 Moscow, Russia.
|
Publication type: Journal Article
Publication date: 2019-03-01
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 5.8
ISSN: 03785173, 18733476
Pharmaceutical Science
Abstract
Despite the presence of a variety of modern anticancer drugs at the market, doxorubicin (Dox) is still widely used in antineoplastic therapy, although its administration causes severe side effects. To enhance specific activity of such molecules, various approaches have been exploited: targeted moieties like monoclonal antibodies, onco-specific proteins and peptides are utilized as specific vector molecules; environment sensitive linkers are exploited to facilitate transported drug release at the target point etc. Acid-labile linkers are frequently used in synthesis due to the ability to be cleaved inside specific cellular compartments with acidic environment, avoiding possible recycling mechanisms. Two types of conjugates containing different acid-labile linkers have been synthesized. In vitro efficiency of doxorubicin conjugates with recombinant receptor-binding domain of human alpha-fetoprotein (3dAFPpG) synthesized with use of cis-aconitic anhydride (CAA) and linker based on succinimidyl 3-(2-pyridyldithio)propionate (SPDP) and 3-(2-pyridyldithio)propionic acid hydrazide (PDPH) was compared. The 3dAFPpG-SPDP-PDPH-Dox revealed a comparable with unmodified doxorubicin cytotoxic effect against the Dox sensitive MCF7 cell line and greater cytotoxicity against the anthracycline resistant MCF7Adr cells. Meanwhile the 3dAFPpG-CAA-Dox cytotoxic effect was significantly lower, although doxorubicin's pH-dependent release profiles and intracellular accumulation rates were similar. These differences in cytotoxic activity were arguably explained by the dissimilarities in intracellular doxorubicin localization, which may originate from thiol reductase activity in lysosomes and late endosomes.
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Mollaev M. D. et al. Type of pH sensitive linker reveals different time-dependent intracellular localization, in vitro and in vivo efficiency in alpha-fetoprotein receptor targeted doxorubicin conjugate // International Journal of Pharmaceutics. 2019. Vol. 559. pp. 138-146.
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Mollaev M. D., Gorokhovets N., Nikolskaya E. D., Faustova M., Zabolotsky A., Zhunina O., Sokol M., Zamulaeva I., Severin E., Yabbarov N. G. Type of pH sensitive linker reveals different time-dependent intracellular localization, in vitro and in vivo efficiency in alpha-fetoprotein receptor targeted doxorubicin conjugate // International Journal of Pharmaceutics. 2019. Vol. 559. pp. 138-146.
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TY - JOUR
DO - 10.1016/j.ijpharm.2018.12.073
UR - https://doi.org/10.1016%2Fj.ijpharm.2018.12.073
TI - Type of pH sensitive linker reveals different time-dependent intracellular localization, in vitro and in vivo efficiency in alpha-fetoprotein receptor targeted doxorubicin conjugate
T2 - International Journal of Pharmaceutics
AU - Mollaev, Murad D
AU - Gorokhovets, N.
AU - Nikolskaya, Elena D
AU - Faustova, M
AU - Zabolotsky, A
AU - Zhunina, O
AU - Sokol, M
AU - Zamulaeva, Irina
AU - Severin, E.
AU - Yabbarov, Nikita G
PY - 2019
DA - 2019/03/01 00:00:00
PB - Elsevier
SP - 138-146
VL - 559
SN - 0378-5173
SN - 1873-3476
ER -
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@article{2019_Mollaev,
author = {Murad D Mollaev and N. Gorokhovets and Elena D Nikolskaya and M Faustova and A Zabolotsky and O Zhunina and M Sokol and Irina Zamulaeva and E. Severin and Nikita G Yabbarov},
title = {Type of pH sensitive linker reveals different time-dependent intracellular localization, in vitro and in vivo efficiency in alpha-fetoprotein receptor targeted doxorubicin conjugate},
journal = {International Journal of Pharmaceutics},
year = {2019},
volume = {559},
publisher = {Elsevier},
month = {mar},
url = {https://doi.org/10.1016%2Fj.ijpharm.2018.12.073},
pages = {138--146},
doi = {10.1016/j.ijpharm.2018.12.073}
}