Unleashing the antitumor power of cyclophosphamide by arabinogalactan and aptamer conjugation.

Autor: Zamay TN; Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center 'Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences', 50 Akademgorodok, Krasnoyarsk 660036, Russia; Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka, Krasnoyarsk 660022, Russia. Electronic address: tzamay@yandex.ru., Kolovskaya OS; Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center 'Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences', 50 Akademgorodok, Krasnoyarsk 660036, Russia; Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka, Krasnoyarsk 660022, Russia., Zamay GS; Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center 'Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences', 50 Akademgorodok, Krasnoyarsk 660036, Russia; Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka, Krasnoyarsk 660022, Russia., Kirichenko AK; Department of Pathological Anatomy, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka, Krasnoyarsk 660022, Russia., Luzan NA; Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka, Krasnoyarsk 660022, Russia., Zamay SS; Department of Molecular Electronics, Federal Research Center 'Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences', 50 Akademgorodok, Krasnoyarsk 660036, Russia., Neverova NA; LLC INPF 'Chemistry of Wood', Irkutsk 664082, Russian Federation., Medvedeva EN; LLC INPF 'Chemistry of Wood', Irkutsk 664082, Russian Federation., Babkin VA; LLC INPF 'Chemistry of Wood', Irkutsk 664082, Russian Federation., Veprintsev DV; Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka, Krasnoyarsk 660022, Russia., Shchugoreva IA; Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center 'Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences', 50 Akademgorodok, Krasnoyarsk 660036, Russia; Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka, Krasnoyarsk 660022, Russia., Kichkailo AS; Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center 'Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences', 50 Akademgorodok, Krasnoyarsk 660036, Russia; Laboratory for Biomolecular and Medical Technologies, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka, Krasnoyarsk 660022, Russia. Electronic address: annazamay@yandex.ru.
Jazyk: angličtina
Zdroj: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V [Eur J Pharm Biopharm] 2024 Nov; Vol. 204, pp. 114531. Date of Electronic Publication: 2024 Oct 14.
DOI: 10.1016/j.ejpb.2024.114531
Abstrakt: Cyclophosphamide (CPA) (2-oxo-2-di(β-chloroethyl)amino tetrahydro-2,1,3-phosphoxazine) is an alkylating cytostatic compound with a broad spectrum of antitumor activity. Despite its efficacy, the clinical application of CPA is hindered by the significant occurrence of adverse side effects. To address these limitations, a promising approach involves the mechanochemical treatment of CPA with arabinogalactan (AG) to facilitate the dispersion of the drug within the AG matrix. AG stands out from other polymers due to its uniformity, low molecular weight, water solubility, and ability to form drug conjugates, thereby enhancing their therapeutic potency. Moreover, AG possesses immune-modulating properties that have the potential to counteract the immunosuppressive effects induced by CPA. By means of mechanical treatment, we successfully obtained CPA-AG complexes with a CPA:AG ratio of 1:10. These complexes were further modified with As42 aptamers that specifically target Erlich ascites cells. Aptamers, a novel class of oligonucleotide ligands obtained through SELEX technology, possess high affinity and specificity for binding to various receptors. An ascitic form of Ehrlich carcinoma was chosen as an in vitro and in vivo tumor model due to its notable drug resistance. In vitro and in vivo evaluations were conducted to compare the antitumor activity of both the CPA-AG and CPA-AG-As42 complexes with pure CPA. In vitro experiments revealed that the CPA-AG complex displayed superior antitumor activity compared to pure CPA, leading to complete tumor cell death primarily through necrosis. Notably, no toxic effects were observed with the CPA-AG and CPA-AG-As42 complexes, and they significantly prolonged the lifespan of tumor-bearing mice by more than 3.5 times. Histological studies further supported the antitumor efficacy of these complexes. These results underscore the potential of utilizing CPA-AG mechanocomposites, functionalized with aptamers, for the targeted delivery of CPA to tumors.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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