Squalenoylated Nanoparticle Pro-Drugs of Adjuvant Antitumor 11α-Hydroxyecdysteroid 2,3-Acetonides Act as Cytoprotective Agents Against Doxorubicin and Paclitaxel

Frontiers in Pharmacology

Zoltán Kónya¹  Péter Bélteky²  Gabriella Spengler³  Márta Nové³  Ahmed D. Latif⁵  Dóra Bogdán⁶  Máté Vágvölgyi⁷  Attila Hunyadi⁸  István Zupkó⁸  Gábor Tóth⁹  Tamás Gáti^1,10 

[1] 0MTA-SZTE Reaction Kinetics and Surface Chemistry Research Group, University of Szeged, Szeged, Hungary;Department of Applied and Environmental Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary;Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary;Department of Organic Chemistry, Semmelweis University, Budapest, Hungary;Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary;Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Budapest, Hungary;Institute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary;Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, Hungary;NMR Group, Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Budapest, Hungary;Servier Research Institute of Medicinal Chemistry (SRIMC), Budapest, Hungary;

关键词: ecdysteroid;    squalene nanoparticle pro-drug;    self-assembly;    low-density lipoprotein targeting;    cancer;    multi-drug resistance;   

DOI  :  10.3389/fphar.2020.552088

来源: DOAJ

【 摘 要 】

Several ecdysteroid acetonides act as adjuvant chemo-sensitizing agents against various cancer cell lines, and they can be formulated to self-assembling nanoparticle (NP) pro-drugs through a hydrolysable conjugation with squalene. In the bloodstream such squalenoylated nanoparticles dissolve into low-density lipoprotein (LDL) that allows targeting tissues containing high levels of LDL-receptors. In this work, ajugasterone C 2,3;20,22-diacetonide (3) and 11α-hydroxypoststerone 2,3-acetonide (4) were squalenoylated to obtain two new ecdysteroid pro-drugs (6 and 7) and their nano-assemblies (6NP and 7NP). A complete NMR signal assignment of 6 and 7 was achieved. Interaction of compounds 3 and 4 with chemotherapeutics was studied by the Chou-Talalay method. Compound 3 showed strong synergism with doxorubicin on a multi-drug resistant lymphoma cell line. In contrast, its nanoassembly 6NP significantly decreased the cytotoxicity of doxorubicin on these MDR cells, strongly suggesting that at least the 2,3-acetonide group was cleaved by the acidic pH of lysosomes after endocytosis of the prodrug. Further, compound 4 acted in strong antagonism with paclitaxel on MCF-7 cells and its nanoassemby 7NP also protected MCF-7 cells from the effect of paclitaxel. Our results suggest that acid-resistant A-ring substitution would be crucial to design adjuvant antitumor squalenoylated ecdysteroid prodrugs. Additionally, our results may be considered as a serendipitous discovery of a novel way to deliver cytoprotective, adaptogen ecdysteroids to healthy tissues with upregulated LDL-R.

【 授权许可】

Unknown