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

Máté Vágvölgyi; Péter Bélteky; Dóra Bogdán; Márta Nové; Gabriella Spengler; Ahmed D Latif; István Zupkó; Tamás Gáti; Gábor Tóth; Zoltán Kónya; Attila Hunyadi

doi:10.3389/fphar.2020.552088

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

Front Pharmacol. 2020 Sep 11:11:552088. doi: 10.3389/fphar.2020.552088. eCollection 2020.

Authors

Máté Vágvölgyi¹, Péter Bélteky², Dóra Bogdán^{3

4}, Márta Nové⁵, Gabriella Spengler⁵, Ahmed D Latif⁶, István Zupkó^{6

7}, Tamás Gáti⁸, Gábor Tóth⁹, Zoltán Kónya^{2

10}, Attila Hunyadi^{1

7}

Affiliations

¹ Institute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary.
² Department of Applied and Environmental Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary.
³ Department of Organic Chemistry, Semmelweis University, Budapest, Hungary.
⁴ Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Budapest, Hungary.
⁵ Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary.
⁶ Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary.
⁷ Interdisciplinary Centre for Natural Products, University of Szeged, Szeged, Hungary.
⁸ Servier Research Institute of Medicinal Chemistry (SRIMC), Budapest, Hungary.
⁹ NMR Group, Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Budapest, Hungary.
¹⁰ MTA-SZTE Reaction Kinetics and Surface Chemistry Research Group, University of Szeged, Szeged, Hungary.

Abstract

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 (6_NP and 7_NP ). 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 6_NP 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 7_NP 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.

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