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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.

frontiers in pharmacology

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