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

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 11a-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.

Phytoecdysteroids: Distribution, Structural Diversity, Biosynthesis, Activity, and Crosstalk with Phytohormones

“…The structure–activity relationship showed a large number of semisynthetic EC analogs with the presence of a 2,3-acetonide group, which has chemosensitizing properties against both multi-drug resistant and drug-susceptible cancer cell lines [ 121 ]. Moreover, the latest approach to develop nanoscale materials based on EC–squalene conjugates has been reported ( Figure 2 e) [ 122 ]. Many new EC ethers and esters have been synthesized via alkylation and condensation of naturally occurring EC and with the help of several aldehydes and ketones for testing their inhibitory activity against transmembrane protein ABCB1.…”

Nanoparticulation of Prodrug into Medicines for Cancer Therapy

“…For instance, PTX-SeSe-CIT NPs exhibited the most potent tumorinhibiting activity hence significantly reduced tumor volume (Figure 2D). [48] The squalenoylation, an antitumor strategy with enhanced activity, [49] was employed to improve pharmacokinetical profiles of both hydrophilic and hydrophobic therapeutic agents. [50] The quick metabolization and rapid clearance heavily compromised neuropharmacological activity of adenosine upon systemic administration.…”