The IonoChem Lipid Tool Box
IonoChem offers a broad spectrum of lipids for the lipophilisation of APIs. It comprises various classes of lipids ranging from natural plant origin, like isoprenoids, to functionalised mono- and double tailed natural or (semi-)synthetic lipids.
IonoChem also includes the synthesis of nucleolipids and their conversion into lipophilic reactive phosphoramidites as further tools for a tunable lipophilisation of nucleic acids. For solide-phase DNA-/RNA synthesis IonoChem has access to a substantial lipophilic phosphoramidite compound library.
Delivery of therapeutic molecules of complex nature like small-interfering (si)RNAs across plasma membranes remains one of the largest obstacle for their in vivo application. IonoChem adresses this challenge by the creation of a specific lipo-DNA as a trafficking tool for the targeted membrane transition of siRNAs.
Improved Efficacy of 6-Azauridine
6-Azauridine (z6U), a synthetic triazine nucleoside and uridine structure analog, is a potent chemotherapeutic agent for the treatment of leukemia, especially of chronic myeloid leukemia (CML). However, 6-Azauridine had to be withdrawn from the market because of severe side effects, like e.g. the lost of motor coordination or sedative effects on the central nervous system. These side effects were aided and abetted by the observed high renal elimination rates of up to 75%, which required high administration rates with high partial doses.
In cooperation with the European ScreeningPort Hamburg various 6-Azauridine derivatives were tested against 10 different human cell lines from the NCI 60 panel. Their selective inhibition of cell proliferation and potency to induce cell death were evaluated by means of a standardised luminescent cell viability assay (CellTiterGlo®, Promega) on a Multimode Plate Reader (EnSpire®, PerkinElmer) after 48 and 72 hours, calculating 50% growth inhibition (GI50), and 50% lethal (LC50) concentration values.
While unmodified z6U shows within nearly all tested cell lines only cytostatic effects (blue bars), the lipophilised derivatives ION-2.1 and ION-2.5 are both highly cytotoxic (orange bars) with LC50 values between 30 - 50 μM.
Acquired Cell Toxicity Through Lipophilisation
A condensation reaction of the two non-toxic nucleosides uridine and ribothymidine with the also non-toxic near-natural lipid nonadecane-10-one leads to nucleolipids with high cell toxic properties. ION-3.1 as well as ION-4.1 both show activity within all tested cell lines with ION-3.1 having the most pronounced, nearly 100% toxic effect within the lung carcenoma cell line A-549 and ION-4.1 in the ovarian cell line IGR-OV1.