Drug Delivery Systems for Proteolysis Targeting Chimera that Improve Tumour Accumulation and Therapeutic Index

11 September 2018 09:30 - 10:05

The Proteolysis targeting chimera (PROTAC) is a promising new technology in the field of oncology. There are several oncology targets that are being pursued by this technology. For many of these targets the pharmacology is driven by AUC over a certain inhibitory concentration and for some targets the therapeutic index (TI) may be very narrow. One way to improve the TI is to deliver the PROTAC via a sustained delivery system like the liposomes.

Two drug delivery systems were developed by incorporating the PROTACs in liposomes. In the first delivery system the PROTAC was incorporated into liposomes via a conventional approach where in the liposomes were formed by mixing the lipids in organic phase and PROTAC in aqueous phase. In another system the lipids were in organic phase and the PROTAC was pre-dissolved in cyclodextrin at very concentration and liposomes were formed. These liposomes were further purified by size exclusion chromatography or dialysis filtration.

In a Rat PK/PD study at 20 mg/kg, the cyclodextrin liposomes had 25X higher plasma concentration and 2.6X higher tumour concentration compared to conventional formulation. This improvement in plasma and tumour concentration could potentially improve the TI for the PROTAC.

A liposomal drug delivery system seems promising based on the above results. Optimization of the liposomes could further improve the tumour concentration and improve the overall TI. This delivery technology may be well suited to bring novel PROTACs into clinic.

Vijay Anand Sethuraman, Senior Scientific Manager, Genentech