Epithelial Ovarian cancer (EOC) is the 5th leading cause of cancer death in the USA and the High Grade Serous-EOC is the most common and aggressive type characterized by mutations in the p53 gene (>90%). Pin1 has been demonstrated to activate a mutant p53 transcriptional program. It binds specific phosphoSer/Thr-Pro-motifs and catalyses the cis/trans conformational switch of target proteins. In HGS-EOC, Pin1 is overexpressed in about 50% of cases suggesting that it may be a potential therapeutic target. The Pin1 inhibition affects cellular proliferation, migration, invasion, new angiogenesis and apoptosis suggesting a pivotal role in cancer. Nevertheless, there are still deficiencies in producing Pin1 ligands: Pfizer has reported inhibitors that have poor permeability and low efficacy. Here, it is reported that the encapsulation of these inhibitors in liposomes increases the cytotoxic activity on ovarian cancer cells.
The inhibitor was encapsulated in ionisable cyclodextrins via a pH gradient. PEG-liposomes were prepared using different molar ratio of cholesterol and lipids. Cell viability was tested with an MTT-like assay. The liposome characteristics were evaluated by DLS and zeta potential. The loading efficiency of drug was calculated via UV-Visible method and the release with a dialysis membrane.
Pegylated liposomes of about 100 nm were synthesized for the encapsulation of drug. This complex has a promising loading efficiency and release rate. These characteristics allow an efficient delivery in different ovarian cancer cells line achieving the IC50 values in the low micromolar range. Instead, inhibitor alone did not change the cell viability.
In summary, we have created a new formulation of Pin1 liposomal inhibitor that can be used to kill ovarian cancer cells. Therefore, for further application in vivo, the inhibitor retention would enhance antitumor efficacy. In fact, the liposome system could have a high concentration in the tumour, thanks to enhanced permeability and retention effect, overtake the tumoral barrier and represents an option for the therapy of ovarian cancer.
Clinical trial identification
Legal entity responsible for the study
Graduate School in Chemistry - University of Trieste
AIRC - Associazione Italiana Ricerca sul Cancro
All authors have declared no conflicts of interest.