Pin1, a prolyl isomerase that sustains tumor progression, is overexpressed in different types of malignancies. Functional inactivation of Pin1 restrains tumor growth and leaves normal cells unaffected making it an ideal pharmaceutical target. Although many studies on Pin1 have focused on malignancies that are influenced by sex hormones, studies in ovarian cancer have lagged behind. Here, we show that Pin1 is an important therapeutic target in high-grade serous epithelial ovarian cancer. Knock down of Pin1 in ovarian cancer cell lines induces apoptosis and restrains tumor growth in a syngeneic mouse model. Since specific and non-covalent Pin1 inhibitors are still limited, the first liposomal formulation of a Pin1 inhibitor was designed. The drug was efficiently encapsulated in modified cyclodextrins and remotely loaded into pegylated liposomes. This liposomal formulation accumulates preferentially in the tumor and has a desirable pharmacokinetic profile. The liposomal inhibitor was able to alter Pin1 cancer driving-pathways trough the induction of proteasome-dependent degradation of Pin1 and was found to be effective in curbing ovarian tumor growth in vivo.
Liposomal delivery of a Pin1 inhibitor complexed with cyclodextrins as new therapy for high-grade serous ovarian cancer
De Stefano L.;Crotti S.;D'Aronco S.;Agostini M.;Corona G.;
2018
Abstract
Pin1, a prolyl isomerase that sustains tumor progression, is overexpressed in different types of malignancies. Functional inactivation of Pin1 restrains tumor growth and leaves normal cells unaffected making it an ideal pharmaceutical target. Although many studies on Pin1 have focused on malignancies that are influenced by sex hormones, studies in ovarian cancer have lagged behind. Here, we show that Pin1 is an important therapeutic target in high-grade serous epithelial ovarian cancer. Knock down of Pin1 in ovarian cancer cell lines induces apoptosis and restrains tumor growth in a syngeneic mouse model. Since specific and non-covalent Pin1 inhibitors are still limited, the first liposomal formulation of a Pin1 inhibitor was designed. The drug was efficiently encapsulated in modified cyclodextrins and remotely loaded into pegylated liposomes. This liposomal formulation accumulates preferentially in the tumor and has a desirable pharmacokinetic profile. The liposomal inhibitor was able to alter Pin1 cancer driving-pathways trough the induction of proteasome-dependent degradation of Pin1 and was found to be effective in curbing ovarian tumor growth in vivo.Pubblicazioni consigliate
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