pH-sensitive niosomes for ATRA delivery: A promising approach to inhibit Pin1 in high-grade serous ovarian cancer.

The peptidyl-prolyl cis/trans isomerase Pin1 positively regulates numerous cancer-driving pathways, and it is overexpressed in several malignancies, including high-grade serous ovarian cancer (HGSOC). The findings that all-trans retinoic acid (ATRA) induces Pin1 degradation strongly support that ATRA treatment might be a promising approach for HGSOC targeted therapy. Nevertheless, repurposing ATRA into the clinics for the treatment of solid tumors remains an unmet need mainly due to the insurgence of resistance and its ineffective delivery. In the present study, niosomes have been employed for improving ATRA delivery in HGSOC cell lines. Characterization of niosomes including hydrodynamic diameter, ζ-potential, morphology, entrapment efficiency and stability over time and in culture media was performed. Furthermore, pH-sensitiveness and ATRA release profile were investigated to demonstrate the capability of these vesicles to release ATRA in a stimuli-responsive manner. Obtained results documented a nanometric and monodispersed samples with negative ζ-potential. ATRA was efficiently entrapped, and a substantial release was observed in the presence of acidic pH (pH 5.5). Finally, unloaded niosomes showed good biocompatibility while ATRA-loaded niosomes significantly increased ATRA Pin1 inhibitory activity, which was consistent with cell growth inhibition. Taken together, ATRA-loaded niosomes might represent an appealing therapeutic strategy for HGSOC therapy.

Opsonin-Deficient Nucleoproteic Corona Endows UnPEGylated Liposomes with Stealth Properties In Vivo.

For several decades, surface grafted polyethylene glycol (PEG) has been a go-to strategy for preserving the synthetic identity of liposomes in physiological milieu and preventing clearance by immune cells. However, the limited clinical translation of PEGylated liposomes is mainly due to the protein corona formation and the subsequent modification of liposomes' synthetic identity, which affects their interactions with immune cells and blood residency. Here we exploit the electric charge of DNA to generate unPEGylated liposome/DNA complexes that, upon exposure to human plasma, gets covered with an opsonin-deficient protein corona. The final product of the synthetic process is a biomimetic nanoparticle type covered by a proteonucleotidic corona, or "proteoDNAsome", which maintains its synthetic identity in vivo and is able to slip past the immune system more efficiently than PEGylated liposomes. Accumulation of proteoDNAsomes in the spleen and the liver was lower than that of PEGylated systems. Our work highlights the importance of generating stable biomolecular coronas in the development of stealth unPEGylated particles, thus providing a connection between the biological behavior of particles in vivo and their synthetic identity.

Notch signaling in female cancers: a multifaceted node to overcome drug resistance.

Drug resistance is one of the main challenges in cancer therapy, including in the treatment of female-specific malignancies, which account for more than 60% of cancer cases among women. Therefore, elucidating the underlying molecular mechanisms is an urgent need in gynecological cancers to foster novel therapeutic approaches. Notably, Notch signaling, including either receptors or ligands, has emerged as a promising candidate given its multifaceted role in almost all of the hallmarks of cancer. Concerning the connection between Notch pathway and drug resistance in the afore-mentioned tumor contexts, several studies focused on the Notch-dependent regulation of the cancer stem cell (CSC) subpopulation or the induction of the epithelial-to-mesenchymal transition (EMT), both features implicated in either intrinsic or acquired resistance. Indeed, the present review provides an up-to-date overview of the published results on Notch signaling and EMT- or CSC-driven drug resistance. Moreover, other drug resistance-related mechanisms are examined such as the involvement of the Notch pathway in drug efflux and tumor microenvironment. Collectively, there is a long way to go before every facet will be fully understood; nevertheless, some small pieces are falling neatly into place. Overall, the main aim of this review is to provide strong evidence in support of Notch signaling inhibition as an effective strategy to evade or reverse resistance in female-specific cancers.