Nucleoside-Lipid-Based Nanoparticles for Phenazine Delivery: A New Therapeutic Strategy to Disrupt Hsp27-eIF4E Interaction in Castration Resistant Prostate Cancer

• Main Authors: Hajer Ziouziou, Clément Paris, Sébastien Benizri, Thi Khanh Le, Claudia Andrieu, Dang Tan Nguyen, Ananda Appavoo, David Taïeb, Frédéric Brunel, Ridha Oueslati, Olivier Siri, Michel Camplo, Philippe Barthélémy, Palma Rocchi
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Pharmaceutics
• Subjects: nucleolipid; dialkoxyphenazine; nanoformulation; prostate cancer
• Online Access: https://www.mdpi.com/1999-4923/13/5/623

Heat shock protein 27 (Hsp27) has an established role in tumor progression and chemo-resistance of castration-resistant prostate cancer (CRPC). Hsp27 protects eukaryotic translation initiation factor 4E (eIF4E) from degradation, thereby maintaining survival during treatment. Phenazine derivative compound #14 was demonstrated to specifically disrupt Hsp27/eIF4E interaction and significantly delay castration-resistant tumor progression in prostate cancer xenografts. In the present work, various strategies of encapsulation of phenazine #14 with either DOTAU (N-[5′-(2′,3′-dioleoyl)uridine]-N′,N′,N′-trimethylammonium tosylate) and DOU-PEG₂₀₀₀ (5′-PEG2000-2′,3′-dioleoyluridine) nucleolipids (NLs) were developed in order to improve its solubilization, biological activity, and bioavailability. We observed that NLs-encapsulated phenazine #14-driven Hsp27-eIF4E interaction disruption increased cytotoxic effects on castration-resistant prostate cancer cell line and inhibited tumor growth in castration-resistant prostate cancer cell xenografted mice compared to phenazine #14 and NLs alone. Phenazine #14 NL encapsulation might represent an interesting nanostrategy for CRPC therapy.