用于吩嗪递送的核苷-脂质纳米颗粒：一种破坏去势抵抗性前列腺癌中Hsp27-eIF4E相互作用的新治疗策略。

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

作者信息

Ziouziou Hajer, Paris Clément, Benizri Sébastien, Le Thi Khanh, Andrieu Claudia, Nguyen Dang Tan, Appavoo Ananda, Taïeb David, Brunel Frédéric, Oueslati Ridha, Siri Olivier, Camplo Michel, Barthélémy Philippe, Rocchi Palma

机构信息

Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR 1068, CNRS, UMR 7258, Aix-Marseille University U105, Institut Paoli-Calmettes, F-13009 Marseille, France.

Unit of Immunology Microbiology Environmental and Carcinogenesis (IMEC), Science Faculty of Bizerte, University of Carthage, 7000 Bizerte, Tunisia.

出版信息

Pharmaceutics. 2021 Apr 27;13(5):623. doi: 10.3390/pharmaceutics13050623.

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-PEG (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.

热休克蛋白27（Hsp27）在去势抵抗性前列腺癌（CRPC）的肿瘤进展和化疗耐药中发挥着既定作用。Hsp27保护真核翻译起始因子4E（eIF4E）不被降解，从而在治疗期间维持细胞存活。吩嗪衍生物化合物#14被证明能特异性破坏Hsp27/eIF4E相互作用，并显著延缓前列腺癌异种移植模型中去势抵抗性肿瘤的进展。在本研究中，开发了多种用DOTAU（N-[5'-(2',3'-二油酰基)尿苷]-N'，N'，N'-三甲基对甲苯磺酸盐）和DOU-PEG（5'-PEG2000-2'，3'-二油酰基尿苷）核脂质（NLs）包裹吩嗪#14的策略，以改善其溶解性、生物活性和生物利用度。我们观察到，与单独的吩嗪#14和NLs相比，NLs包裹的吩嗪#14对去势抵抗性前列腺癌细胞系的Hsp27-eIF4E相互作用破坏增强了细胞毒性作用，并抑制了去势抵抗性前列腺癌细胞异种移植小鼠的肿瘤生长。吩嗪#14的NL包裹可能是一种用于CRPC治疗的有趣纳米策略。