聚脲树枝状大分子靶向叶酸递送L-丁硫氨酸亚砜亚胺作为克服卵巢癌化疗耐药性的工具

Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance.

作者信息

Cruz Adriana, Mota Pedro, Ramos Cristiano, Pires Rita F, Mendes Cindy, Silva José P, Nunes Sofia C, Bonifácio Vasco D B, Serpa Jacinta

机构信息

iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Avenida Rovisco Pais, 1049-001 Lisboa, Portugal.

CEDOC, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.

出版信息

Antioxidants (Basel). 2020 Feb 3;9(2):133. doi: 10.3390/antiox9020133.

Ovarian cancer is a highly lethal disease, mainly due to chemoresistance. Our previous studies on metabolic remodeling in ovarian cancer have supported that the reliance on glutathione (GSH) bioavailability is a main adaptive metabolic mechanism, also accounting for chemoresistance to conventional therapy based on platinum salts. In this study, we tested the effects of the in vitro inhibition of GSH synthesis on the restoration of ovarian cancer cells sensitivity to carboplatin. GSH synthesis was inhibited by exposing cells to l-buthionine sulfoximine (l-BSO), an inhibitor of -glutamylcysteine ligase (GCL). Given the systemic toxicity of l-BSO, we developed a new formulation using polyurea (PURE) dendrimers nanoparticles (l-BSO@PURE-FA), targeting l-BSO delivery in a folate functionalized nanoparticle.

卵巢癌是一种致死率很高的疾病，主要原因是化疗耐药性。我们之前关于卵巢癌代谢重塑的研究表明，对谷胱甘肽（GSH）生物利用度的依赖是一种主要的适应性代谢机制，这也解释了对基于铂盐的传统疗法的化疗耐药性。在本研究中，我们测试了体外抑制GSH合成对恢复卵巢癌细胞对卡铂敏感性的影响。通过将细胞暴露于γ-谷氨酰半胱氨酸连接酶（GCL）抑制剂L-丁硫氨酸亚砜胺（L-BSO）来抑制GSH合成。鉴于L-BSO的全身毒性，我们开发了一种使用聚脲（PURE）树枝状聚合物纳米颗粒（L-BSO@PURE-FA）的新制剂，将L-BSO靶向递送至叶酸功能化纳米颗粒中。