Wei Xue, Yang Ming, Zou Haoyang, Shen Songjie, Li Yuechong, Chen Li, Liu Yahui, Li Di, Ding Jianxun
Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130061, PR China; Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China.
Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130061, PR China.
J Control Release. 2025 Apr 10;380:760-772. doi: 10.1016/j.jconrel.2025.02.020. Epub 2025 Feb 18.
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) selectively arrest malignant cells in the G1 phase of cell cycle by inhibiting CDK4/6-mediated phosphorylation of retinoblastoma protein. However, CDK4/6i therapy is often ineffective against triple-negative breast cancer (TNBC) due to the high lysosomal content in TNBC cells, which sequesters the drugs and prevents them from reaching their nuclear target. To address this challenge, three pH- and glutathione-responsive poly(amino acid) nanogels composed of methoxy poly(ethylene glycol) of various lengths and poly(L-glutamic acid-co-L-cystine) (mPEG-P(Glu-co-Cys)) were developed to efficiently deliver the CDK4/6i abemaciclib (ABE) to TNBC cells. These nanogels bypassed lysosomal sequestration, thereby enhancing the efficacy of molecularly targeted immunotherapy. Among the nanogels, the formulation with mPEG2000 (NG2000) exhibited the highest efficiency in delivering ABE, resulting in increased cell apoptosis, activation of an anti-cancer immune response, reduction of immunosuppression, and improved therapeutic outcomes against TNBC. Furthermore, NG2000/ABE enhanced immune checkpoint therapy for TNBC, achieving a tumor inhibition rate of 89.66%. These findings demonstrate the potential of poly(amino acid) nanoformulations for delivering CDK4/6 inhibitors as molecularly targeted immunotherapy for TNBC in clinical applications.
细胞周期蛋白依赖性激酶4和6抑制剂（CDK4/6i）通过抑制CDK4/6介导的视网膜母细胞瘤蛋白磷酸化，在细胞周期的G1期选择性地使恶性细胞停滞。然而，由于三阴性乳腺癌（TNBC）细胞中溶酶体含量高，CDK4/6i治疗对TNBC往往无效，溶酶体会隔离药物并阻止它们到达细胞核靶点。为应对这一挑战，研究人员开发了三种由不同长度的甲氧基聚（乙二醇）和聚（L-谷氨酸-co-L-胱氨酸）（mPEG-P（Glu-co-Cys））组成的pH和谷胱甘肽响应性聚（氨基酸）纳米凝胶，以有效地将CDK4/6i阿贝西利（ABE）递送至TNBC细胞。这些纳米凝胶绕过了溶酶体隔离，从而提高了分子靶向免疫治疗的疗效。在这些纳米凝胶中，含有mPEG2000的制剂（NG2000）在递送ABE方面表现出最高效率，导致细胞凋亡增加、抗癌免疫反应激活、免疫抑制降低以及针对TNBC的治疗效果改善。此外，NG2000/ABE增强了TNBC的免疫检查点治疗，实现了89.66%的肿瘤抑制率。这些发现证明了聚（氨基酸）纳米制剂作为CDK4/6抑制剂的递送载体在临床应用中作为TNBC分子靶向免疫治疗的潜力。
