Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China.
ACS Nano. 2022 May 24;16(5):7409-7427. doi: 10.1021/acsnano.1c09794. Epub 2022 May 13.
Glioblastoma (GBM) is an invasive cancer with high mortality in central nervous system. Resistance to temozolomide (TMZ) and immunosuppressive microenvironment lead to low outcome of the standardized treatment for GBM. In this study, a 2-deoxy-d-glucose modified lipid polymer nanoparticle loaded with TMZ and siPD-L1 (TMZ/siPD-L1@GLPN/dsb) was prepared to reprogram the TMZ-resistant and immunosuppressive microenvironment in orthotopic GBM. TMZ/siPD-L1@GLPN/dsb simultaneously delivered a large amount of TMZ and siPD-L1 to the deep area of the orthotopic TMZ-resistant GBM tissue. By inhibiting PD-L1 protein expression, TMZ/siPD-L1@GLPN/dsb markedly augmented the percentage of CD3CD8IFN-γ cells (T cells) and reduced the percentage of CD4CD25FoxP3 cells (T cells) in orthotopic TMZ-resistant GBM tissue, which enhanced T-cell mediated cytotoxicity on orthotopic TMZ-resistant GBM. Moreover, TMZ/siPD-L1@GLPN/dsb obviously augmented the sensitivity of orthotopic TMZ-resistant GBM to TMZ through decreasing the protein expression of -methyl-guanine-DNA methyltransferase (MGMT) in TMZ-resistant GBM cells. Thus, TMZ/siPD-L1@GLPN/dsb markedly restrained the growth of orthotopic TMZ-resistant GBM and extended the survival time of orthotopic GBM rats through reversing a TMZ-resistant and immunosuppressive microenvironment. TMZ/siPD-L1@GLPN/dsb shows potential application to treat orthotopic TMZ-resistant GBM.
胶质母细胞瘤（GBM）是一种中枢神经系统高死亡率的侵袭性癌症。替莫唑胺（TMZ）耐药和免疫抑制微环境导致 GBM 的标准治疗效果不佳。在这项研究中，制备了一种 2-脱氧-d-葡萄糖修饰的脂质聚合物纳米颗粒，负载 TMZ 和 siPD-L1（TMZ/siPD-L1@GLPN/dsb），以重新编程原位 GBM 中的 TMZ 耐药和免疫抑制微环境。TMZ/siPD-L1@GLPN/dsb 同时将大量 TMZ 和 siPD-L1 递送到原位 TMZ 耐药 GBM 组织的深部。通过抑制 PD-L1 蛋白表达，TMZ/siPD-L1@GLPN/dsb 显著增加了原位 TMZ 耐药 GBM 组织中 CD3CD8IFN-γ细胞（T 细胞）的百分比，并降低了 CD4CD25FoxP3细胞（T 细胞）的百分比，增强了 T 细胞对原位 TMZ 耐药 GBM 的细胞毒性。此外，TMZ/siPD-L1@GLPN/dsb 通过降低 TMZ 耐药 GBM 细胞中-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）的蛋白表达，显著提高了原位 TMZ 耐药 GBM 对 TMZ 的敏感性。因此，TMZ/siPD-L1@GLPN/dsb 通过逆转 TMZ 耐药和免疫抑制微环境，显著抑制了原位 TMZ 耐药 GBM 的生长，并延长了原位 GBM 大鼠的生存时间。TMZ/siPD-L1@GLPN/dsb 显示出治疗原位 TMZ 耐药 GBM 的潜力。
