胶质母细胞瘤多形性（GBM）被视为一种具有恶性侵袭性和不良预后的脑癌。P-糖蛋白（P-gp）的表达增加，负责多药耐药（MDR），使其成为提高药物反应的潜在靶点。此外，胶质母细胞瘤干细胞（GSCs）增加了对化疗和放疗的抵抗力，并在癌症复发中起着重要作用。在本研究中，我们使用小分子抑制剂reversan（RV）来靶向P-gp，以抑制MDR，延长药物在细胞质中的保留时间。为了消除GBM和GSCs，我们使用了两种公认的抗癌药物regorafenib（RF）和curcumin（CMN）。为改善药物的药代动力学和减少系统给药，我们开发了纳米结构的混合脂质胶囊（nHLCs），其中疏水药物可以被加载在核心中，并使用动态光散射（DLS）和冷冻扫描电子显微镜（SEM）确定其物理化学性质。RV抑制MDR还显示了nHLC在GBM细胞中的增强保留。经RV预处理的药物负载的nHLCs共同递送，在GBM和GSCs中表现出更强的细胞毒性，并有效减小了肿瘤球的大小和干细胞状态，并加速了凋亡的速度，为胶质母细胞瘤的治疗提供了有希望的方案。© 2023 Controlled Release Society.

Glioblastoma multiforme (GBM) is regarded as a highly aggressive brain cancer with a poor prognosis. There is an increase in the expression of P-glycoprotein (P-gp), responsible for multidrug resistance (MDR), making it a potential target for improving drug responses. Additionally, glioblastoma stem cells (GSCs) increase resistance to chemo- and radiotherapy and play a major role in cancer relapse. In this study, we targeted P-gp using a small molecule inhibitor, reversan (RV), to inhibit MDR that prolonged the retention of drugs in the cytosolic milieu. To eliminate GBM and GSCs, we have used two well-established anti-cancer drugs, regorafenib (RF) and curcumin (CMN). To improve the pharmacokinetics and decrease systemic delivery of drugs, we developed nanostructure hybrid lipid capsules (nHLCs), where hydrophobic drugs can be loaded in the core, and their physicochemical properties were determined by dynamic light scattering (DLS) and cryo-scanning electron microscopy (SEM). Inhibition of MDR by RV has also shown enhanced retention of nHLC in GBM cells. Co-delivery of drug-loaded nHLCs, pre-treated with RV, exhibited superior cytotoxicity in both GBM and GSCs than their individual doses and effectively reduced the size and stemness of tumor spheres and accelerated the rate of apoptosis, suggesting a promising treatment for glioblastoma.© 2023. Controlled Release Society.