Department of Biotechnology, Indian Institute of Technology, Hyderabad, India.
Department of Biomedical Engineering, Indian Institute of Technology, Hyderabad, India.
Drug Deliv Transl Res. 2024 Feb;14(2):342-359. doi: 10.1007/s13346-023-01401-z. Epub 2023 Aug 16.
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.
多形性胶质母细胞瘤（GBM）被认为是一种侵袭性很强的脑癌，预后较差。多药耐药（MDR）相关的 P-糖蛋白（P-gp）表达增加，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耐药性，并在癌症复发中起主要作用。在这项研究中，我们使用小分子抑制剂瑞凡（RV）靶向 P-gp，抑制 MDR，从而延长药物在细胞质中的滞留时间。为了消除 GBM 和 GSCs，我们使用了两种已确立的抗癌药物，regorafenib（RF）和姜黄素（CMN）。为了改善药物的药代动力学并减少全身药物输送，我们开发了纳米结构混合脂质胶囊（nHLCs），其中疏水药物可以装载在核心中，并通过动态光散射（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 也显示出 nHLC 在 GBM 细胞中的保留增加。用 RV 预处理的载药 nHLC 的共递送在 GBM 和 GSCs 中表现出比其单独剂量更高的细胞毒性，并有效减小肿瘤球体的大小和干性，加速细胞凋亡，为治疗胶质母细胞瘤提供了一种有前途的方法。
