Taha Safa, Aljishi Muna, Sultan Ameera, Sridharan Kannan, Taurin Sebastien, Greish Khaled, Bakhiet Moiz
Department of Molecular Medicine, College of Medicine and Health Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain.
Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain.
Int J Mol Sci. 2025 May 9;26(10):4544. doi: 10.3390/ijms26104544.
Glioblastoma (GBM), a devastating brain malignancy, resists conventional therapies due to molecular heterogeneity and the blood-brain barrier's significant restriction on drug delivery. Cannabinoids like WIN 55,212-2 show promise but are limited by poor solubility and systemic toxicity. To address these challenges, we evaluated styrene-maleic acid (SMA) micellar encapsulation of WIN 55,212-2 (SMA-WIN) against free WIN in epithelial (LN18) and mesenchymal (A172) GBM cell lines, targeting cytotoxicity and receptor modulation (CB1, CB2, TRPV1, PPAR-γ). SMA-WIN exhibited significantly enhanced cytotoxicity, achieving IC50 values of 12.48 µM (LN18) and 16.72 µM (A172) compared to 20.97 µM and 30.9 µM for free WIN, suggesting improved cellular uptake via micellar delivery. In LN18 cells, both formulations upregulated CB1 and CB2, promoting apoptosis. Notably, SMA-WIN uniquely increased PPAR-γ expression by 2.3-fold in A172 cells, revealing a mesenchymal-specific mechanism absent in free WIN, which primarily modulated CB1/CB2. These findings position SMA-WIN as a promising candidate for precision GBM therapy, particularly for resistant mesenchymal subtypes, paving the way for in vivo validation to confirm blood-brain barrier penetration and clinical translation.
胶质母细胞瘤（GBM）是一种极具破坏性的脑恶性肿瘤，由于分子异质性以及血脑屏障对药物递送的显著限制，它对传统疗法具有抗性。像WIN 55,212-2这样的大麻素显示出前景，但受限于溶解度差和全身毒性。为应对这些挑战，我们评估了WIN 55,212-2的苯乙烯-马来酸（SMA）胶束包封物（SMA-WIN）相对于游离WIN对上皮型（LN18）和间充质型（A172）GBM细胞系的细胞毒性和受体调节作用（CB1、CB2、TRPV1、PPAR-γ）。SMA-WIN表现出显著增强的细胞毒性，其IC50值在LN18细胞系中为12.48 μM，在A172细胞系中为16.72 μM，而游离WIN在这两种细胞系中的IC50值分别为20.97 μM和30.9 μM，这表明通过胶束递送改善了细胞摄取。在LN18细胞中，两种制剂均上调了CB1和CB2，促进了细胞凋亡。值得注意的是，SMA-WIN在A172细胞中独特地使PPAR-γ表达增加了2.3倍，揭示了游离WIN中不存在的间充质特异性机制，游离WIN主要调节CB1/CB2。这些发现使SMA-WIN成为精准治疗GBM的有前景的候选物，特别是对于耐药的间充质亚型，为体内验证以确认血脑屏障穿透和临床转化铺平了道路。
