Department of Pharmacology, Universite de Sherbrooke, 3001, 12th Ave North, Sherbrooke, Quebec J1H 5N4, Canada.
Int J Pharm. 2010 Aug 16;395(1-2):251-9. doi: 10.1016/j.ijpharm.2010.05.017. Epub 2010 Jun 1.
Glioblastoma (GBM) is the most malignant primary brain tumor in adults, and its prognosis remains very limited despite decades of research. Enhanced drug delivery to GBM using liposomes represents a promising therapeutic strategy. In this study, we describe a novel cationic and pH-sensitive liposome formulation composed of DPPC:DC-Chol:DOPE:DHPE Oregon Green producing efficient internalization and intracellular delivery to F98 and U-118 GBM cells. With a series of derived modifications of the lipid composition, we investigated the impact of membrane fluidity, steric stabilization and loss of both cationic and pH-sensitive components on cellular uptake and intracellular release kinetics by flow cytometry and confocal microscopy, respectively. DPPC:DC-Chol:DOPE:DHPE Oregon Green liposomes were strongly internalized in both cell lines within 6h. Following cellular uptake, liposomes traveled towards the nucleus (12h) and gradually released their cargo in the cytosol (over 24h). Modifications in liposomal composition of our original formulation had detrimental consequences on both the uptake and intracellular release kinetics in the two tested cell lines. Thus, we report a novel potent liposomal formulation for efficient cytosolic delivery of intracellular therapeutics such as chemotherapy agents and siRNAs to GBM cells.
胶质母细胞瘤（GBM）是成人中最恶性的原发性脑肿瘤，尽管经过几十年的研究，其预后仍然非常有限。使用脂质体增强对 GBM 的药物递送代表了一种很有前途的治疗策略。在这项研究中，我们描述了一种新型阳离子和 pH 敏感的脂质体制剂，由 DPPC：DC-Chol：DOPE：DHPE Oregon Green 组成，可有效地内化并向 F98 和 U-118 GBM 细胞内传递。通过一系列衍生的脂质组成修饰，我们通过流式细胞术和共聚焦显微镜分别研究了膜流动性、空间稳定性以及阳离子和 pH 敏感成分的丧失对细胞摄取和细胞内释放动力学的影响。DPPC：DC-Chol：DOPE：DHPE Oregon Green 脂质体在两种细胞系中均在 6 小时内被强烈内化。在细胞摄取后，脂质体向细胞核移动（12 小时），并逐渐在细胞质中释放其货物（超过 24 小时）。我们原始配方中脂质体组成的修饰对两种测试细胞系的摄取和细胞内释放动力学都产生了不利影响。因此，我们报告了一种新型有效的脂质体制剂，可将细胞内治疗剂（如化疗药物和 siRNA）高效递送至 GBM 细胞的细胞质中。
