Oyewumi Moses O, Mumper Russell J
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
Bioconjug Chem. 2002 Nov-Dec;13(6):1328-35. doi: 10.1021/bc025560x.
Microemulsions (oil-in-water) have been employed as templates to engineer nanoparticles containing high concentrations of gadolinium for potential application in neutron capture therapy of tumors. Gadolinium hexanedione (GdH), synthesized by complexation of Gd(3+) with 2,4-hexanedione, was used as the nanoparticle matrix alone or in combination with either emulsifying wax or PEG-400 monostearate. Solid nanoparticles (<125 nm size) were obtained by simple cooling of the microemulsions prepared at 60 degrees C to room temperature in one vessel. The feasibility of tumor targeting via folate receptors was studied. A folate ligand was synthesized by chemically linking folic acid to distearoylphosphatidylethanolamine (DSPE) via a poly(ethylene glycol) (PEG; MW 3350) spacer. To obtain folate-coated nanoparticles, the folate ligand (0.75% w/w to 15% w/w) was added to either the microemulsion templates at 60 degrees C or nanoparticle suspensions at 25 degrees C. Efficiencies of folate ligand attachment/adsorption to nanoparticle formulations were monitored by gel permeation chromatography. Cell uptake studies were carried out in KB cells (human nasopharyngeal epidermal carcinoma cell line), known to overexpress folate receptors. The uptake of folate-coated nanoparticles was about 10-fold higher than uncoated nanoparticles after 30 min at 37 degrees C. The uptake of folate-coated nanoparticles at 4 degrees C was 20-fold lower than the uptake at 37 degrees C and comparable to the uptake of uncoated nanoparticles at 37 degrees C. Folate-mediated endocytosis was further verified by the inhibition of folate-coated nanoparticles uptake by free folic acid. It was observed that folate-coated nanoparticles uptake decreased to approximately 2% of its initial value with the coincubation of 0.001 mM of free folic acid. The results suggested that these tumor-targeted nanoparticles containing high concentrations of Gd may have potential for neutron capture therapy.
微乳液（水包油型）已被用作模板来制备含有高浓度钆的纳米颗粒，用于肿瘤的中子俘获治疗。通过钆（3 +）与2,4 -己二酮络合合成的钆己二酮（GdH），单独或与乳化蜡或聚乙二醇400单硬脂酸酯组合用作纳米颗粒基质。通过在一个容器中将60℃制备的微乳液简单冷却至室温，获得了尺寸小于125nm的固体纳米颗粒。研究了通过叶酸受体进行肿瘤靶向的可行性。通过聚乙二醇（PEG；分子量3350）间隔物将叶酸化学连接到二硬脂酰磷脂酰乙醇胺（DSPE）上，合成了叶酸配体。为了获得叶酸包被的纳米颗粒，将叶酸配体（0.75％w / w至15％w / w）添加到60℃的微乳液模板或25℃的纳米颗粒悬浮液中。通过凝胶渗透色谱法监测叶酸配体附着/吸附到纳米颗粒制剂上的效率。在已知过表达叶酸受体的KB细胞（人鼻咽表皮癌细胞系）中进行细胞摄取研究。在37℃下30分钟后，叶酸包被的纳米颗粒的摄取量比未包被的纳米颗粒高约10倍。4℃下叶酸包被的纳米颗粒的摄取量比37℃下的摄取量低20倍，与37℃下未包被的纳米颗粒的摄取量相当。游离叶酸对叶酸包被的纳米颗粒摄取的抑制进一步证实了叶酸介导的内吞作用。观察到，在与0.001mM游离叶酸共同孵育时，叶酸包被的纳米颗粒摄取量降至其初始值的约2％。结果表明，这些含有高浓度钆的肿瘤靶向纳米颗粒可能具有中子俘获治疗的潜力。
