Jain Vikas, Nath Banashree, Gupta Girish K, Shah Parag P, Siddiqui Maqsood A, Pant Aditya B, Mishra Prabhat R
Department of Pharmaceutics, Central Drug Research Institute, Lucknow, India.
J Pharm Pharmacol. 2009 Mar;61(3):303-10. doi: 10.1211/jpp/61.03.0004.
A chylomicron-mimicking lipid emulsion was prepared and loaded with paclitaxel (paclitaxel-CM) and was further grafted with galactose (paclitaxel-GCM) using palmitoyl-galactosamine, which was synthesized by reacting galactosamine hydrochloride with N-hydroxy succinimide ester of palmitic acid. Palmitoyl-galactosamine was used as a ligand for asialoglycoprotein receptors.
The uptake characteristics of the emulsions were evaluated in HepG-2 cells (human hepatocarcinaoma), which express asialoglycoprotein receptors, and MCF-7 (breast cancer) cells, which are devoid of these receptors.
The incorporation efficiency of paclitaxel-CM was 68.05 +/- 4.80% and that of paclitaxel-GCM was 72.10 +/- 3.93% when the emulsion was prepared with 7.5% (w/w) paclitaxel/lipid phase. The globule size of paclitaxel-GCM and paclitaxel-CM was 124 +/- 8.67 and 96.45 +/- 5.78 nm, respectively. The release of paclitaxel from both of the formulations was fairly sustained: 50 +/- 3.2% of paclitaxel in 24 h. The cytotoxicity and uptake of paclitaxel-GCM were significantly higher (P < 0.05) in HepG-2 cells than MCF-7 cells, while for paclitaxel-CM cytotoxicity and uptake were similar in the two cell lines. This study clearly demonstrates that upon surface modification palmitoyl-galactosamine remains an integral part of the formulation. Paclitaxel solubility can be improved using optimum paclitaxel/lipid phase ratios. The paclitaxel-GCM formulation recognizes asialoglycoprotein receptors overexpressed on HepG-2 cells.
Under our experimental conditions, the proposed paclitaxel-GCM formulation is an ideal delivery vehicle for specific targeting to liver cancer cells, which is anticipated to result in improved efficacy and reduced toxicity to normal cells.
制备了一种模拟乳糜微粒的脂质乳剂，将紫杉醇载入其中（紫杉醇 - CM），并使用通过盐酸半乳糖胺与棕榈酸N - 羟基琥珀酰亚胺酯反应合成的棕榈酰 - 半乳糖胺进一步将其接枝半乳糖（紫杉醇 - GCM）。棕榈酰 - 半乳糖胺用作去唾液酸糖蛋白受体的配体。
在表达去唾液酸糖蛋白受体的HepG - 2细胞（人肝癌细胞）和缺乏这些受体的MCF - 7（乳腺癌）细胞中评估乳剂的摄取特性。
当用7.5%（w/w）紫杉醇/脂质相制备乳剂时，紫杉醇 - CM的包封效率为68.05±4.80%，紫杉醇 - GCM的包封效率为72.10±3.93%。紫杉醇 - GCM和紫杉醇 - CM的球粒大小分别为124±8.67和96.45±5.78 nm。两种制剂中紫杉醇的释放相当持久：24小时内紫杉醇释放50±3.2%。紫杉醇 - GCM在HepG - 2细胞中的细胞毒性和摄取显著高于MCF - 7细胞（P < 0.05），而紫杉醇 - CM在两种细胞系中的细胞毒性和摄取相似。该研究清楚地表明，表面修饰后棕榈酰 - 半乳糖胺仍是制剂的一个组成部分。使用最佳的紫杉醇/脂质相比可以提高紫杉醇的溶解度。紫杉醇 - GCM制剂识别HepG - 2细胞上过表达的去唾液酸糖蛋白受体。
在我们的实验条件下，所提出的紫杉醇 - GCM制剂是一种用于特异性靶向肝癌细胞的理想递送载体，预计可提高疗效并降低对正常细胞的毒性。
