Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
Eur J Med Chem. 2012 Aug;54:429-38. doi: 10.1016/j.ejmech.2012.05.024. Epub 2012 May 28.
The aim of the present study was to reduce 5-FU side effects by targeted nanostructured lipid carriers (NLCs) to LDL receptors that are over expressed in colorectal carcinoma and also use of a new synthesized conjugate of retinoic acid as a cytotoxic agent. Fatty acyl amide derivative of retinoic acid was synthesized by its conjugation to octadecylamine with the expectation to improve its loading capacity in NLCs of 5-FU. The NLCs were prepared by an emulsification-solvent evaporation method using cholesterol and cholesteryl stearate. Physical properties and drug release were studied in NLCs. The cytotoxicity of NLCs loaded with 5-FU and retinoic acid conjugate was studied on colon cancer cells (HT29) using MTT assay. To confirm that drug targeting has been done through LDL receptors, APO-E was omitted from the cell culture and the MTT assay was repeated. FTIR and (1)H NMR spectra confirmed successful production of the conjugate. Results showed the IC(50) of free 5-FU was about 7.6 μM while in comparable concentration, the cytotoxicity of 5-FU loaded in NLCs containing the retinoic acid conjugate was nearly 2 fold of NLCs just loaded with 5-FU and more than 5 fold of free 5-FU. The retinoic acid conjugate loaded NLCs prepared by cholesterol can target LDL receptors of HT29 cells and seems promising in reducing 5-FU dose in colorectal cancer.
本研究旨在通过靶向载脂蛋白 B 受体（在结直肠癌中过度表达）的纳米结构脂质载体（NLCs）来减少 5-FU 的副作用，同时使用新合成的维甲酸缀合物作为细胞毒性剂。通过将维甲酸与十八胺缀合来合成维甲酸的脂肪酸酰胺衍生物，期望提高其在载有 5-FU 的 NLCs 中的载药量。通过乳化-溶剂蒸发法用胆固醇和胆甾醇硬脂酸酯制备 NLCs。研究了 NLCs 的物理性质和药物释放。使用 MTT 测定法研究了载有 5-FU 和维甲酸缀合物的 NLCs 在结肠癌细胞（HT29）上的细胞毒性。为了确认已经通过 LDL 受体进行了药物靶向，从细胞培养物中省略了 APO-E 并重复了 MTT 测定。FTIR 和（1）H NMR 谱证实了缀合物的成功合成。结果表明，游离 5-FU 的 IC50 约为 7.6 μM，而在可比浓度下，载有维甲酸缀合物的 5-FU 负载 NLCs 的细胞毒性是仅负载 5-FU 的 NLCs 的近 2 倍，是游离 5-FU 的 5 倍以上。用胆固醇制备的维甲酸缀合物负载的 NLCs 可以靶向 HT29 细胞的 LDL 受体，并有望减少结直肠癌中的 5-FU 剂量。
