Khoeeniha Mohammad Kazem, Esfandyari-Manesh Mehdi, Behrouz Hossein, Amini Mohsen, Varnamkhasti Behrang Shiri, Atyabi Fatemeh, Dinarvand Rassoul
Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran. Iran.
Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran. Iran.
Curr Drug Deliv. 2017;14(8):1120-1129. doi: 10.2174/1567201814666161122150302.
Cabazitaxel (CBZ) is a new taxane approved by FDA for treatment of castration- resistant prostate cancer not responding to docetaxel. However, CBZ is not a suitable substrate for p-glycoprotein 60, an efflux pump which transports anticancer drugs out of malignant cells and is therefore a promising drug for treatment of multidrug resistant tumors. Similar to other taxanes, the presence of Tween 80 in the CBZ formulation shows that it is insoluble in water.
In order to increase the solubility and circulation time of this drug, CBZ-human serum albumin (HSA) conjugate was synthesized. The designed linker was composed of methacrylic acid and N-acetyl cysteine to increase the solubility of CBZ and to increase the efficiency of conjugation. Targeting was performed by poly(ethylene glycol)-folic acid amide bound formation with carboxyl groups of HSA during in the step of nanoparticle formation. Cytotoxicity of nanoparticles was evaluated in vitro on HT-29, as a folate negative cell line, and MDA-MB-231, as a folate positive cell line.
H-NMR, Gel Permeation Chromatography, High Pressure Liquid Chromatography and UV spectrophotometry analysis confirmed the composition of conjugates. The resulting nanoparticles had a spherical shape, narrow size distribution and mean diameter of 138 nm. The efficiency of conjugation was 41.6 %. The IC50 of CBZ in targeted nanoparticles was 10.1 and 17.4% lower than that of the free CBZ for HT-29 and MDA-MB-231 cells, respectively.
This designed drug delivery system was more water-soluble and had enhanced in vitro characteristics and higher cytotoxic activity on cancer cells.
卡巴他赛（CBZ）是一种新的紫杉烷类药物，已获美国食品药品监督管理局（FDA）批准，用于治疗对多西他赛无反应的去势抵抗性前列腺癌。然而，CBZ不是P-糖蛋白60的合适底物，P-糖蛋白60是一种外排泵，可将抗癌药物转运出恶性细胞，因此是治疗多药耐药肿瘤的一种有前景的药物。与其他紫杉烷类药物类似，CBZ制剂中吐温80的存在表明它不溶于水。
为了提高该药物的溶解度和循环时间，合成了CBZ-人血清白蛋白（HSA）偶联物。设计的连接体由甲基丙烯酸和N-乙酰半胱氨酸组成，以增加CBZ的溶解度并提高偶联效率。在纳米颗粒形成步骤中，通过聚乙二醇-叶酸酰胺与HSA的羧基结合形成靶向。在体外对叶酸阴性细胞系HT-29和叶酸阳性细胞系MDA-MB-231评估纳米颗粒的细胞毒性。
氢核磁共振（H-NMR）、凝胶渗透色谱法、高压液相色谱法和紫外分光光度法分析证实了偶联物的组成。所得纳米颗粒呈球形，粒径分布窄，平均直径为138nm。偶联效率为41.6%。对于HT-29和MDA-MB-231细胞，靶向纳米颗粒中CBZ的半数抑制浓度（IC50）分别比游离CBZ低10.1%和17.4%。
这种设计的药物递送系统具有更高的水溶性，体外特性得到增强，对癌细胞具有更高的细胞毒性活性。
