Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India.
Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India; SD College of Pharmacy and Vocational Studies, Bhopa Road, Muzaffarnagar, Uttar Pradesh, India.
Int J Pharm. 2023 Jul 25;642:123160. doi: 10.1016/j.ijpharm.2023.123160. Epub 2023 Jun 26.
Current anticancer drug research includes tumor-targeted administration as a critical component because it is the best strategy to boost efficacy and decrease toxicity. Low drug concentration in cancer cells, nonspecific distribution, rapid clearance, multiple drug resistance, severe side effects, and other factors contribute to the disappointing results of traditional chemotherapy. As an innovative technique of treatments for hepatocellular carcinoma (HCC) in recent years, nanocarrier-mediated targeted drug delivery systems can overcome the aforesaid limitations via enhanced permeability and retention effect (EPR) and active targeting. Epidermal growth factor receptor (EGFR) inhibitor Gefitinib (Gefi) has dramatic effects on hepatocellular carcinoma. Herein, we developed and assessed an αβ integrin receptor targeted c(RGDfK) surface modified liposomes for better targeting selectivity and therapeutic efficacy of Gefi on HCC cells. The conventional and modified Gefi loaded liposomes, i.e., denoted as Gefi-L and Gefi-c(RGDfK)-L, respectively, were prepared through the ethanol injection method and optimized via Box Behnken design (BBD). The FTIR and H NMR spectroscopy verified that the c(RGDfK) pentapeptides had formed an amide bond with the liposome surface. In addition, the particle size, Polydispersity index, zeta potential, encapsulation efficiency, and in-vitro Gefi release of the Gefi-L and Gefi-c(RGDfK)-L were measured and analyzed. As indicated by the MTT assay on HepG2 cells, Gefi-c(RGDfK)-L displayed considerably higher cytotoxicity than Gefi-L or Gefi alone. Throughout the incubation period, HepG2 cells took up significantly more Gefi-c(RGDfK)-L than Gefi-L. According to the in vivo biodistribution analysis, Gefi-c(RGDfK)-L accumulated more strongly at the tumor site than Gefi-L and free Gefi. Furthermore, HCC-bearing rats treated with Gefi-c(RGDfK)-L showed a substantial drop in liver marker enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, and total bilirubin levels) compared to the disease control group. Gefi-c(RGDfK)-L suppresses tumour growth more effectively than Gefi-L and free Gefi, according to an in vivo analysis of their anticancer activities. Thus, c(RGDfK)-surface modified liposomes, i.e., Gefi-c(RGDfK)-L may serve as an efficient carrier for the targeted delivery of anticancer drugs.
当前的抗癌药物研究包括肿瘤靶向给药作为一个关键组成部分，因为这是提高疗效和降低毒性的最佳策略。癌细胞内药物浓度低、非特异性分布、快速清除、多药耐药、严重的副作用等因素导致传统化疗的结果令人失望。作为近年来肝细胞癌（HCC）治疗的创新技术，纳米载体介导的靶向药物传递系统可以通过增强通透性和保留效应（EPR）和主动靶向克服上述限制。表皮生长因子受体（EGFR）抑制剂吉非替尼（Gefi）对肝癌具有显著疗效。在这里，我们开发并评估了一种 αβ 整联蛋白受体靶向 c（RGDfK）表面修饰的脂质体，以提高 Gefi 对 HCC 细胞的靶向选择性和治疗效果。通过乙醇注入法制备了常规和修饰的吉非替尼负载脂质体，分别表示为 Gefi-L 和 Gefi-c（RGDfK）-L，并通过 Box Behnken 设计（BBD）进行了优化。傅里叶变换红外光谱（FTIR）和核磁共振氢谱（H NMR）光谱验证了 c（RGDfK）五肽与脂质体表面形成了酰胺键。此外，还测量和分析了 Gefi-L 和 Gefi-c（RGDfK）-L 的粒径、多分散指数、Zeta 电位、包封效率和体外吉非替尼释放。HepG2 细胞 MTT 试验表明，Gefi-c（RGDfK）-L 的细胞毒性明显高于 Gefi-L 或 Gefi 单独。在整个孵育期间，HepG2 细胞摄取的 Gefi-c（RGDfK）-L 明显多于 Gefi-L。根据体内生物分布分析，Gefi-c（RGDfK）-L 在肿瘤部位的积累明显强于 Gefi-L 和游离 Gefi。此外，与疾病对照组相比，荷瘤大鼠用 Gefi-c（RGDfK）-L 治疗后，肝标志物酶（丙氨酸转氨酶、碱性磷酸酶、天冬氨酸转氨酶和总胆红素水平）显著下降。体内抗肿瘤活性分析表明，Gefi-c（RGDfK）-L 比 Gefi-L 和游离 Gefi 更有效地抑制肿瘤生长。因此，c（RGDfK）-表面修饰的脂质体，即 Gefi-c（RGDfK）-L 可以作为靶向递送抗癌药物的有效载体。
