Pharmaceutics Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
Pharmaceutics Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
Life Sci. 2023 Mar 15;317:121467. doi: 10.1016/j.lfs.2023.121467. Epub 2023 Feb 1.
This research aims to compare the therapeutic potential of target-specific phosphorothioate backbone-modified aptamer L5 (TLS9a)-functionalized paclitaxel (PTX)-loaded nanocarrier (PTX-NPL5) that we formulated with that of non-targeted commercial formulation, protein albumin-bound nanoparticles of PTX, Abraxane® (CF) against hepatocellular carcinoma (HCC) through a myriad of preclinical investigations.
A variety of in vitro and in vivo assays have been executed to compare the therapeutic effects of the formulations under investigation, including the investigation of the degree of apoptosis induction and its mechanism, cell cycle analysis, the level of ROS production, and redox status, the morphological and histological characteristics of malignant livers, and in vivo imaging. The formulations were also compared concerning pharmacokinetic behaviors. Finally, in silico molecular docking has been performed to predict the possible interactions between aptamer and target(s).
PTX-NPL5 exhibited therapeutic superiority over CF in terms of inducing apoptosis, cell cycle arrest, endorsing oxidative stress to neoplastic cells, and reducing hepatic cancerous lesions. Unlike CF, PTX-NPL5 did not exhibit any significant toxicity in healthy hepatocytes, proving enough impetus regarding the distinctive superiority of PTX-NPL5 over CF. The pharmacokinetic analysis further supported superior penetration and retention of PTX-NPL5 in neoplastic hepatocytes compared to CF. A molecular modeling study proposed possible interaction between aptamer L5 and heat shock protein 70 (HSP70).
The target-specificity of PTX-NPL5 towards neoplastic hepatocytes, probably achieved through HSP70 recognition, enhanced its therapeutic efficacy over CF, which may facilitate its real clinical deployment against HCC in the near future.
本研究旨在比较靶向特异性硫代磷酸酯骨架修饰适体 L5（TLS9a）功能化紫杉醇（PTX）负载纳米载体（PTX-NPL5）与非靶向商业制剂紫杉醇白蛋白结合纳米粒（Abraxane®（CF））在治疗肝细胞癌（HCC）方面的治疗潜力，通过一系列临床前研究。
进行了各种体外和体内实验来比较所研究制剂的治疗效果，包括诱导细胞凋亡及其机制、细胞周期分析、ROS 产生和氧化还原状态、恶性肝脏的形态和组织学特征、体内成像等。还比较了制剂的药代动力学行为。最后，进行了计算机分子对接，以预测适体和靶标之间可能的相互作用。
PTX-NPL5 在诱导细胞凋亡、细胞周期阻滞、促进肿瘤细胞氧化应激和减少肝癌病变方面优于 CF。与 CF 不同，PTX-NPL5 对健康肝细胞没有任何显著毒性，这充分证明了 PTX-NPL5 优于 CF 的独特优势。药代动力学分析进一步支持了与 CF 相比，PTX-NPL5 在肿瘤肝细胞中的更好穿透和保留。分子建模研究提出了适体 L5 与热休克蛋白 70（HSP70）之间可能的相互作用。
PTX-NPL5 对肿瘤肝细胞的靶向特异性，可能通过 HSP70 识别实现，提高了其相对于 CF 的治疗效果，这可能有助于其在不久的将来在 HCC 的实际临床应用。
