Pharmaceutics Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, 188, Raja, S.C. Mullick Road, Kolkata, West Bengal, 700032, India.
Department of Pharmacy, College of Medicine and Health Science, Bahir Dar University, Bahir Dar, Ethiopia.
AAPS PharmSciTech. 2020 Feb 5;21(3):89. doi: 10.1208/s12249-020-1629-z.
Aptamers offer a significant promise to target various cancers including hepatocellular carcinoma (HCC), for their high affinity and ability to reach the target site(s), non-immunogenicity, and low cost. The targeting ability to neoplastic hepatocytes by the aptamer, TLS 9a with phosphorothioate backbone modification (designated as L5), has not been explored yet. Hence, we investigated the comparative potential of L5 with some other previously reported liver cancer cell-specific aptamers, conjugated on the surface of drug-nanocarriers. Various in vitro studies such as cytotoxicity, in vitro cellular uptake, cell cycle analysis, and investigations related to apoptosis were performed. In vivo studies carried out here include macroscopic and microscopic hepatic alterations in chemically induced hepatocarcinogenesis in rats, upon experimental treatments. The outcome of the investigations revealed that L5-functionalized drug-nanocarrier (PTX-NPL5) had the highest apoptotic potential compared with the other aptamer-conjugated experimental formulations. Further, its maximum internalization by neoplastic hepatocytes and minimum internalization by normal hepatocytes indicate that it had the potential to preferentially target the neoplastic hepatocytes. Data of in vivo studies revealed that PTX-NPL5 reduced tumor incidences and tumor progress. Superior potency of PTX-NPL5 may be due to the maximum affinity of L5 towards neoplastic hepatocytes resulting in maximum permeation of drug-nanocarrier in them. An effective site-specific targeting of neoplastic hepatocytes can be achieved by L5 for preferential delivery of therapeutics. Further, investigations are needed to identify the target protein(s) on neoplastic hepatocytes responsible for ligand-receptor interaction of L5.
适配体在靶向各种癌症方面具有重要的应用前景，包括肝细胞癌（HCC），因为它们具有高亲和力和到达靶位的能力、非免疫原性和低成本。TLS 9a 是一种带有硫代磷酸酯骨架修饰的适配体（命名为 L5），尚未探索其对肿瘤性肝细胞的靶向能力。因此，我们研究了 L5 与其他一些先前报道的肝癌细胞特异性适配体的比较潜力，这些适配体被连接在药物纳米载体的表面。进行了各种体外研究，如细胞毒性、体外细胞摄取、细胞周期分析和凋亡相关研究。在这里进行的体内研究包括在大鼠化学诱导肝癌发生过程中，实验治疗后肝的宏观和微观改变。研究结果表明，与其他适配体结合的实验制剂相比，L5 功能化药物纳米载体（PTX-NPL5）具有最高的凋亡潜力。此外，它对肿瘤细胞的最大内化和对正常肝细胞的最小内化表明，它有可能优先靶向肿瘤性肝细胞。体内研究数据表明，PTX-NPL5 降低了肿瘤发生率和肿瘤进展。PTX-NPL5 的优越效力可能归因于 L5 对肿瘤性肝细胞的最大亲和力，导致药物纳米载体在其中的最大渗透。L5 可以实现对肿瘤性肝细胞的有效特异性靶向，从而优先递送达药物。还需要进一步研究来确定肿瘤性肝细胞上负责 L5 配体-受体相互作用的靶蛋白。
