Abstract

Topotecan (TPT) is a semi-synthetic, water-soluble derivative of camptothecin, which inhibits the action of topoisomerase I in the S-phase of the cell cycle leading to cell death. For the effective delivery of TPT to cancer cells, pH-sensitive sialic acid modified liposomes were developed. These liposomes were prepared by the thin-film hydration method using the active loading technique. Vesicle size, polydispersity index (PDI), zeta potential, and percentage entrapment efficiency were determined to be 167 ± 3.78 nm, 0.243, −8.39 mV, and 79.88 ± 1.67%, respectively. The pH-sensitive sialic acid (SA) conjugated liposomes enhanced the drug release at acidic pH 4 (92.33 ± 4.21%) as compared to physiological pH 7.4 (63.11 ± 4.51%). A Sulforhodamine B (SRB) cytotoxicity assay was performed in Murine sarcoma S180 cell lines and the GI₅₀ value of free TPT, Lipo, P-Lipo, SA-P-Lipo, and Adriamycin (ADR) were determined to be 10.07 ± 0.15, 27.33 ± 1.01, 28.76 ± 0.87, 15.7 ± 0.45, and 11.5 ± 0.21 µg/mL, respectively. Results obtained from the apoptosis study revealed that cell death by a combination of early apoptosis and apoptosis caused by SA-P-Lipo was ∼24 fold higher than the control. These results demonstrated that pH-sensitive sialic acid conjugated liposomes will be a potential formulation for improving the antitumor efficacy of TPT. However, further research is necessitated to expedite its applicability in clinical regimen in order to ascertain its safety and efficacy.

摘要

拓扑替康 (TPT) 是喜树碱的半合成水溶性衍生物，可抑制拓扑异构酶 I 在导致细胞死亡的细胞周期 S 期的作用。为了将 TPT 有效递送至癌细胞，开发了 pH 敏感的唾液酸修饰脂质体。这些脂质体是通过使用主动加载技术的薄膜水合法制备的。囊泡大小、多分散指数 (PDI)、zeta 电位和截留效率百分比分别为 167  ±  3.78  nm、0.243、-8.39  mV 和 79.88  ±  1.67%。pH敏感唾液酸（SA）缀合增强在酸性pH 4（92.33药物释放脂质体 ±  4.21％）相比，生理pH 7.4（如63.11  ± 4.51%）。Sulforhodamine B (SRB) 细胞毒性试验在鼠肉瘤 S180 细胞系中进行，游离 TPT、Lipo、P-Lipo、SA-P-Lipo 和阿霉素 (ADR)的 GI ₅₀值确定为 10.07  ±  0.15， 27.33  ±  1.01，28.76  ±  0.87，15.7  ±  0.45，11.5  ±  0.21 分别为 µg/mL。从细胞凋亡研究中获得的结果表明，早期细胞凋亡和 SA-P-Lipo 引起的细胞凋亡相结合导致的细胞死亡比对照高约 24 倍。这些结果表明，pH 敏感性唾液酸偶联脂质体将成为提高 TPT 抗肿瘤功效的潜在制剂。然而，需要进一步研究以加快其在临床方案中的适用性，以确定其安全性和有效性。