CSIRO Manufacturing, P.O. BOX 52, North Ryde, NSW, 1670, Australia.
Cancer Surgery and Metabolism Group, University of Sydney, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.
Chempluschem. 2020 Jun;85(6):1283-1291. doi: 10.1002/cplu.202000253.
Gemcitabine (Gem) is a key drug for pancreatic cancer, yet limited by high systemic toxicity, low bioavailability and poor pharmacokinetic profiles. To overcome these limitations, Gem prodrug amphiphiles were synthesised with oleyl, linoleyl and phytanyl chains. Self-assembly and lyotropic mesophase behaviour of these amphiphiles were examined using polarised optical microscopy and Synchrotron SAXS (SSAXS). Gem-phytanyl was found to form liquid crystalline inverse cubic mesophase. This prodrug was combined with phospholipids and cholesterol to create biomimetic Gem-lipid prodrug nanoparticles (Gem-LPNP), verified by SSAXS and cryo-TEM to form liposomes. In vitro testing of the Gem-LPNP in several pancreatic cancer cell lines showed lower toxicity than Gem. However, in a cell line-derived pancreatic cancer mouse model Gem-LPNP displayed greater tumour growth inhibition than Gem using a fraction (<6 %) of the clinical dose and without any systemic toxicity. The easy production, improved efficacy and low toxicity of Gem-LPNP represents a promising new nanomedicine for pancreatic cancer.
吉西他滨（Gem）是胰腺癌的关键药物，但由于其全身毒性高、生物利用度低和药代动力学特性差，应用受到限制。为了克服这些限制，合成了具有油酰基、亚油酰基和植烷酰基链的吉西他滨前药两亲物。使用偏光显微镜和同步加速器小角 X 射线散射（SSAXS）研究了这些两亲物的自组装和溶致液晶相行为。发现吉西他滨植烷酰物形成了液晶立方反向介相。将该前药与磷脂和胆固醇结合，制备了仿生吉西他滨脂质前药纳米粒（Gem-LPNP），通过 SSAXS 和冷冻透射电镜证实形成了脂质体。在几种胰腺癌细胞系中的体外试验表明，Gem-LPNP 的毒性低于 Gem。然而，在细胞系衍生的胰腺癌小鼠模型中，Gem-LPNP 的肿瘤生长抑制作用优于 Gem，使用的临床剂量不到 6%，且无任何全身毒性。Gem-LPNP 易于生产、疗效提高、毒性低，代表了一种有前途的胰腺癌新型纳米医学。
