Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, UK.
Department of HPB Surgery, Mater Hospital, Belfast, Northern Ireland BT14 6AB, UK.
Eur J Pharm Biopharm. 2021 Aug;165:374-382. doi: 10.1016/j.ejpb.2021.05.018. Epub 2021 May 24.
Gemcitabine and nab-paclitaxel (Abraxane®) is a standard of care chemotherapy combination used in the treatment of patients with advanced pancreatic cancer. While the combination has shown a survival benefit when compared to gemcitabine monotherapy, it is associated with significant off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the site-specific deposition of drug-payloads. However, loading a single microbubble formulation with two drug payloads can be challenging and often involves several manipulations post-microbubble preparation that can be cumbersome and generally results in low / inconsistent drug loadings. In this manuscript, we report the one-pot synthesis of a gemcitabine functionalised phospholipid and use it to successfully generate stable microbubble formulations loaded with gemcitabine (Lipid-Gem MB) or a combination of gemcitabine and paclitaxel (Lipid-Gem-PTX MB). Efficacy of the Lipid-Gem MB and Lipid-Gem-PTX MB formulations, following ultrasound (US) stimulation, was evaluated in a three-dimensional (3D) PANC-1 spheroid model of pancreatic cancer and a mouse model bearing ectopic BxPC-3 tumours. The results demonstrated a significant reduction in the cell viability in spheroids for both formulations reducing from 90 ± 10% to 62 ± 5% for Lipid-Gem MB and 84 ± 10% to 30 ± 6% Lipid-Gem-PTX MB following US irradiation. When compared with a clinically relevant dose of free gemcitabine and paclitaxel (i.e. non-particle bound) in a BxPC-3 murine pancreatic tumour model, both formulations also improved tumour growth delay with tumours 40 ± 20% and 40 ± 30% smaller than the respective free drug formulation when treated with Lipid-Gem MB and Lipid-Gem-PTX MB respectively, at the conclusion of the experiment. These results highlight the potential of UTMD mediated Gem / PTX as a treatment for pancreatic cancer and the facile preparation of Lipid-Gem-PTX MBs using a gemcitabine functionalised lipid should expedite clinical translation of this technology.
吉西他滨和 nab-紫杉醇（Abraxane®）是一种标准的治疗方案，用于治疗晚期胰腺癌患者。虽然与吉西他滨单药治疗相比，该联合用药具有生存获益，但它与显著的脱靶毒性相关。超声靶向微泡破坏（UTMD）已成为一种有效的靶向药物传递策略。然而，将两种药物有效负载加载到单个微泡制剂中可能具有挑战性，并且通常涉及微泡制备后的多次操作，这些操作繁琐且通常导致药物负载低/不一致。在本手稿中，我们报告了一种吉西他滨功能化磷脂的一锅合成方法，并使用它成功地生成了负载吉西他滨的稳定微泡制剂（脂质-吉西他滨 MB）或吉西他滨和紫杉醇的组合（脂质-吉西他滨-紫杉醇 MB）。脂质-吉西他滨 MB 和脂质-吉西他滨-紫杉醇 MB 制剂在超声（US）刺激后的疗效在胰腺癌三维（3D）PANC-1 球体模型和携带异位 BxPC-3 肿瘤的小鼠模型中进行了评估。结果表明，两种制剂均可显著降低球体中的细胞活力，脂质-吉西他滨 MB 从 90 ± 10%降至 62 ± 5%，脂质-吉西他滨-紫杉醇 MB 从 84 ± 10%降至 30 ± 6%。与临床相关剂量的游离吉西他滨和紫杉醇（即非颗粒结合）相比，在 BxPC-3 小鼠胰腺癌模型中，两种制剂也改善了肿瘤生长延迟，当用脂质-吉西他滨 MB 和脂质-吉西他滨-紫杉醇 MB 治疗时，肿瘤分别缩小了 40 ± 20%和 40 ± 30%，与各自的游离药物制剂相比，在实验结束时。这些结果强调了 UTMD 介导的 Gem/PTX 作为胰腺癌治疗方法的潜力，以及使用吉西他滨功能化脂质方便地制备脂质-吉西他滨-紫杉醇 MB 应该会加速该技术的临床转化。
