Purpose

PEGylated pH-sensitive liposomes (PSL) dual-loaded with gemcitabine and curcumin were investigated for the potential application in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC) treatment. Curcumin was employed as an inhibitor of the efflux transporter, multidrug resistance protein 5 (MRP5) in PDAC cells.

Methods

Liposomes were prepared with gemcitabine in the core and curcumin in the bilayers. The effects of curcumin on pH-sensitivity and ‘endosome escape’ of PSL with different PEGylation were investigated using a calcein self-quench assay. The effects of curcumin on intracellular gemcitabine concentrations, and cytotoxicity to a MIA PaCa-2 PDAC cell line was evaluated. The pharmacokinetics were investigated in rats following intravenous injection.

Results

The addition of curcumin to the PSL bilayers (0.2-1 mol%)slightly decreased the pH-sensitivity of PSL, but to a less extent than PEGylation (0–5 mol%). Co-treatment with curcumin increased gemcitabine cellular accumulation in a concentration-dependent manner, and resulted in synergistic cytotoxicity towards MIA PaCa-2cells.Both these effects were augmented by the use of PSL, particularly when the two drugs were co-loaded in PSL. In rats, the dual-drug loaded PSL produced significantly reduced (p < 0.05) plasma clearance (CL) and volume of distribution (V_d) for both drugs, alongside 3 to 4-fold increases in the area-under-the-concentration-time curves compared to the free drugs. Additionally, curcumin slightly increase the plasma concentrations of gemcitabine possibly also via the MRP5 inhibition effect.

Conclusion

Co-delivery of curcumin with gemcitabine using PSL not only increased the intracellular gemcitabine concentration thus cytotoxicity to MIA PaCa-2 cells but also significantly improved the pharmacokinetic profiles for both drugs.

中文翻译：

---

使用 pH 敏感脂质体共递送至胰腺癌细胞：姜黄素对吉西他滨细胞浓度和药代动力学的影响

目的

研究了双载吉西他滨和姜黄素的聚乙二醇化 pH 敏感脂质体 (PSL) 在抗吉西他滨的胰腺导管腺癌 (PDAC) 治疗中的潜在应用。姜黄素被用作 PDAC 细胞中外排转运蛋白、多药耐药蛋白 5 (MRP5) 的抑制剂。

方法

脂质体是用核心的吉西他滨和双层的姜黄素制备的。使用钙黄绿素自淬灭试验研究姜黄素对具有不同聚乙二醇化的 PSL 的 pH 敏感性和“内体逃逸”的影响。评估了姜黄素对细胞内吉西他滨浓度的影响，以及对 MIA PaCa-2 PDAC 细胞系的细胞毒性。静脉注射后在大鼠中研究药代动力学。

结果

在 PSL 双层中加入姜黄素 (0.2-1 mol%) 略微降低 PSL 的 pH 敏感性，但程度低于聚乙二醇化 (0-5 mol%)。与姜黄素共同处理以浓度依赖性方式增加吉西他滨细胞积累，并导致对 MIA PaCa-2 细胞的协同细胞毒性。使用 PSL 可以增强这两种效果，特别是当两种药物共同加载到 PSL 中时。在大鼠中，双药负载 PSL 产生显着降低 ( p  < 0.05) 的血浆清除率 (CL) 和分布容积 (V _d) 对于这两种药物，与游离药物相比，浓度时间曲线下的面积增加了 3 到 4 倍。此外，姜黄素也可能通过 MRP5 抑制作用略微增加吉西他滨的血浆浓度。

结论

使用 PSL 将姜黄素与吉西他滨共同递送不仅增加了细胞内吉西他滨的浓度，从而增加了对 MIA PaCa-2 细胞的细胞毒性，而且还显着改善了两种药物的药代动力学特征。