Purpose

The clinical application of gemcitabine (GEM) is limited by its pharmacokinetic properties. The aim of this study was to characterize the stability in circulating plasma, tumor targeting, and payload release of liposome-encapsulated GEM, FF-10832.

Methods

Antitumor activity was assessed in xenograft mouse models of human pancreatic cancer. The pharmacokinetics of GEM and its active metabolite dFdCTP were also evaluated.

Results

In mice with Capan-1 tumors, the dose-normalized areas under the curve (AUCs) after FF-10832 administration in plasma and tumor were 672 and 1047 times higher, respectively, than after using unencapsulated GEM. The tumor-to-bone marrow AUC ratio of dFdCTP was approximately eight times higher after FF-10832 administration than after GEM administration. These results indicated that liposomal encapsulation produced long-term stability in circulating plasma and tumor-selective targeting of GEM. In mice with Capan-1, SUIT-2, and BxPC-3 tumors, FF-10832 had better antitumor activity and tolerability than GEM. Internalization of FF-10832 in tumor-associated macrophages (TAMs) was revealed by flow cytometry and confocal laser scanning microscopy, and GEM was efficiently released from isolated macrophages of mice treated with FF-10832. These results suggest that TAMs are one of the potential reservoirs of GEM in tumors.

Conclusion

This study found that FF-10832 had favorable pharmacokinetic properties. The liposomal formulation was more effective and tolerable than unencapsulated GEM in mouse xenograft tumor models. Hence, FF-10832 is a promising candidate for the treatment of pancreatic cancer.

中文翻译：

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脂质体吉西他滨 FF-10832 可提高吉西他滨在胰腺癌异种移植模型中的血浆稳定性、肿瘤靶向性和抗肿瘤功效

目的

吉西他滨 (GEM) 的临床应用受到其药代动力学特性的限制。本研究的目的是表征脂质体包裹的 GEM FF-10832 的循环血浆稳定性、肿瘤靶向性和有效载荷释放。

方法

在人类胰腺癌的异种移植小鼠模型中评估了抗肿瘤活性。还评估了 GEM 及其活性代谢物 dFdCTP 的药代动力学。

结果

在 Capan-1 肿瘤小鼠中，FF-10832 在血浆和肿瘤中给药后的剂量标准化曲线下面积 (AUC) 分别比使用未封装 GEM 后高 672 倍和 1047 倍。FF-10832 给药后 dFdCTP 的肿瘤与骨髓 AUC 比约为 GEM 给药后的 8 倍。这些结果表明脂质体封装在循环血浆中产生了长期稳定性和 GEM 的肿瘤选择性靶向。在患有 Capan-1、SUIT-2 和 BxPC-3 肿瘤的小鼠中，FF-10832 比 GEM 具有更好的抗肿瘤活性和耐受性。FF-10832 在肿瘤相关巨噬细胞 (TAM) 中的内化通过流式细胞术和共聚焦激光扫描显微镜显示出来，并且 GEM 从用 FF-10832 治疗的小鼠的分离巨噬细胞中有效释放。

结论

该研究发现 FF-10832 具有良好的药代动力学特性。在小鼠异种移植肿瘤模型中，脂质体制剂比未封装的 GEM 更有效和更耐受。因此，FF-10832 是治疗胰腺癌的有希望的候选药物。