ABSTRACT

Background

Multidrug resistance (MDR) limits the beneficial outcomes of conventional breast cancer chemotherapy. Ras-related nuclear protein (Ran-GTP) plays a key role in these resistance mechanisms, assisting cancer cells to repair damage to DNA. Herein, we investigate the co-delivery of Ran-RCC1 inhibitory peptide (RAN-IP) and doxorubicin (DOX) to breast cancer cells using liposomal nanocarriers.

Research design

A liposomal delivery system, co-encapsulating DOX, and RAN-IP, was prepared using a thin-film rehydration technique. Dual-loaded liposomes were optimized by systematic modification of formulation variables. Real-Time-Polymerase Chain Reaction was used to determine Ran-GTP mRNA expression. In vitro cell lines were used to evaluate the effect of loaded liposomes on the viability of breast and lung cancer cell lines. In vivo testing was performed on a murine Solid Ehrlich Carcinoma model.

Results

RAN-IP reversed the Ran-expression-mediated MDR by inhibiting the Ran DNA damage repair function. Co-administration of RAN-IP enhanced sensitivity of DOX in breast cancer cell lines. Finally, liposome-mediated co-delivery with RAN-IP improved the anti-tumor effect of DOX in tumor-bearing mice when compared to single therapy.

Conclusions

This study is the first to show the simultaneous delivery of RAN-IP and DOX using liposomes can be synergistic with DOX and lead to tumor regression in vitro and in vivo.

中文翻译：

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使用双重负载的脂质体载体共同递送RanGTP抑制肽和阿霉素，以对抗乳腺癌细胞的化疗耐药性。

摘要

背景

多药耐药性（MDR）限制了常规乳腺癌化疗的有益结果。与Ras相关的核蛋白（Ran-GTP）在这些耐药机制中起关键作用，协助癌细胞修复对DNA的损伤。本文中，我们研究了使用脂质体纳米载体将Ran-RCC1抑制肽（RAN-IP）和阿霉素（DOX）共同递送至乳腺癌细胞的过程。

研究设计

使用薄膜水化技术制备脂质体递送系统，共包囊DOX和RAN-IP。通过系统地修改配方变量来优化双负载脂质体。实时聚合酶链反应用于确定Ran-GTP mRNA表达。体外细胞系用于评估负载的脂质体对乳腺癌和肺癌细胞系活力的影响。在鼠类固体艾氏癌模型上进行了体内测试。

结果

RAN-IP通过抑制Ran DNA损伤修复功能来逆转Ran表达介导的MDR。RAN-IP的共同给药可增强DOX在乳腺癌细胞系中的敏感性。最后，与单药疗法相比，脂质体介导的RAN-IP共递送改善了DOX在荷瘤小鼠中的抗肿瘤作用。

结论

这项研究是第一个显示使用脂质体同时递送RAN-IP和DOX可以与DOX协同作用，并导致体内外肿瘤消退的研究。