BACKGROUND Multidrug resistance (MDR) is a pressing obstacle in clinical chemotherapy for breast cancer. Based on the fact that the drug efflux is an important factor in MDR, we designed a codelivery system to guide the drug efflux inhibitor verapamil (VRP) and the chemotherapeutic agent novantrone (NVT) synergistically into breast cancer cells to reverse MDR. RESULTS This co-delivery system consists of following components: the active targeting peptide RGD, an inorganic calcium phosphate (CaP) shell and an organic inner core. VRP and NVT were loaded into CaP shell and phosphatidylserine polyethylene glycol (PS-PEG) core of nanoparticles (NPs) separately to obtain NVT- and VRP-loaded NPs (NV@CaP-RGD). These codelivered NPs allowed VRP to prevent the efflux of NVT from breast cancer cells by competitively combining with drug efflux pumps. Additionally, NV@CaP-RGD was effectively internalized into breast cancer cells by precise delivery through the effects of the active targeting peptides RGD and EPR. The pH-triggered profile of CaP was also able to assist the NPs to successfully escape from lysosomes, leading to a greatly increased effective intracellular drug concentration. CONCLUSION The concurrent administration of VRP and NVT by organic/inorganic NPs is a promising therapeutic approach to reverse MDR in breast cancer.

中文翻译：

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将药物外流抑制剂和化疗剂纳入无机/有机平台，有效治疗多重耐药乳腺癌。

背景技术多药耐药（MDR）是乳腺癌临床化疗面临的紧迫障碍。基于药物外排是MDR的重要因素，我们设计了一种共递送系统，引导药物外排抑制剂维拉帕米（VRP）和化疗药物诺凡酮（NVT）协同进入乳腺癌细胞，逆转MDR。结果该共递送系统由以下组件组成：活性靶向肽RGD、无机磷酸钙（CaP）壳和有机内核。将VRP和NVT分别负载到纳米粒子（NPs）的CaP壳和磷脂酰丝氨酸聚乙二醇（PS-PEG）核中，得到负载NVT和VRP的NPs（NV@CaP-RGD）。这些共同递送的 NP 使 VRP 通过与药物外排泵竞争性结合来阻止 NVT 从乳腺癌细胞中外流。此外，通过主动靶向肽RGD和EPR的作用，NV@CaP-RGD通过精确递送被有效地内化到乳腺癌细胞中。CaP 的 pH 触发特性还能够帮助 NP 成功逃离溶酶体，从而大大提高有效的细胞内药物浓度。结论 通过有机/无机纳米粒子同时给予 VRP 和 NVT 是逆转乳腺癌 MDR 的一种有前景的治疗方法。