Introduction

Inherent or acquired resistance to paclitaxel (PTX) is a pivotal challenge for chemotherapy treatment of multidrug-resistant (MDR) breast cancer. Although various targeted drug-delivery systems, including nanoparticles and liposomes, are effective for MDR cancer treatment, their efficacy is restricted by immunosuppressive tumor microenvironment (TME).

Methods

Ginsenosides Rg3 was used to formulate unique Rg3-based liposomes loaded with PTX to establish Rg3-PTX-LPs, which were prepared by the thin-film hydration method. The stability of the Rg3-PTX-LPs was evaluated by particle size analysis through dynamic light scattering. The active targeting effect of Rg3-based liposomes was examined in an MCF-7/T xenograft model by an in a vivo imaging system. To evaluate the antitumor activity and mechanism of Rg3-PTX-LP, MTT, apoptosis assays, TAM regulation, and TME remodeling were performed in MCF-7/T cells in vitro and in vivo.

Results

Rg3-PTX-LPs could specifically distribute to MCF7/T cancer cells and TME simultaneously, mainly through the recognition of GLUT-1. The drug resistance reversing capability and in vivo antitumor effect of Rg3-PTX-LPs were significantly improved compared with conventional cholesterol liposomes. The TME remodeling mechanisms of Rg3-PTX-LPs included inhibiting IL-6/STAT3/p-STAT3 pathway activation to repolarize protumor M2 macrophages to antitumor M1 phenotype, suppressing myeloid-derived suppressor cells (MDSCs), decreasing tumor-associated fibroblasts (TAFs) and collagen fibers in TME, and promoting apoptosis of tumor cells. Hence, through the dual effects of targeting tumor cells and TME remodeling, Rg3-PTX-LPs achieved a high tumor inhibition rate of 90.3%.

Conclusion

Our multifunctional Rg3-based liposome developed in the present study offered a promising strategy for rescuing the drug resistance tumor treatment.

中文翻译：

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负载紫杉醇的人参皂苷 Rg3 脂质体通过肿瘤微环境和癌细胞的双重靶向治疗耐药癌症

介绍

对紫杉醇 (PTX) 的固有或获得性耐药是多重耐药 (MDR) 乳腺癌化疗的关键挑战。尽管包括纳米颗粒和脂质体在内的各种靶向药物递送系统对于MDR癌症治疗有效，但其疗效受到免疫抑制肿瘤微环境（TME）的限制。

方法

采用人参皂苷Rg3配制独特的基于Rg3的负载PTX的脂质体，建立Rg3-PTX-LPs，并通过薄膜水合法制备。通过动态光散射进行粒度分析来评估 Rg3-PTX-LP 的稳定性。通过体内成像系统在 MCF-7/T 异种移植模型中检查基于 Rg3 的脂质体的主动靶向效果。为了评估 Rg3-PTX-LP 的抗肿瘤活性和机制，在体外和体内的 MCF-7/T 细胞中进行了 MTT、细胞凋亡测定、TAM 调节和 TME 重塑。

结果

Rg3-PTX-LPs可以同时特异性分布到MCF7/T癌细胞和TME，主要是通过识别GLUT-1。与常规胆固醇脂质体相比，Rg3-PTX-LPs的耐药逆转能力和体内抗肿瘤作用显着提高。Rg3-PTX-LPs 的 TME 重塑机制包括抑制 IL-6/STAT3/p-STAT3 通路激活，使促肿瘤 M2 巨噬细胞复极化为抗肿瘤 M1 表型，抑制骨髓源性抑制细胞 (MDSC)，减少肿瘤相关成纤维细胞 (TAF) ）和TME中的胶原纤维，促进肿瘤细胞凋亡。因此，通过靶向肿瘤细胞和TME重塑的双重作用，Rg3-PTX-LPs实现了高达90.3%的肿瘤抑制率。

结论

我们在本研究中开发的基于 Rg3 的多功能脂质体为挽救耐药肿瘤治疗提供了一种有前途的策略。