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Background: Most solid tumors are not diagnosed and treated until the advanced stage, in which tumors have shaped mature self-protective power, leading to off-target drugs and nanomedicines. In the present studies, we established a more realistic large tumor model to test the antitumor activity of a multifunctional ginsenoside Rh2-based liposome system (Rh2-lipo) on advanced breast cancer., Methods: Both cholesterol and PEG were substituted by Rh2 to prepare the Rh2-lipo using ethanol-water system and characterized. The effects of Rh2-lipo on cell uptake, penetration of the tumor spheroid, cytotoxicity assay was investigated with 4T1 breast cancer cells and L929 fibroblast cells. The 4T1 orthotopic-bearing large tumor model was established to study the targeting effect of Rh2-lipo and inhibitory effect of paclitaxel loaded Rh2-lipo (PTX-Rh2-lipo) on advanced breast tumors., Results: Rh2-lipo exhibit many advantages that address the limitations of current liposome formulations against large tumors, such as enhanced uptake in TAFs and tumor cells, high targeting and penetration capacity, cytotoxicity against TAFs, normalization of the vessel network, and depletion of stromal collagen. In in vivo study, PTX-Rh2-lipo effectively inhibiting the growth of advanced breast tumors and outperformed most reported PTX formulations, including Lipusu ® and Abraxane ® ., Conclusion: Rh2-lipo have improved drug delivery efficiency and antitumor efficacy in advanced breast cancer, which offers a novel promising platform for advanced tumor therapy., Competing Interests: Co-authors Dan Wang and Huaxing Zhan are employed by Xiamen Ginposome Pharmaceutical Co., Ltd. Co-author Xinnan Jiang is employed by Shanghai Jahwa United Co., Ltd. The other authors have no conflicts of interest in this work., (© 2024 Hong et al.)

PEGylated cholesterol-containing liposomes (Chol-PEG-lipo) have been widely used as a drug carrier for their good stealth property in blood circulation where cholesterol maintains the stability of the liposomal lipid bilayer and PEGylation endows liposomes with long circulation capability. However, cholesterol-related disadvantages and the accelerated blood clearance (ABC) phenomenon caused by PEGylation greatly limit the application of conventional stealth liposomes in clinic. Herein, ginsenoside Rg3 was selected to substitute cholesterol and PEG for liposomes preparation (Rg3-lipo). Rg3 was proved with similar liposomal membrane regulation ability to cholesterol and comparable long circulation effect to PEG. In addition, repeated administrations of Chol-PEG-lipo and Rg3-lipo were performed. The circulation time of the second dose of Chol-PEG-lipo was substantially reduced accompanied by a greatly increased accumulation in the liver due to the induction of anti-PEG IgM and the subsequent activated complement system. In contrast, no significantly increased level of relative plasma cells, IgM secretion and the complement activation in blood circulation was observed after the second injection of Rg3-lipo. As a result, Rg3-lipo showed great stealth property without ABC phenomenon. Therefore, developing liposomes utilizing Rg3 instead of PEG and cholesterol presents a promising strategy to prolong the blood circulation time of liposomes without triggering the ABC phenomenon and activated immune responses., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

A schematic illustration of Rg3-PTX-LPs to reverse cancer drug resistance. (A) Ginsenoside Rg3 substitutes cholesterol as the membrane material in preparing Rg3-PTX-LPs. (B) The immunosuppressive and drug resistance tumor microenvironment. (C) Rg3-PTX-LPs downregulate the expression of Pgp and reduce the efflux of PTX from the cell. (D) Rg3-PTX-LPs remodel TME by 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 Inhibiting tumor angiogenesis. [Display omitted] • Functional Rg3-based liposomes loaded with paclitaxel (Rg3-PTX-LPs) can specifically distribute to MCF7/T cancer cells and TME simultaneously, mainly through the recognition of GLUT-1. • Rg3-PTX-LPs can promote apoptosis of tumor cells and remodel TME to reverse the MDR state effectively. • Rg3-PTX-LPs can repolarize protumor M2 macrophages to antitumor M1 phenotype, suppressing MDSCs, and decreasing TAFs and collagen fibers in TME by inhibiting the IL-6/STAT3/p-STAT3 pathway. 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). 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. 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%. Our multifunctional Rg3-based liposome developed in the present study offered a promising strategy for rescuing the drug resistance tumor treatment. [ABSTRACT FROM AUTHOR]

Liposomes have been widely used for targeted drug delivery. However, nonselective distribution, low blood-brain barrier penetration, and the disadvantages of cholesterol greatly limit the application of conventional liposomes in the treatment of brain tumors. In the present study, we aimed to develop a multifunctional ginsenoside Rg3-based liposomal system (Rg3-LPs). Compared to cholesterol liposomes (C-LPs), Rg3-LPs not only significantly improved cellular uptake and penetration across glioma spheroids in vitro , but also remarkably enhanced active glioma targeting and intratumoral diffusion capability in vivo. Paclitaxel-loaded Rg3-LPs (Rg3-PTX-LPs) exhibited a substantially stronger anti-proliferation effect on C6 glioma cells than paclitaxel-loaded C-LPs and re-educated tumor-associated macrophages from the protumor M2 phenotype to the antitumor M1 phenotype in vivo. Rg3-PTX-LPs significantly prolonged median survival time of intracranial C6-bearing mice/rats by activating the immune microenvironment in glioma, facilitating T-cell immune responses with expansion of the CD8+ T-cell population, increasing the M1/M2 ratio, and decreasing regulatory T and myeloid-derived suppressor cells. Together, the results demonstrated that ginsenoside Rg3 is a good alternative for cholesterol in drug delivery liposomes and has a synergistic effect with loaded anticancer drugs. Rg3-PTX-LPs can serve as a multifunctional potential drug for the treatment of glioma. A schematic illustration of the multifunctional activities of Rg3-PTX-LPs. (A) Ginsenoside Rg3 substitutes cholesterol as the membrane material in preparing Rg3-PTX-LPs. The glucose chains of ginsenoside Rg3 specifically bind to the GLUTs of BBB and enhance the penetration of liposomes into the brain across the BBB. (B) Rg3-PTX-LPs target to TAMs, promote the normalization of M2 to M1 and elicit anti-tumor immunity. (C) The release of loaded drugs of Rg3-PTX-LPs and the induction of apoptosis of tumor cells. (D) Rg3-PTX-LPs reduce the T-reg cells and MDSCs while induce T cells differentiation into CD8+ T cell and CD4+ T cells in tumor. Unlabelled Image • Ginsenoside Rg3 engineered liposomes can significantly improve the glioma targeting by interacting with glucose transporter. • Ginsenoside Rg3 engineered liposomes can enhance the BBB transport and facilitate the cellular uptake of PTX. • Ginsenoside Rg3 engineered liposomes can reverse the immuno-suppressive glioma microenvironment. • Ginsenoside Rg3 engineered liposomes are easily manufactured and provide a novel potential platform for glioma treatment. [ABSTRACT FROM AUTHOR]