Targeting therapy and tumor microenvironment remodeling of triple-negative breast cancer by ginsenoside Rg3 based liposomes

Abstract

The chemotherapy effect of docetaxel (DTX) against triple-negative breast cancer (TNBC) remains mediocre and limited when encapsulated in conventional cholesterol liposomes, mainly ascribed to poor penetration and immunosuppressive tumor microenvironment (TME) caused by tumor stroma cells, especially cancer-associated fibroblasts (CAFs). Many studies have attempted to address these problems but trapped into the common dilemma of excessively complicated formulation strategies at the expense of druggability as well as clinical translational feasibility. To better address the discrepancy, ginsenoside Rg3 was utilized to substitute cholesterol to develop a multifunctional DTXloaded Rg3 liposome (Rg3-Lp/DTX). The obtained Rg3-Lp/DTX was proved to be preferentially uptake by 4T1 cells and accumulate more at tumor site via the interaction between the glycosyl moiety of Rg3 exposed on liposome surface and glucose transporter1 (Glut1) overexpressed on tumor cells. After reaching tumor site, Rg3 was shown to reverse the activated CAFs to the resting stage and attenuate the dense stroma barrier by suppressing secretion of TGF-β from tumor cells and regulating TGF-β/Smad signaling. Therefore, reduced levels of CAFs and collagens were found in TME after incorporation of Rg3, inducing enhanced penetration of Rg3-Lp/DTX in the tumor and reversed immune system which can detect and neutralize tumor cells. Compared with wooden cholesterol liposomes, the smart and versatile Rg3-Lp/DTX could significantly improve the anti-tumor effect of DTX, providing a promising approach for TNBC therapy with excellent therapeutic efficacy and simple preparation process.

SERPINE2 promotes liver cancer metastasis by inhibiting c‐Cbl‐mediated EGFR ubiquitination and degradation

“…Additionally, the CCL5 levels were slightly reduced (Supplementary Figure S4H), whereas no consistent decrease was observed for the other cytokines (Supplementary Figure S4I). Moreover, many studies have reported that tumor cells can promote the activation of CAFs by secreting TGF‐β [25–28]. We hypothesized that TGF‐β plays an important role in the activation of CAFs, and the rescue experiments with exogenous TGF‐β further confirmed that SERPINE2 knockdown inhibited the activation of CAFs, while TGF‐β treatment rescued the above inhibitory effects (Figure 3G, Supplementary Figure S4J).…”

Bioinspired ginsenoside Rg3 PLGA nanoparticles coated with tumor-derived microvesicles to improve chemotherapy efficacy and alleviate toxicity

“…Furthermore, it has been reported that Rg3 has been demonstrated to revert activated cancer-associated fibroblasts (CAFs) to a quiescent state and reduce the dense stromal barrier by inhibiting the secretion of TGF-β from tumor cells and modulating the TGF-β/Smad signaling pathway. 16,64 Consequently, upon arrival at the tumor site, Rg3-PLGA@TMVs had the potential to decrease the levels of CAFs and collagen in the TME. As a result, it may promote the enhanced penetration of DOX and Rg3-PLGA@TMVs into the tumor and achieve TME remodeling.…”

“…9,10 Ginsenoside Rg3 is a natural compound in ginseng with a unique tetracyclic triterpene saponin structure. [11][12][13] It exhibits noteworthy anticancer properties, including the reduction of cancer metastasis and recurrence, 14 inhibition of tumor proliferation, 15,16 suppression of angiogenesis, 17 and promotion of tumor cell apoptosis. 18,19 As a result, it is frequently employed in clinical adjuvant chemotherapy to enhance treatment outcomes, alleviate the toxic side effects associated with chemotherapy drugs, and, most importantly, fortify the immune system.…”

“…22,29,30 For instance, ginsenoside Rg3 was employed as a cholesterol substitute in the formulation of a multifunctional liposome loaded with DTX, denoted as Rg3-Lp/DTX. 16 Rg3-Lp/ DTX could significantly improve the anti-tumor effect of DTX, providing a promising strategy for 4T1 breast cancer therapy. In addition, a folate-targeted polyethylene glycol-modified amphiphilic cyclodextrin nanoparticle was designed for the encapsulation of Rg3 and quercetin (termed CD-PEG-FA.Rg3.…”

Unveiling the experimental proof of the anticancer potential of ginsenoside Rg3 (Review)

“…Through dual action of targeting tumor cells and remodeling the TME, to 90.3% of paclitaxel-resistant breast cancer cells are killed ( 55 ). In addition to paclitaxel, GS-Rg3-based liposomes can significantly enhance the antitumor effects of docetaxel in triple-negative breast cancer ( 56 ). Moreover, GS-Rg3-modified nanoparticles can enhance the immunogenic cell death (ICD) effect induced by doxorubicin ( 57 ).…”