Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME). In hepatocellular carcinoma (HCC), quiescent hepatic stellate cells (HSCs) could be activated to become CAFs, which play a critical role in tumor progression and drug resistance. Therefore, recent efforts have been focused on combining anti-HSC and pro-apoptotic activities to improve anti-tumor efficacy of drugs. In this study, glycyrrhetinic acid and hyaluronic acid–modified liposomes (GA-HA-Lip) were prepared for co-delivery of curcumin (CUR) and berberine (BBR) for the treatment of HCC. Furthermore, we established the LX-2+BEL-7402 co-cultured cell model and implanted the m-HSCs+H22 cells into a mouse to evaluate the anti-tumor effect of CUR&BBR/GA-HA-Lip both in vitro and in vivo. The results showed that CUR&BBR/GA-HA-Lip could accumulate in tumor tissues and be taken up by HSCs and BEL-7402 cells simultaneously. Compared with free CUR, the combination therapy based on GA-HA-Lip exhibits stronger pro-apoptotic and anti-proliferation effect both in vitro and in vivo. The anti-tumor mechanistic study revealed that CUR&BBR/GA-HA-Lip could inhibit the activation of HSCs and restrain drug resistance of tumor cells. In summary, CUR&BBR/GA-HA-Lip could be a promising nano-sized formulation for anti-tumor therapy.

Hepatic stellate cells (HSCs), as an important part of the tumor microenvironment (TME), could be activated by tumor cells as cancer-associated fibroblasts (CAFs), thereby promoting the production of extracellular matrix (ECM) and favoring the development of tumors. Therefore, blocking the "CAFs-ECM" axis is a promising pathway to improve antitumor efficacy. Based on this, we developed a multifunctional nanosized delivery system composed of hyaluronic acid-modified pHsensitive liposomes (CTHLs) and glycyrrheic acid-modified nanomicelles (DGNs), which combines the advantages of targeted delivery, pH-sensitivity, and deep drug penetration. To mimic actual TME, a novel HSCs+BEL-7402 cocultured cell model and a m-HSCs+H22 coimplanted mice model were established. As expected, CTHLs and DGNs could target CAFs and tumor cells, respectively, and promote the drug penetration and retention in tumor regions. Notably, CTHLs+DGNs not only exhibited a superior antitumor effect in three-level tumor-bearing mice but also presented excellent antimetastasis efficiency in lung-metastatic mice. The antitumor mechanism revealed that the lipid&micelle mixed formulations effectively inhibited the activation of CAFs, reduced the deposition of ECM, and reversed the epithelialmesenchymal transition (EMT) of tumor cells. In brief, the nanosized delivery system composed of CTHLs and DGNs could effectively improve the therapeutic effect of liver cancer by blocking the "CAFs-ECM" axis, which has a good clinical application prospect.

Background: Tumor metastasis is a main cause of death in patients with breast cancer. The cross-talk between cancer associated fibroblasts (CAFs) and tumor cells plays an important role in promoting tumor invasion and metastasis. It is important to develop a novel delivery system to inhibit tumor development by simultaneously targeting both CAFs and tumor cells. Objective: The main objective of this research was to prepare nanoparticles to inhibit tumor proliferation and migration by blocking the cross-talk of tumor-CAFs. Additionally, a novel “MCF-7+NIH/3T3” mixed cell model was established to mimic tumor microenvironment (TME). Methods: In this study, the pH-responsive nanoparticles (MIF/DOX-sul-HA NPs) basing on sulfated hyaluronic acid (sul-HA) polymers were prepared for co-delivery of doxorubicin (DOX) and mifepristone (MIF). The effects of anti-proliferation and anti-metastasis of MIF/DOX-sul-HA NPs were investigated both in vitro and in vivo. Results: The results showed that MIF/DOX-sul-HA NPs were nearly spherical in shape with narrow particle size distribution and pH-responsive drug release, and could be taken up by both of MCF-7 and NIH/3T3 cells. Compared with MCF-7 cells alone, the anti-tumor effect of single DOX was weak in the “MCF-7+NIH/3T3” mixed cell model. MIF/DOX-sul-HA NPs exhibited strong effects of anti-proliferation and anti-metastasis than free single drug. Conclusion: The sul-HA nanoparticles for co-delivery of DOX and MIF could be a promising combined therapy strategy for the treatment of breast cancer.

The combination therapy based on nanoscale materials has been proven an effective approach for cancer treatment. In this study, berberine (BBR) and curcumin (CUR) were loaded into mixed liposomes (CUR-GL/BBR-HL). To simulate a tumor microenvironment (TME), the dual-cell research model (SMMC7721 + LX-2) and orthotopic tumor-bearing mice model were established for antiproliferation and antimetastasis evaluation. The results showed that the mixed liposomes exhibited strong cytotoxicity and antimigration effect against the dual-cell research model. Notably, CUR-GL/BBR-HL effectively inhibited the activation of hepatic stellate cells (HSCs), extracellular matrix deposition, and tumor angiogenesis in vivo, resulting in an enhanced anticancer effect. The anti-HCC mechanism revealed that CUR-GL/BBR-HL could inhibit drug resistance and the metastasis of tumor cells by downregulating the expression of P-gp and vimentin, respectively. Hence, the combined therapeutic strategy could effectively inhibit cancer growth, and CUR-GL/BBR-HL might be a potential formulation for anticancer therapy.

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