Liposomal Nanoparticles Carrying anti-IL6R Antibody to the Tumour Microenvironment Inhibit Metastasis in Two Molecular Subtypes of Breast Cancer Mouse Models

Abstract

Tumour microenvironment (TME) contributes significantly towards potentiating the stemness and metastasis properties of cancer cells. IL6-Stat3 is one of the important cell signaling pathways in mediating the communication between tumour and immune cells. Here, we have systematically developed a novel anti-CD44 antibody-mediated liposomal nanoparticle delivery system loaded with anti-IL6R antibody, which could specifically target the TME of CD44+ breast cancer cells in different mouse models for triple negative and luminal breast cancer. This nanoparticle had an enhanced and specific tumour targeting efficacy with dramatic anti-tumour metastasis effects in syngeneic BALB/c mice bearing 4T1 cells as was in the syngeneic MMTV-PyMT mice. It inhibited IL6R-Stat3 signaling and moderated the TME, characterized by the reduced expression of genes encoding Stat3, Sox2, VEGFA, MMP-9 and CD206 in the breast tissues. Furthermore, this nanoparticle reduced the subgroups of Sox2+ and CD206+ cells in the lung metastatic foci, demonstrating its inhibitory effect on the lung metastatic niche for breast cancer stem cells. Taken together, the CD44 targeted liposomal nanoparticles encapsulating anti-IL6R antibody achieved a significant effect to inhibit the metastasis of breast cancer in different molecular subtypes of breast cancer mouse models. Our results shed light on the application of nanoparticle mediated cancer immune-therapy through targeting TME.

CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages

“…Liposomal nanoparticles were prepared as previously described 35. The lipid mixture was composed of DOPE, DOPC and cholesterol (1:1:1 molar ratio).…”

“…The advantage of NPs delivery systems is their ability to deliver agents efficiently to target cells in their bioavailable forms 34. For example, CD44-targeted NPs can specifically deliver antibodies to tumor sites specially, thereby exerting the therapeutic effect on tumor 35. This delivery method can reduce the side-effect of agents, thereby improve their therapeutic efficacy.…”

A highly potent and selective inhibitor Roxyl-WL targeting IDO1 promotes immune response against melanoma

“…The frozen sections were fixed in cold methanol for 15 min and then incubated with anti-IDO1 (1:100) or anti-Foxp3 (1:100) antibody overnight at 4 °C, followed by incubation with Alexa Fluor 549 goat anti-rat IgG or Alexa Fluor 488 goat anti-rabbit IgG, correspondingly at room temperature for 1 h. They were finally incubated with 4’,6-diamidino-2-phenylindole (DAPI; Sigma-Aldrich, St. Louis, MO) for nuclear counterstaining. Images were acquired by using a laser scanning confocal microscope (Leica, Wetzlar, Germany) 22 .…”

Cytokines, breast cancer stem cells (BCSCs) and chemoresistance

“…The tumor microenvironment (TME) comprises immune system elements (such as macrophages and lymphocytes), fibroblast, cells composing blood vessels, myofibroblast, mesenchymal stem cells, adipocytes and extracellular matrix (ECM). Tumor microenvironment (or the tumor niche) plays a vital role in the progression of cancer [63–68], and affects many processes such as tumor growth, metastasis, relapse and drug resistance [69–73].…”