Doxorubicin-polyglycerol-nanodiamond conjugates disrupt STAT3/IL-6-mediated reciprocal activation loop between glioblastoma cells and astrocytes.

Astrocytes are key stromal components in glioblastoma (GBM) and have complex interactions with the GBM cells (GBC) promoting the survival, progression and therapy resistance of GBM. In this study, we first demonstrated the existence of a reciprocal activation loop mediated by the STAT3/IL-6 signaling between GBC and astrocytes. This loop of reciprocity was found to be initiated by the constitutive activity of STAT3 and downstream expression of IL-6 in the GBC. GBC-derived IL-6 activated STAT3 and thereby upregulated IL-6 expression in the astrocytes. Astrocyte-derived IL-6 acted back on the GBC causing further activation of STAT3 and leading to enhanced downstream events that promote proliferation, migration, invasion and apoptosis resistance of the GBC. Next, we showed that doxorubicin-polyglycerol-nanodiamond conjugates (Nano-DOX), which could be delivered via GBM-associated macrophages, suppressed STAT3 activity in the GBC reducing their IL-6 output to the astrocytes and thereby abolished the astrocytes' feedback activation of the GBC. Moreover, Nano-DOX also suppressed stimulated activation of STAT3 and IL-6 induced by temozolomide, a first-line anti-GBM chemotherapy, resistance to which critically involves STAT3 activation. In conclusion, Nano-DOX could disrupt the STAT3/IL-6-mediated reciprocal activation loop between the GBC and astrocytes. Nano-DOX also provides a novel approach to therapeutic modulation of the GBM microenvironment.

Doxorubicin-polyglycerol-nanodiamond conjugate is a cytostatic agent that evades chemoresistance and reverses cancer-induced immunosuppression in triple-negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes and is one of the most fatal diseases for women. Combining cytotoxic chemotherapy with immunotherapy has shown great promise for TNBC treatment. However, chemotherapy often leads to the development of chemoresistance and severe systemic toxicity compromising the immune functions that are crucial to anti-TNBC immune therapy. Tumor-induced immunosuppression also poses a great hindrance to efficacious anti-TNBC immunotherapy. Nanomedicine holds great promise to overcome these hurdles. RESULTS: Doxorubicin-polyglycerol-nanodiamond conjugate (Nano-DOX) was firstly found to be a cytostatic agent to the 4T1 cells and displayed a lower apparent therapeutic potency than DOX. However, the tumor-bearing animals, particularly some key immune cells thereof, showed good tolerance of Nano-DOX as opposed to the severe toxicity of DOX. Next, Nano-DOX did not induce significant upregulation of P-gp and IL-6, which were demonstrated to be key mediators of chemoresistance to DOX in the 4T1 cells. Then, Nano-DOX was shown to downregulate tumor-derived granulocyte-colony stimulating factor (G-CSF) and suppresses the induction and tissue filtration of myeloid-derived suppressor cells (MDSCs) that are the principal effectors of cancer-associated systemic immunosuppression. Nano-DOX also alleviated the phenotype of MDSCs induced by 4T1 cells. Finally, Nano-DOX induced the 4T1 cells to emit damage associated molecular patterns (DAMPs) that stimulated the tumor immune microenvironment through activating key immune effector cells involved in anti-tumor immunity, such as macrophages, dendritic cells and lymphocytes in the tumor tissue. CONCLUSIONS: Nano-DOX is a cytostatic agent with good host tolerance which is capable of evading chemoresistance and reversing cancer-induced immunosuppression both at the systemic level and in the tumor microenvironment in TNBC. Our work presents Nano-DOX as an interesting example that a chemotherapeutic agent in nano-form may possess distinct biochemical properties from its free form, which can be exploited to join chemotherapy with immunotherapy for better treatment of cancer.