High-dose paclitaxel and its combination with CSF1R inhibitor in polymeric micelles for chemoimmunotherapy of triple negative breast cancer

• Published in: Nano today Vol. 51; p. 101884
• Main Authors: Lim, Chaemin, Hwang, Duhyeong, Yazdimamaghani, Mostafa, Atkins, Hannah Marie, Hyun, Hyesun, Shin, Yuseon, Ramsey, Jacob D., Rädler, Patrick D., Mott, Kevin R., Perou, Charles M., Sokolsky-Papkov, Marina, Kabanov, Alexander V.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-08-2023
• Subjects: Chemoimmunotherapy; High-dose therapy; Polymeric micelle; TNBC model; Polymeric micelle; High-dose therapy; Chemoimmunotherapy; TNBC model; High-Dose therapy
• ISSN: 1748-0132; 1878-044X
• DOI: 10.1016/j.nantod.2023.101884

The presence of immunosuppressive immune cells in tumors is a significant barrier to the generation of therapeutic immune responses. Similarly, in vivo triple-negative breast cancer (TNBC) models often contain prevalent, immunosuppressive tumor-associated macrophages in the tumor microenvironment (TME), resulting in breast cancer initiation, invasion, and metastasis. Here, we test systemic chemoimmunotherapy using small-molecule agents, paclitaxel (PTX), and colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397, to enhance the adaptive T cell immunity against TNBCs in immunocompetent mouse TNBC models. We use high-capacity poly(2-oxazoline) (POx)-based polymeric micelles to greatly improve the solubility of insoluble PTX and PLX3397 and widen the therapeutic index of such drugs. The results demonstrate that high-dose PTX in POx, even as a single agent, exerts strong effects on TME and induces long-term immune memory. In addition, we demonstrate that the PTX and PLX3397 combination provides consistent therapeutic improvement across several TNBC models, resulting from the repolarization of the immunosuppressive TME and enhanced T cell immune response that suppress both the primary tumor growth and metastasis. Overall, the work emphasizes the benefit of drug reformulation and outlines potential translational path for both PTX and PTX with PLX3397 combination therapy using POx polymeric micelles for the treatment of TNBC.
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•POx micelles greatly improve the solubility of PTX and PLX3397 and widen the therapeutic index of such drugs.•PTX and PLX3397 combination enhance the adaptive T cell immunity against mouse TNBC models.•PTX and PLX3397 combination provides consistent therapeutic improvement across several TNBC models.