In situ Injection of pH- and Temperature-Sensitive Nanomaterials Increases Chemo-Photothermal Efficacy by Alleviating the Tumor Immunosuppressive Microenvironment

Jianhua Liu,1,* Liantao Guo,1,* Yan Rao,2 Weijie Zheng,1 Dongcheng Gao,1 Jing Zhang,2 Lan Luo,1 Xinwen Kuang,1 Saraswati Sukumar,3 Yi Tu,1 Chuang Chen,1 Shengrong Sun1 1Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Animal Biosafety Level III Laboratory at the Center for Animal Experiment, Wuhan University School of Medicine, Wuhan, People’s Republic of China; 3Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA*These authors contributed equally to this workCorrespondence: Shengrong Sun; Chuang Chen, Tel +86-13707198696 ; +86-1476064785, Email sun137@sina.com; chenc2469@163.comPurpose: Triple-negative breast cancer (TNBC) is challenging to treat with traditional “standard of care” therapy due to the lack of targetable biomarkers and rapid progression to distant metastasis.Methods: We synthesized a novel combination regimen that included chemotherapy and photothermal therapy (PTT) to address this problem. Here, we tested a magnetic nanosystem (MNs-PEG/IR780-DOX micelles) loaded with the near-infrared (NIR) photothermal agent IR780 and doxorubicin (DOX) to achieve chemo-photothermal and boost antitumor immunity. Intraductal (i.duc) administration of MNs-PEG/IR780-DOX could increase the concentration of the drug in the tumor while reducing systemic side effects.Results: We showed more uptake of MNs-PEG/IR780-DOX by 4T1-luc cells and higher penetration in the tumor. MNs-PEG/IR780-DOX exhibited excellent photothermal conversion in vivo and in vitro. The release of DOX from MNs-PEG/IR780-DOX is pH- and temperature-sensitive. Facilitated by i.duc administration, MNs-PEG/IR780-DOX displayed antitumor effects and prevented distant organs metastasis under NIR laser (L) irradiation and magnetic field (MF)while avoiding DOX-induced toxicity. More importantly, MNs-PEG/IR780-DOX alleviated tumor immunosuppressive microenvironment by increasing tumor CD8+ T cells infiltration and reducing the proportion of myeloid-derived suppressor cells (MDSCs) and Tregs.Conclusion: Intraductal administration of pH- and temperature-sensitive MNs-PEG/IR780-DOX with L and MF had the potential for achieving minimally invasive, targeted, and accurate treatment of TNBC.Keywords: triple-negative breast cancer, photothermal therapy, near-infrared image, intraductal administration, tumor immunosuppressive microenvironment