1. Tumor-targeted delivery of silibinin and IPI-549 synergistically inhibit breast cancer by remodeling the microenvironment
- Author
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Tong Qiu, Qi Liu, Jiang Min, Kaiyong He, Hua Zheng, Jiahui Sun, and Xueqiong Zhang
- Subjects
Myeloid ,Angiogenesis ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,02 engineering and technology ,030226 pharmacology & pharmacy ,Polyethylene Glycols ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Cancer-Associated Fibroblasts ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Microenvironment ,Medicine ,media_common ,Drug Carriers ,Drug Synergism ,021001 nanoscience & nanotechnology ,medicine.anatomical_structure ,Benzamides ,Administration, Intravenous ,Female ,0210 nano-technology ,Drug ,media_common.quotation_subject ,Polyesters ,Silibinin ,Breast Neoplasms ,03 medical and health sciences ,Breast cancer ,Immunity ,Cell Line, Tumor ,Animals ,Humans ,Protein Kinase Inhibitors ,Tumor microenvironment ,business.industry ,medicine.disease ,Isoquinolines ,Antineoplastic Agents, Phytogenic ,Disease Models, Animal ,Pyrimidines ,chemistry ,Apoptosis ,Silybin ,Cancer research ,Nanoparticles ,Pyrazoles ,Drug Screening Assays, Antitumor ,business - Abstract
We induced changes in the tumor microenvironment (TME) through the synergistic actions of two drugs used in breast cancer therapy. The anti-fibrotic drug silibinin (SLB) targets tumor-associated fibroblasts and exerts immune-mediated anti-cancer effects. IPI-549, an efficient and highly selective phosphoinositide-3-kinase-gamma (PI3Kγ) inhibitor, was applied to alter the balance of immunosuppressive cells by inhibiting PI3Kγ molecules; it also promotes anti-tumor immunity. We developed nanoparticle formulations to encapsulate both drugs into the targeting carrier aminoethyl anisamide-polyethylene glycol-polycaprolactone (AEAA-PEG-PCL) respectively. The drugs were intravenously delivered in mice and resulted in an increase in anti-tumor efficacy and apoptotic tumor tissue compared with either IPI-549 or SLB alone in 4T1 breast cancer cell-derived tumors. Furthermore, a significant reduction in regulatory T (Treg) cells and myeloid suppressor cells (MDSCs) was observed. A normalized TME structure was also observed, including angiogenesis suppression, antifibrotic effects and the inhibition of collagen formation in the tumor tissue, significantly enhancing the anti-tumor effects. In summary, this combination strategy may offer an alternative treatment for breast cancer.
- Published
- 2019