International Journal of Nanomedicine (Mar 2021)
A Triptolide Loaded HER2-Targeted Nano-Drug Delivery System Significantly Suppressed the Proliferation of HER2-Positive and BRAF Mutant Colon Cancer
Abstract
Ayimukedisi Yalikong,1,2,* Xu-Quan Li,1,3,* Ping-Hong Zhou,1,2 Zhi-Peng Qi,1,2 Bing Li,1,2 Shi-Lun Cai,1,2 Yun-Shi Zhong1,2 1Endoscopy Center, Zhongshan Hospital of Fudan University, Shanghai, 200032, People’s Republic of China; 2Endoscopy Research Institute of Fudan University, Shanghai, 200032, People’s Republic of China; 3Shanghai Henlius Biopharmaceuticals Co., Ltd., Shanghai, 200033, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shi-Lun Cai; Yun-Shi ZhongZhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of ChinaEmail [email protected]; [email protected]: Colon cancer (CRC) was a malignant tumor and there were about 25% of patients with tumor metastasis at diagnosis stage. Chemotherapeutic agents for metastatic CRC patients were with great side effects and the clinical treatment results of advanced CRC were still not satisfactory. Human epidermal growth factor receptor 2 (HER2) is overexpressed in some CRC patients and is an effective target for CRC patient treatment. Anti-HER2 therapy had a beneficial role in the treatment of HER2-positive metastatic CRC with fewer side effects. CRC patients with BRAF mutations were resistant to HER2 antibodies treatment. Therefore, there was an urgent need to develop new therapeutic agents.Methods: HER2 targeted nanoparticles (TPLNP) drug delivery system loading triptolide (TPL) were prepared and identified. The effects of TPLNP and free TPL on cell viability, targeting and cell cycle progression on HT29 (BRAF mutation) with HER2 overexpression, were evaluated by Cell Counting Kit-8 (CCK8), Fluorescence Activating Cell Sorter (FACS) and immunofluorescence methods, respectively. The anti-tumor efficacies of TPLNP were evaluated in subcutaneous xenograft model of colon cancer and the survival rate, tumor volume, liver and kidney indexes of tumor-bearing mice were measured.Results: TPLNP was small in nanosize (73.4± 5.2nm) with narrow size distribution (PDI=0.15± 0.02) and favorable zeta potential (pH=9.6, zeta potential: − 57.3± 6.69mV; pH=7.0, zeta potential: − 28.7± 5.1mV; pH=5.6, zeta potential: − 21.1± 4.73mV). Comparing with free TPL treatment group, TPLNP developed stranger colon cancer-killing efficiency in a dose- and time-dependent manner detected with CCK8 method; achieved good in vitro colon cancer targeting detected with flow cytometry and immunofluorescence experiments; enhanced more HT29-HER2 apoptosis and induced more cell cycle arrested in G1-S phase detected with FACS in vitro. As for in vivo antitumor response, TPLNP remarkably inhibited the growth of colon cancer in the colon cancer xenograft model, significantly improved the survival rate and did not exhibit significant liver and kidney toxicity in contrast with free TPL in vivo.Conclusion: TPLNP was effectively against colon cancer with HER2 overexpression and BRAF mutation in pre-clinical models. In summary, the TPLNP appeared to be a promising treatment option for CRC in clinical application based on improved efficacy and the favorable safety profile.Keywords: colon cancer, HER2, triptolide, BRAF mutation
