A Novel Systemic siDR6 Delivery System Based on DP7-C for the Treatment of Metastatic Lung Cancer

Hongyou Zhou,* Rui Zhang,* Ke Men, Lin Tang, Yusi Wang, Li Yang Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rui Zhang, Email [email protected] Li Yang, Email [email protected]: The treatment of metastatic lung cancer, a common complication of many primary cancers, has historically been a significant clinical challenge. Once lung metastasis occurs, patients’ survival is often significantly shortened. Therefore, prevention and treatment of lung metastases is an important aspect of cancer treatment. In this study, a simple, low-toxicity, cholesterol-modified cationic cell-penetrating peptide DP7 (DP7-C), in combination with siDR6 was used for intravenous administration for the treatment of lung metastases.Methods: Initially, clinical databases were analyzed to determine the expression levels of death receptor 6 (DR6) in metastatic tumors and the correlation between DR6 expression and patient survival times. The DP7-C/siDR6 micelles were prepared by a self-assembly method. By cultivating 293T, B16F10 and LL2 cells, the in vitro experiments were performed to assess the transfection efficiency, safety and anti-cancer ability of DP7-C/siDR6, while its targeting efficiency and prevention of lungs were investigated by mouse experiments. Furthermore, the therapeutic efficacy of DP7-C/siDR6 was demonstrated in the LL2 model of lung cancer in situ, the B16F10 model of artificial lung metastasis, and the 4T1 model of spontaneous lung metastasis.Results: The clinical data analysis revealed that DR6 was highly expressed in the majority of metastatic tumors and that patients with high DR6 expression exhibited significantly shorter survival times. The DP7-C/siDR6 showed high transfection efficiency, and it could inhibit tumor cell growth by suppressing the STAT3 signaling pathway. Subsequent mouse experiments demonstrated that intravenous administration of DP7-C/siDR6 resulted in efficient lung targeting. The inhibition of DR6 expression on lung endothelial cells was found to prevent metastasis-induced primary necrosis of lung endothelial cells, thereby preventing tumor metastasis. And the DP7-C/siDR6 treatment showed excellent therapeutic efficacy in the tumor models.Conclusion: The systemic delivery of DP7-C micelles carrying siDR6 provide an alternative therapeutic strategy to halt cancer lung metastasis.Keywords: DP7-C, siDR6, gene therapy, delivery system, metastatic cancer