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

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.

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.

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.

The systemic delivery of DP7-C micelles carrying siDR6 provide an alternative therapeutic strategy to halt cancer lung metastasis.