A prodrug nanodevice co-delivering docetaxel and ROR1 siRNA for enhanced triple negative breast cancer therapy

Abstract

Triple-negative breast cancer (TNBC) has been a clinical challenge due to its high recurrence and metastasis rates. Chemotherapy remains the primary treatment for TNBC after surgery ablation, but it lacks targeted specificity and causes side effects in normal tissues. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is significantly expressed in TNBC cells, and small interference RNA (siRNA) targeting ROR1 can effectively suppress ROR1 gene expression, thereby inhibiting proliferation and metastasis. However, clinical application of ROR1 siRNA is limited by susceptibility to clearance and difficulty in endosomal escape. In this study, the docetaxel (DTX) prodrug nanoparticle BBRM delivering ROR1 siRNA was constructed. The BBRM could be effectively internalized by tumor cells and endosomal escape to release DTX and ROR1 siRNA. In 4T1 tumor-bearing mice, BBRM could be targeting delivered to tumor and lung tissues, with good biosafety, achieving a tumor inhibition rate of 74.1 % and inhibiting lung metastasis. By integrating chemotherapy and RNA interference therapy, BBRM successfully co-delivered chemotherapeutic agents and siRNA to improve the therapeutic efficacy of triple-negative breast cancer and provided a promising strategy for clinical transformation. STATEMENT OF SIGNIFICANCE: Chemotherapy is still the primary treatment for triple-negative breast cancer (TNBC) after surgery ablation, but it causes side effects without targeting capacity. ROR1 is significantly expressed in TNBC cells, and RNA interference for ROR1 can suppress ROR1 gene expression to inhibit tumor proliferation. However, as oligonucleotides, effect of ROR1 siRNA is limited by susceptibility to clearance and difficulty in endosomal escape. In this work, we designed a nanodevice based on a docetaxel (DTX) prodrug that targets ROR1 for the synergistic therapy of TNBC. We constructed a nanoparticle (BBRM) for co-delivery of the DTX and ROR1 siRNA. The BBRM could be effectively internalized by tumor cells and endosomal escape. The ROR1 siRNA downregulated ROR1 protein expression and improved the anti-proliferative and anti-metastatic effects. In addition, BBRM reversed the immunosuppressive tumor microenvironment, thus improving breast cancer therapeutic efficacy. It was a pioneering investigation in synergistic chemo-gene therapy by co-delivering DTX and ROR1 siRNA for TNBC treatment.

Keywords: Docetaxel; Prodrug nanoparticle; ROR1 siRNA; Triple-negative breast cancer; pH responsive.