Systemic Delivery of NAC-1 siRNA by Neuropilin-Targeted Polymersomes Sensitizes Antiangiogenic Therapy of Metastatic Triple-Negative Breast Cancer.

Abstract

Antiangiogenic therapy with bevacizumab while being interesting for metastatic triple-negative breast cancer (mTNBC) is restrained by tumor hypoxia elevation and cancer stem cell enrichment. Here, we find that neuropilin-1 (NRP-1)-targeted delivery of nucleus accumbens-associated protein-1 (NAC-1) siRNA mediated by tLyP-1 peptide-functionalized chimaeric polymersomes (tLyP-1-Ps) effectively sensitizes antiangiogenic therapy of mTNBC in vivo. tLyP-1-Ps showed good encapsulation (up to 14.4 wt. %) of siNAC-1, giving robust tLyP-1-Ps-siNAC-1 nanoformulation with a defined size of 48.5 nm (PDI = 0.13) and a surface charge of -9.2 mV, and mediated efficient cytoplasmic transportation of siNAC-1 in MDA-MB-231 TNBC cells, resulting in significant silencing of NAC-1 mRNA and the corresponding oncoprotein. Transwell invasion and wound healing assays revealed that tLyP-1-Ps-siNAC-1 potently inhibited MDA-MB-231 cell invasion and migration. Intriguingly, tLyP-1-Ps-siNAC-1 was shown to markedly improve the bevacizumab therapy of mTNBC, significantly curbing lung metastasis and prolonging the survival time of the MDA-MB-231 metastatic model. The combination of targeted NAC-1 gene silencing and antiangiogenic therapy appears to be an innovative treatment for mTNBC.