Lipidoid nanoparticle mediated silencing of Mcl-1 induces apoptosis in mantle cell lymphoma.

Abstract

Conventional chemo-immunotherapy fails to cure the majority of mantle cell lymphoma patients and causes substantial toxicity. Resistant mantle cell lymphoma cells commonly overexpress and are dependent on the anti-apoptotic protein, Mcl-1, for survival. In this study, we use potent lipidoid nanoparticles to deliver siRNA to silence Mcl-1 expression. Studies were conducted using two different mantle cell lymphoma cell lines, a normal (JeKo-1) and an aggressive (MAVER-1) line, to assess the ability of lipidoid nanoparticles to be used broadly in the treatment of mantle cell lymphoma. Mcl-1 mRNA silencing and protein knockdown was observed as early as one day after treatment and the lipidoid nanoparticles achieved sustained silencing of Mcl-1 mRNA for at least four days in both JeKo-1 and MAVER-1 cells. Eighty percent silencing was achieved at three days post-transfection in JeKo-1 cells while 50% silencing was achieved in MAVER-1 cells, which are more resistant to transfection. Interestingly, silencing of Mcl-1 induced apoptosis in nearly 30% of both JeKo-1 and MAVER-1 cells three days post-transfection. Additionally, Mcl-1 silencing and the resultant apoptosis in mantle cell lymphoma cells were dose dependent. These data suggest that lipidoid nanoparticles siRNA therapy targeting Mcl-1 has potential as a new treatment modality for mantle cell lymphoma and many other cancers that overexpress Mcl-1. The combination of anti-Mcl-1 lipidoid nanoparticles with other forms of targeted therapy offers hope for reducing or replacing cytotoxic chemotherapy as standard treatment for mantle cell lymphoma.