title: 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.
authors.affiliation: Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Knapp
authors.affiliation: Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: He
authors.affiliation: Division of Hematology and Cellular Therapy, Allegheny Health Network Cancer Institute, Pittsburgh, PA 15224, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lister
authors.affiliation: Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA kawhite@cmu.edu.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Whitehead
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014162:Transfection
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D034741:RNA, Small Interfering
keywords: Mcl-1; mantle cell lymphoma; nanomedicine; nanoparticles; siRNA