Lipid nanoparticle siRNA cocktails for the treatment of mantle cell lymphoma

Abstract

Mantle cell lymphoma is an aggressive and incurable subtype of non‐Hodgkin B cell lymphoma. Patients typically present with advanced disease, and most patients succumb within a decade of diagnosis. There is a clear and urgent need for novel therapeutic approaches that will affect mantle cell lymphoma through a unique mechanism compared to current therapies. This study examined the use of RNA interference (RNAi) therapy to attack mantle cell lymphoma at the mRNA level, silencing genes associated with cancer cell proliferation. We identified a lipid nanoparticle formulated with the lipidoid 306O13 that delivered siRNA to JeKo‐1 and MAVER‐1 mantle cell lymphoma cell lines. Three therapeutic gene targets were examined for their effect on lymphoma growth. These included Cyclin D1, which is a cell cycle regulator, as well as Bcl‐2 and Mcl‐1, which prevent apoptosis. Gene knockdown with siRNA doses as low at 10 nM increased lymphoma cell apoptosis without carrier‐mediated toxicity. Silencing of Cyclin D1 induced apoptosis despite a twofold “compensation” upregulation of Cyclin D2. Upon simultaneous silencing of all three genes, nearly 75% of JeKo‐1 cells were apoptosing 3 days post‐transfection. Furthermore, cells proliferated at only 15% of their pretreatment rate. These data suggest that lipid nanoparticles‐formulated, multiplexed siRNA “cocktails” may serve as a beneficial addition to the treatment regimens for mantle cell lymphoma and other aggressive cancers.

Recent advances in siRNA delivery mediated by lipid-based nanoparticles

“…They intravenously injected LNPs into a xenograft leukemia mouse model and observed a 60% knockdown of BCR-ABL expression by LNP-anti-BCR-ABL siRNA in leukemia cells sorted from the myelosarcoma tissue, thus indicating that LNPs efficiently delivered siRNA to human leukemia cells in vivo . Knapp et al tried to cure non-Hodgkin lymphoma by using cationic LNPs formulated with lipidoid [ 137 ]. The gold standard for therapy of non-Hodgkin lymphoma is now chemotherapy such as that with R-hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose methotrexate and cytarabine, and R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone, and doxorubicin) [ 138 , 139 ].…”

Recent Developments in Nanomedicine for Pediatric Cancer

“…In addition to the delivery of small-molecule chemotherapy agents, using nanoparticles to deliver nucleic acid has been explored as an immediate treatment for cancer cells. A recent study shows the lipid nanoparticle-based delivery of siRNA as interference therapy to attack mantle cell lymphoma by silencing their mRNA associated with cancer cell proliferation [ 62 ]. To overcome the compensatory upregulation of the cell cycle regulator cyclin D2 that results from the silencing of cyclin D1 by delivering siRNA, two more target molecules, Bcl-2 and Mcl-1, which prevent apoptosis, were treated with these nanoparticles to encapsulate the corresponding siRNA.…”

Bioengineering & Translational Medicine: Year 2020 in review

“…Translationally focused reports, for example, novel tumor models for nanomedicine and scalable synthesis methods, represent a particular need of time and we look forward to receiving more similar translationally focused nanomedicine manuscripts in future. Studies demonstrating novel applications of nanoparticles were also featured prominently in our recent publications, including the use of nanoparticles for improved residence of sunscreens on the skin 18 and siRNA delivery for applications in lymphoma and wound healing 19,20 . Papers on medical devices included control algorithms for artificial pancreas 21 .…”

“…Studies demonstrating novel applications of nanoparticles were also featured prominently in our recent publications, including the use of nanoparticles for improved residence of sunscreens on the skin 18 and siRNA delivery for applications in lymphoma and wound healing. 19,20 Papers on medical devices included control algorithms for artificial pancreas. 21 Along with original research articles, we also published reviews on some of the active current topics in translational medicine including ionic liquids for biomedical applications, 22 clinical landscape of nanomedicine, 23 and translational status of nanocrystals.…”