In Vivo Activity of MiR-34a Mimics Delivered by Stable Nucleic Acid Lipid Particles (SNALPs) against Multiple Myeloma

Abstract

Multiple myeloma (MM) is a disease with an adverse outcome and new therapeutic strategies are urgently awaited. A rising body of evidence supports the notion that microRNAs (miRNAs), master regulators of eukaryotic gene expression, may exert anti-MM activity. Here, we evaluated the activity of synthetic miR-34a in MM cells. We found that transfection of miR-34a mimics in MM cells induces a significant change of gene expression with relevant effects on multiple signal transduction pathways. We detected early inactivation of pro-survival and proliferative kinases Erk-2 and Akt followed at later time points by caspase-6 and -3 activation and apoptosis induction. To improve the in vivo delivery, we encapsulated miR-34a mimics in stable nucleic acid lipid particles (SNALPs). We found that SNALPs miR-34a were highly efficient in vitro in inhibiting growth of MM cells. Then, we investigated the activity of the SNALPs miR-34a against MM xenografts in SCID mice. We observed significant tumor growth inhibition (p<0.05) which translated in mice survival benefits (p = 0.0047). Analysis of miR-34a and NOTCH1 expression in tumor retrieved from animal demonstrated efficient delivery and gene modulation induced by SNALPs miR-34a in the absence of systemic toxicity. We here therefore provide evidence that SNALPs miR-34a may represent a promising tool for miRNA-therapeutics in MM.

Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest

“…The novel BERA miR-34a prodrug examined in current study is a natural RNA agent produced and folded within the cells2425, which are distinguished from synthetic miR-34a mimics and precursors1619293035 consisting of extensive chemical modifications on the ribose and phosphate bone that may alter the tertiary structure, physicochemical properties, biological/pharmacological activity, and/or safety profiles31. In addition, bioengineered miR-34a prodrug is literally large molecule RNA agent, in contrast to viral or non-viral vector-based miR-34a expression plasmids/systems36 that are rather DNA materials and may complicate these RNA-based processes.…”

Activation of p53/miR‐34a Tumor Suppressor Axis by Chinese Herbal Formula JP‐1 in A549 Lung Adenocarcinoma Cells

“…A lipid/polymer nanoparticle named 7C1 has been employed to deliver miR-34a mimic for treatment of lung tumor in animal model [18]. In parallel, nanoplexes such as chitosan/PLGA (Poly(D,L-lactide-co-glycolide)) and SNALPs (stable nucleic acid lipid particles) have been used for the delivery of miR-34a mimics to treat multiple myeloma xenografts in SCID mice [45, 46]. Regarding the elevated miR-34a transcription and significant repression of its downstream targets in JP-1-treated A549 cells, our results suggest the alternative approach for restoring the miR-34a level in p53 wild-type cancers by treatment with Chinese herbal formula such as JP-1.…”

MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers

“…Among non-viral nanocarriers, lipid-based vector are frequently applied because of the high transfection efficiency, but they are limited on account of the poor stability in serum and the toxicity . To solve this, stable nucleic acid lipid particles (SNALPs) was synthesized, and SNALPs encapsulating miR-34a showed inhibition of MM xenograft growth with low toxicity (Di Martino et al, 2014). Besides, polymeric vector, another non-viral delivery system with the low immunogenicity and cytotoxicity is also used to inhibit the tumor via integrating miR-34a (Lin et al, 2019).…”