Synthesis, characterization, and evaluation of poly (D,L-lactide-co-glycolide)-based nanoformulation of miRNA-150: potential implications for pancreatic cancer therapy

Abstract

MicroRNAs are small (18–22 nucleotide long) noncoding RNAs that play important roles in biological processes through posttranscriptional regulation of gene expression. Their aberrant expression and functional significance are reported in several human malignancies, including pancreatic cancer. Recently, we identified miR-150 as a novel tumor suppressor microRNA in pancreatic cancer. Furthermore, expression of miR-150 was downregulated in the majority of tumor cases, suggesting that its restoration could serve as an effective approach for pancreatic cancer therapy. In the present study, we developed a nanoparticle-based miR-150 delivery system and tested its therapeutic efficacy in vitro. Using double emulsion solvent evaporation method, we developed a poly (D,L-lactide- co -glycolide) (PLGA)-based nanoformulation of miR-150 (miR-150-NF). Polyethyleneimine (a cationic polymer) was incorporated in PLGA matrix to increase the encapsulation of miR-150. Physical characterization of miR-150-NF demonstrated that these nanoparticles had high encapsulation efficiency (~78%) and exhibited sustained release profile. Treatment of pancreatic cancer cells with miR-150-NF led to efficient intracellular delivery of miR-150 mimics and caused significant downregulation of its target gene ( MUC4 ) expression. Inhibition of MUC4 correlated with a concomitant decrease in the expression of its interacting partner, HER2, and repression of its downstream signaling. Furthermore, treatment of pancreatic cancer cells with miR-150-NF suppressed their growth, clonogenicity, motility, and invasion. Together, these findings suggest that PLGA-based nanoformulation could potentially serve as a safe and effective nanovector platform for miR-150 delivery to pancreatic tumor cells.

Clinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer

“…Arora et al developed a poly (D, L-lactide-co-glycolide) (PLGA)-based nanoformulation of miR-150 (miR-150-NF) having high encapsulation efficiency (~78%) and sustained release capacity. When PC cells were treated with miR-150-NF, it resulted in effective intracellular concentration of miR-150 mimics leading to down regulation of its target gene (MUC4), which resulted in the inhibition of cell growth, clonogenicity, motility, and invasion [260]. Further, intra-peritoneal injection of LNA-based miR-21 antagonist resulted in down regulation of oncomir miR-21 leading to decreased splenomegaly in mice with systemic lupus erythematous [261].…”

miRNA nanotherapeutics for cancer

“…A solid lipid NP delivery system in conjugation with miR-375 efficiently reached pancreatic tumors and inhibited pancreatic cancer growth in vitro and in in vivo models. The delivery of miR-150-encapsulated NPs increased the expression of miR-150 in Colo-357 and HPAF cells by 28- and 26-fold, respectively, compared with transfection of miRNA via lipofectamine [37]. …”

MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma

“…The small size of miR-mimetics results in their rapid clearance from the body and thus mandates the development of efficient delivery or vector systems to target DNA sequences encoding miRs to tumor site. Recently, Arora et al developed a poly(lactic-co-glycolic acid) (PLGA)-based nanoparticle formulation to encapsulate miR-150 and demonstrated its utility to downregulate MUC4 and HER2 in vitro [83]. Although the miR-, and RNAi-based approaches to silence MUC4 expression have shown promise, for clinical translation, the significant first step would be to test these approaches in immunocompetent animal models that express human MUC4 in normal physiological context.…”