Abstract
MicroRNAs (miRNAs) play a pivotal role in regulating the expression of genes involved in tumor development, invasion, and metastasis. In particular, microRNA-124 (miR-124) modulates the expression of carnitine palmitoyltransferase 1A (CPT1A) at the post-transcriptional level, impairing the ability of androgen-independent prostate cancer (PC3) cells to completely metabolize lipid substrates. However, the clinical translation of miRNAs requires the development of effective and safe delivery systems able to protect nucleic acids from degradation. Herein, biodegradable polyethyleneimine-functionalized polyhydroxybutyrate nanoparticles (PHB-PEI NPs) were prepared by aminolysis and used as cationic non-viral vectors to complex and deliver miR-124 in PC3 cells. Notably, the PHB-PEI NPs/miRNA complex effectively protected miR-124 from RNAse degradation, resulting in a 30% increase in delivery efficiency in PC3 cells compared to a commercial transfection agent (Lipofectamine RNAiMAX). Furthermore, the NPs-delivered miR-124 successfully impaired hallmarks of tumorigenicity, such as cell proliferation, motility, and colony formation, through CPT1A modulation. These results demonstrate that the use of PHB-PEI NPs represents a suitable and convenient strategy to develop novel nanomaterials with excellent biocompatibility and high transfection efficiency for cancer therapy.
Highlights
Prostate cancer (PC) remains a significant leading cause of male death in developed occidental countries [1,2]
Shi et al showed that low expression of miR-124 contributes to the pathogenesis of PC via increased expression of the androgen receptor [17], while Kang et al demonstrated miR-124 anti-proliferative and anti-aggressive effects related to the inhibition of PACE4 transcription [18]
Cationic polymeric vectors could potentially overcome these limitations, protecting nucleic acid from enzymatic degradation and increasing their bioavailability and loading efficiency. They are regarded as efficient tools in in vitro and in vivo miRNA systemic delivery for cancer therapy [36]
Summary
Prostate cancer (PC) remains a significant leading cause of male death in developed occidental countries [1,2]. Forced expression of the synthetic miR-124 mimic in androgen-dependent and androgen-independent PC cells (LNCaP and PC3, respectively) affects tumorigenic properties, regardless of their hormone sensitivity. Together, these studies suggest that administration of an miR-124 mimic may represent a promising therapeutic tool for PC management. The successful translation of miRNA therapy from bench to bedside is still a severe challenge due to the short half-life and poor stability of miRNA mimics Their clinical translation requires effective delivery systems able to enhance cellular uptake in the tumor site as well as able to protect nucleic acids from degradation
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