Therapeutic Delivery of MicroRNA-29b by Cationic Lipoplexes for Lung Cancer

Abstract

MicroRNA-29b (miR-29b) expression has been shown to be reduced in non-small–cell lung cancer (NSCLC) tissues. Here, we have identified the oncogene cyclin-dependent protein kinase 6 (CDK6) as a direct target of miR-29b in lung cancer. We hypothesized that in vivo restoration of miR-29b and thus targeting of genes important to tumor initiation and progression may represent an option for lung cancer treatment. We developed a cationic lipoplexes (LPs)-based carrier that efficiently delivered miR-29b both in vitro and in vivo. LPs containing miR-29b (LP-miR-29b) efficiently delivered miR-29b to NSCLC A549 cells, reduced the expression of key targets CDK6, DNMT3B, and myeloid cell leukemia sequence 1 (MCL1), as well as cell growth and clonogenicity of A549 cells. In addition, the IC50 for cisplatin in the miR-29b–treated cells was effectively reduced. In a xenograft murine model, LPs efficiently accumulated at tumor sites. Systemic delivery of LP-miR-29b increased the tumor miR-29b expression by approximately fivefold, downregulated the tumor mRNA expression of CDK6, DNMT3B, and MCL1 by ~57.4, ~40.5, and ~52.4%, respectively, and significantly inhibited tumor growth by ~60% compared with LP-miR-NC (negative control). Our results demonstrate that cationic LPs represent an efficient delivery system that holds great potential in the development of miRNA-based therapeutics for lung cancer treatment.

miR-29b Mediates NF-κB Signaling in KRAS-Induced Non–Small Cell Lung Cancers

“…Expression of BCL2 family members is also induced by NF-kB conferring insensitivity to cisplatin (40). However, it is well established that miR-29b directly targets the antiapoptotic gene MCL1 in lung cancer (41), tipping the balance toward intrinsic apoptosis (Fig. 6E).…”

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…Also, the level of expression of the exogenous gene is usually too low to mount a full treatment effect [195]. Another method of transferring specific miRNA into the lung tumour tissue is a cationic lipid-based miRNA delivery system, which had good efficiency both in vitro and in vivo, as was reported by Wu et al [189,196]. Most challenges to overcome in liposomebased therapies are related to toxicity due to charged liposomes, inability to escape the immune system, and low stability [197,198].…”

Long and short noncoding RNAs in lung cancer precision medicine: Opportunities and challenges

“…Systemic delivery of cationic LPs-miR-29b significantly inhibited lung tumor growth by ~60% compared with LP-miR-NC (negative control). 61 The combination of therapeutical delivery of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression in a genetically engineered KRAS mouse model. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone.…”