Chloroquine Assisted Delivery of microRNA Mimic Let-7b to NSCLC Cell Line by PAMAM (G5) - HA Nano-Carrier.

AIM: Polyamidoamine (PAMAM) dendrimers are attracting interest of the scientists as vehicles for nucleic acid delivery due to their suitable properties. The highly positive surface charged of PAMAM enables an adequate interaction with negatively charged microRNAs. PURPOSE: The purpose of this study is to investigate the anti-tumor effect of microRNA Mimic let-7b loaded in PAMAM dendrimers (G5) on Non-Small Cell Lung Cancer (NSCLC) cells. OBJECTIVE: In order to increase the anti-tumor effect, chloroquine is employed to enhance the endosomal escape which is counted as a limitation in the advancement of gene delivery. Nanoparticles (NPs) were coated with natural polysaccharide "Hyaluronic Acid (HA)" to develop biodegradable carriers with targeting moiety for over-expressed CD44 receptors on NSCLC cells. The size and zeta potential measurements, gel retardation, cellular uptake, cell viability and gene expression studies were investigated for the designed delivery system. RESULTS: DLS analysis showed monodispersed small nanoparticles, which was in agreement with TEM results. Remarkably, NPs in the cells pretreated with chloroquine exhibited the highest cytotoxicity and were capable of inducing apoptosis. In cellular uptake study, NPs labeled with Fluorescein Isothiocyanate (FITC), were successfully taken up in cancer cells. Moreover, the expression study of three genes linked with cancer initiation and development in NSCLC, including KRAS, p-21, and BCL-2 indicated a decrease in KRAS and BCL-2 (oncogenic and anti-apoptotic genes) and increase in p-21 (apoptotic gene). CONCLUSION: All factors considered, the results declare that application of let-7b-loaded PAMAM-HA NPs in combination with chloroquine can be a promising therapeutic option in cancer cells inhibition. This fact has frequently been highlighted by many researchers upon the potentials of micro RNA delivery in cancer cells.

Mitochondrial delivery of microRNA mimic let-7b to NSCLC cells by PAMAM-based nanoparticles.

Many biological mechanisms including cellular metabolism and cell death are regulated by mitochondria known as powerhouse of the cell. Recently, let-7b, a tumour-suppressor microRNA has been detected in mitochondria of human cells targeting several mitochondrial-encoded respiratory chain genes. Triphenylphosphonium cation (TPP) is one of the major classes of mitochondriotropics that possess the ability of specifically targeting the mitochondria. PAMAM dendrimers are one of the most available agents in gene delivery due to their well-defined and beneficial features such as large density of surface functional groups. Hyaluronic acid (HA), a natural polysaccharide has been demonstrated to have the abilities such as good biocompatibility and targeting CD44 overexpressed receptors on non-small cell lung cancer (NSCLC) cells. In this research, let-7b-PAMAM (G5)-TPP and let-7b-PAMAM (G5)-TPP-HA nano-carriers were designed to deliver let-7b miRNA mimic to NSCLC cells' mitochondria as a novel way of cancer cells inhibition. Nano-carriers were capable of being successfully taken up by A549 cells and localised in mitochondria environment. Let-7b loaded nanoparticles reduced cell viability and induced apoptosis significantly. Expression of genes involved in mitochondrial oxidative function was decreased resulting in nanoparticles effect on mitochondria. Application of mitochondria targeted-miRNA delivery systems could regulate cellular functions to inhibit lung cancer.

Co-Delivery Nanosystems for Cancer Treatment: A Review.

Massive data available on cancer therapy more than ever lead our mind to the general concept that there is no perfect treatment for cancer. Indeed, the biological complexity of this disease is too excessive to be treated by a single therapeutic approach. Current delivery systems containing a specific drug or gene have their particular opportunities and restrictions. It is worth noting that a considerable number of studies suggest that single- drug delivery systems result in insufficient suppression of cancer growth. Therefore, one of the main ideas of co-delivery system designing is to enhance the intended response or to achieve the synergistic/combined effect compared to the single drug strategy. This review focuses on various strategies for co-delivery of therapeutic agents in the treatment of cancer. The primary approaches within the script are categorized into co-delivery of conventional chemotherapeutics, gene-based molecules, and plant-derived materials. Each one is explained in examples with the recent researches. In the end, a brief summary is provided to conclude the gist of the review.