[Corrigendum] Phospho‑valproic acid inhibits pancreatic cancer growth in mice: Enhanced efficacy by its formulation in poly‑(L)‑lactic acid‑poly(ethylene glycol) nanoparticles.

Subsequently to the publication of the aobve article, the authors have realized that they overlooked including a Competing Interests section. This should have been included in the paper as follows: GM, RW and GGM declare they have no competing interests. BR has an equity position in Medicon Pharmaceuticals, Inc., the company that provided the test agent. The authors regret that this statement was not included in the paper, and apologize for any inconvenience caused. [the original article was published in the International Journal of Oncology 51: 1035-1044, 2017; DOI: 10.3892/ijo.2017.4103]

Dual upregulation of miRNA-143 and miRNA-506 in non-small cell lung cancer inhibits proliferation, motility, migration, and tumor growth

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide and is primarily treated with chemotherapy or radiotherapy. The role of microRNAs (miRs) is increasingly studied in cancer therapeutics, as miRs can regulate multiple cancer-related pathways simultaneously. While numerous miRs are individually explored for LC therapy, research on therapeutic miR combinations is limited. Our work here evaluates the stable deregulation of two miRs, miR-143-3p, and miR-506-3p, individually and in combination, to elucidate their roles upon prolonged exposure in non-small cell lung cancer (NSCLC) cell lines. Following stable transductions using lentiviruses in A549 and H1975 cells, we evaluated cell cycle distribution, proliferation, migration, and in vivo tumor growth. Sustained combined upregulation of miR-143-3p and miR-506-3p demonstrated a miR-expression dependent response, with advantageous responses for regulating tumor progression. The dual miR upregulation increased the G2 phase cell population and decreased cell proliferation, motility, migration, and colony formation. Furthermore, the dual upregulation significantly inhibited tumor growth in vivo compared to the respective dual downregulation, in contrast to the individual miR deregulations. Our study highlights the advantages of investigating combinatorial miRs for cancer treatment, particularly miR-143/506 against LC

Advanced Bioinformatic Analysis and Pathway Prediction of NSCLC Cells Upon Cisplatin Resistance

This study aims to identify pathway involvement in the development of cisplatin (cis-diamminedichloroplatinum (II); CDDP) resistance in A549 lung cancer (LC) cells by utilizing advanced bioinformatics software. We developed CDDP-resistant A549 (A549/DDP) cells through prolonged incubation with the drug and performed RNA-seq on RNA extracts to determine differential mRNA and miRNA expression between A549/DDP and A549 cells. We analyzed the gene dysregulation with Ingenuity Pathway Analysis (IPA; QIAGEN) software. In contrast to prior research, which relied on the clustering of dysregulated genes to pathways as an indication of pathway activity, we utilized the IPA software for the dynamic evaluation of pathway activity depending on the gene dysregulation levels. We predicted 15 pathways significantly contributing to the chemoresistance, with several of them to have not been previously reported or analyzed in detail. Among them, the PKR signaling, cholesterol biosynthesis, and TEC signaling pathways are included, as well as genes, such as PIK3R3, miR-34c-5p, and MDM2, among others. We also provide a preliminary analysis of SNPs and indels, present exclusively in A549/DDP cells. This study\u27s results provide novel potential mechanisms and molecular targets that can be explored in future studies and assist in improving the understanding of the chemoresistance phenotype

Abstract 302: Passive and active nucleic acid delivery against colon cancer cells using a novel nanocarrier aimed for oral administration

Abstract Oral delivery of nucleic acids has been challenging, due to unfavorable physiological factors that do not comply with the nucleic acids' properties. Firstly, nucleic acids break down in the harsh acidic gastric environment. Secondly, they are hydrophilic, negatively charged, large-molecular-weight molecules, unable to efficiently penetrate through the mucus membrane and enter the epithelial intestinal wall. We developed a novel nano delivery system of nucleic acids complexed with mannosylated PEI encapsulated in PEG-PCL matrix. We will use this carrier to overcome the above-mentioned limitations of oral nucleic acid delivery aiming for colon cancer treatment. We synthesized the mannosylated PEI with the objective to target colon cancer cells. We will use active targeting as these cells overexpress mannose receptors. We complexed a model nucleic acid, the PGL-3 luciferase expressing plasmid, with mannosylated PEI at the optimal N/P ratio of 20:1. We transfected cancer cells in vitro and analyzed the luciferase expression. Furthermore, we analyzed the cytotoxicity of PCL-PEG nanoparticles containing mannosylated PEI/PGL-3 complexes, as well as the nanoparticles capacity to protect nucleic acids and release their load. Mannosylated PEI successfully complexed with the nucleic acids, protecting from degradation against nucleases. Mannosylated PEI/PGL-3 complexes transfected colon cancer cells and the luciferase expression was significantly higher when compared to PEI alone, at 24 and 48 h. The complexes were successfully up taken by cell lines in a time dependent manner. Competitive transfection assay with free mannose demonstrated the active targeting effect caused due to the mannose receptors. Similarly, the PCL-PEG nanoparticles with mannose PEI/PGL-3 complexes had a limited cytotoxicity. Most importantly, the carrier successfully protected the mannose PEI/PGL-3 complexes in a simulated gastric fluid environment and released them in a simulated intestinal fluid environment. This indicates that the nanocarriers can potentially protect the nucleic acids in an acidic environment, such as the stomach, and release their mannosylated PEI/PGL-3 in a neutral environment, such as in the intestines. Such a behavior would indicate a passive targeting to the small and large intestines. We can conclude that the formulated polymeric nanoparticles were successful in protecting the nucleic acids. The mannosylated PEI was able to completely complex with nucleic acids and actively target colon cancer. This promising nanocarrier and our approach merits further evaluation for the oral administration of nucleic acids in therapeutic applications of passive and active targeting against colon cancer. Citation Format: Sagun Poudel, George Mattheolabakis. Passive and active nucleic acid delivery against colon cancer cells using a novel nanocarrier aimed for oral administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 302.</jats:p

Pulmonary Delivery for miRs: Present and Future Potential

Administration through the respiratory tract can be advantageous, with high drug bioavailability, limited enzymatic activity, reduced dose requirements compared to oral, and potentially diminished side effects. Among the different types of drugs studied for pulmonary delivery, genetic material delivery has gained favorable scientific interest, using polymer-, lipid-, inorganic-, or vector-based nanocarriers. As pulmonary drug delivery has been associated with challenges, including physiological barriers and lung metabolism, the delivery of sensitive molecules such as nucleic acids can exacerbate these challenges. While short-interfering RNAs (siRNAs) have been extensively reported as suitable ribonucleic acid interference (RNAi) candidates for pulmonary delivery, discussion on micro-RNA (miR) pulmonary delivery is limited despite their significant therapeutic potential. Recently, these non-coding RNAs have been explored in targeted or non-targeted pulmonary administration against various diseases. This review addresses the information gap on miR-pulmonary delivery with updated and concentrated literature. We briefly discuss the barriers to lung administration, describe different functional nanocarriers for miR delivery, and provide an extensive literature update on the different miRs and their targeted diseases currently being studied