Nucleic Acid-based Agents Research Articles

A chitosan derivative-crosslinked hydrogel with controllable release of polydeoxyribonucleotides for wound treatment

Nucleic acid-based agents have advantages in therapeutic efficacy and biological safety. However, due to its facile degradability, it lacks an effective route of administration in wound treatment. Designing smart hydrogels for the spatiotemporally controllable delivery of nucleic acids is of great significance for clinical applications. Here, a near-infrared (NIR)-responsive nanocomposite hydrogel was prepared using methyl methacrylate (GMA)-modified chitosan as the macromolecular cross-linker, N-isopropylacrylamide (NIPAAm) as the backbone, and molybdenum disulfide nanosheets (MoS2 NSs) as the nanocomponents. The polydeoxyribonucleotide (PDRN), a nucleic acid-based agent that promotes tissue regeneration, was loaded and delivered. The photothermal conversion capability of MoS2 NSs enables customized care of PDRNs and antibacterial enhancement. In a full-thickness skin defect model, high-quality wound healing effects were demonstrated under the action of nanocomposite hydrogels. The proposed nanocomposite hydrogel provides a new reference for local delivery of nucleic acid-based agents.

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts.

Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles.

Integration of Polylactide into Polyethylenimine Facilitates the Safe and Effective Intracellular siRNA Delivery.

Polyethylenimine (PEI) is a gold standard polymer with excellent transfection efficacy, yet its severe toxicity and nondegradability hinders its therapeutic application as a gene delivery vector. To tackle this problem, herein we incorporated the biodegradable polylactide (PLA) into the branched PEI by synthesizing a PEI-PLA copolymer via a facile synthetic route. PLA modification significantly improved the cytocompatibility of PEI, PEI-PLA copolymer showed much higher cell viability than PEI as verified in three different human cancer cell lines (HCT116, HepG2 and SKOV3). Interestingly, the PEI-PLA copolymer could effectively bind siRNA targeting PKM2, and the obtained polyplex displayed much higher stability in serum than naked siRNA as determined by agarose gel electrophoresis. Moreover, cellular uptake study demonstrated that PEI-PLA could efficiently deliver the Cy5-labled siRNA into the three tested cancer cell lines, and the transfection efficiency is equivalent to the commercial Lipofectamine® 2000. Finally, it is noteworthy that the polyplex is comparable to Lipo2000 in down-regulating the expression of PKM2 at both mRNA and protein level as measured by q-PCR and western blotting, respectively. Overall, the PEI-PLA copolymer developed in this study has the potential to be developed as a versatile carrier for safe and effective delivery of other nucleic acid-based agents.

Strategies to Enhance Drug Absorption via Nasal and Pulmonary Routes.

New therapeutic agents such as proteins, peptides, and nucleic acid-based agents are being developed every year, making it vital to find a non-invasive route such as nasal or pulmonary for their administration. However, a major concern for some of these newly developed therapeutic agents is their poor absorption. Therefore, absorption enhancers have been investigated to address this major administration problem. This paper describes the basic concepts of transmucosal administration of drugs, and in particular the use of the pulmonary or nasal routes for administration of drugs with poor absorption. Strategies for the exploitation of absorption enhancers for the improvement of pulmonary or nasal administration are discussed, including use of surfactants, cyclodextrins, protease inhibitors, and tight junction modulators, as well as application of carriers such as liposomes and nanoparticles.

Nanomaterials for delivery of nucleic acid to the central nervous system (CNS)

Billions of dollars have been invested in the therapeutic application of nucleic acid-based agents in humans in recent years. There are inspirable data from ongoing clinical trial for different diseases. However, in order to widely apply nucleic acid in prevention, diagnosis and treatment of age-related disease, such as neurodegeneration and disorders, suitable, safe and effective drug delivery nanocarriers have to been developed to overcome the blood brain barrier (BBB), which is the most inflexible barrier in human body. Here, we highlight the structure and function of barriers in the central nervous system (CNS) and summary several types of nanomaterials which can be potentially used in the brain delivery nucleic acid.

Potential use of nucleic acid-based agents in the sensitization of nasopharyngeal carcinoma to radiotherapy

Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer. The 2-year survival rate of patients with stage III or IV disease is only about 50%. Due to its high radiosensitivity, radiotherapy is the standard treatment for early-stage of NPC. However, the radioresistance observed in some patients can cause distant metastases and local recurrence after radiotherapy. Special emphasis has been given to the discovery of effective radiosensitizers. Oncogenic proteins encoded by EBV genomes may serve as part of targeted radiosensitization, such as NF кB-mediated expression of latent membrane protein-1. We here review the major nucleic acid-based options currently used in cancer therapeutic approaches and the selected candidate genes that can be targeted for NPC radiosensitization.

Novel Nucleic Acid-Based Agents: siRNAs and miRNAs

Novel Nucleic Acid-Based Agents: siRNAs and miRNAs

Combinatorial Application of Nucleic Acid-Based Agents Targeting Protein Kinases for Cancer Treatment

The progress made in cancer biology, genetics and biotechnology has led to a major transition in cancer drug design and development, from an emphasis on non-specific, cytotoxic agents to specific, molecular-targeted smart cancer drugs. Many of these targeted agents have shown to have improved selectivity for cancer versus normal cells and are associated with better anti-tumor efficacy and lower toxicity. The new generation of anti-cancer drugs requires low concentrations and minimizes unwanted side effects. Their use leads to enhanced anti-cancer effects and to a reduction of chemotherapy resistance. Still, resistance to common chemotherapeutic agents is a major obstacle in cancer treatment. Silencing of cancer-relevant genes is a challenging strategy to reduce resistance and to sensitize cancer cells towards anti-neoplastic agents. Resistance can be an intrinsic problem of the tumor or can be acquired during the life time of the tumor. A fascinating species of anti-cancer drugs include antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) which are able to specifically down-regulate the expression of the target genes. The combination of nucleic acid-based agents with anti-neoplastic drugs can induce synergistic induction of cell cycle arrest, apoptosis and reduced cell proliferation in vitro or tumor growth in vivo. These two strategies (ASOs and siRNAs) will help to improve current therapeutic regimens. In addition, the combination of targeted drugs with common chemotherapeutic agents might be able to make resistant cells again sensitive towards a chemotherapeutic agent.

CpG RNA: Identification of Novel Single-Stranded RNA That Stimulates Human CD14+CD11c+ Monocytes

Synthetic immunostimulatory nucleic acids such as CpG DNA are being harnessed therapeutically as vaccine adjuvants, anticancer or antiallergic agents. Efforts to identify nucleic acid-based agents capable of more specifically modulating the immune system are being developed. The current study identifies a novel class of single-stranded oligoribonucleotides (ORN) containing unmethylated CpG motifs and a poly(G) run at the 3' end (CpG ORN) that directly stimulate human CD14+CD11c+ monocytes but not dendritic cells or B cells. CpG ORN activate NF-kappaB and p38 MAPK, resulting in IL-6 and IL-12 production and costimulatory molecule up-regulation but not IFNalpha. Methylation of cytosine at the 5' portion in core CpG motif abrogates such activation. TLR3, 7, 8, or 9 alone did not confer response to CpG ORN, in contrast to previously reported respective nucleic acid ligands. These data suggest that CpG ORN represent a novel class of synthetic immunostimulatory nucleic acids with distinct target cells, receptors, and functions from that of previously known immunomodulatory nucleic acids.