MicroRNAs as therapeutic targets and their potential applications in cancer therapy

INTRODUCTION: The results of cancer-associated miRNA research have yielded surprising insights into the pathogenesis of a range of different cancers. Many of the dysregulated miRNAs are involved in the regulation of genes that are essential for carcinogenesis. AREAS COVERED: This review discusses the latest discovery of miRNAs acting as oncogenes and tumor suppressor genes, as well as the potential applications of miRNA regulations in cancer therapy. Several translational studies have demonstrated the feasibility of targeting oncogenic miRNAs and restoring tumor-suppressive miRNAs for cancer therapy using in vivo model systems. EXPERT OPINION: miRNAs are extensive regulators of cancer progression. With increasing understanding of the miRNA target genes and the cellular behaviors influenced by them, modulating the miRNA activities may provide exciting opportunities for cancer therapy. Despite the hurdles incurred in acquiring effective systemic drug delivery systems, in vivo delivery of miRNAs for therapeutic purposes in preclinical animal models is rapidly developing. Accumulating evidences indicate that using miRNA expression alterations to influence molecular pathways has the potential of being translated into clinical applications.     

Nanoparticle-mediated delivery of therapeutic genes: focus on miRNA therapeutics

Introduction: Micro RNAs (miRNA) are 21 – 23 nucleotides long and regulate the expression of coding genes by binding imperfectly with their 3′ UTR region. The miRNA profile is altered in pathological processes, making miRNAs good targets for drug therapy. Restoration of down-regulated miRNA or inhibition of overexpressed miRNA to return miRNA to its normal state is the basis of miRNA-based therapy. This review focuses on nanocarriers used for the delivery of miRNA that confer physical stability to the unstable RNA structure, protect the RNA from nuclease degradation and aid in effective silencing of target genes.

Areas covered: The necessity of the nanocarrier for the delivery of the miRNA is emphasized and the recent research on liposome-, metal- and polymer-mediated miRNA delivery for the inhibition or replacement of the disease-related miRNA is summarized.

Expert opinion: The size, charge and surface properties of nanocarriers have to be tuned to ensure effective and safe delivery of the miRNA in clinical practice. The immune responses related to the nanocarriers and the double-stranded nucleotide delivery remain to be addressed. Also, the binding of miRNAs to non-specific targets has to be studied in more detail because miRNAs have multiple targets due to partial binding unlike siRNA.     

MicroRNA-targeted therapeutics for lung cancer treatment

Introduction: Lung cancer is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that repress the expression of a broad array of target genes. Many efforts have been made to therapeutically target miRNAs in cancer treatments using miRNA mimics and miRNA antagonists.

Areas covered: This article summarizes the recent findings with the role of miRNAs in lung cancer, and discusses the potential and challenges of developing miRNA-targeted therapeutics in this dreadful disease.

Expert opinion: The development of miRNA-targeted therapeutics has become an important anti-cancer strategy. Results from both preclinical and clinical trials of microRNA replacement therapy have shown some promise in cancer treatment. However, some obstacles, including drug delivery, specificity, off-target effect, toxicity mediation, immunological activation and dosage determination should be addressed. Several delivery strategies have been employed, including naked oligonucleotides, liposomes, aptamer-conjugates, nanoparticles and viral vectors. However, delivery remains a main challenge in miRNA-targeting therapeutics. Furthermore, immune-related serious adverse events are also a concern, which indicates the complexity of miRNA-based therapy in clinical settings.     

MicroRNAs as potential drug targets for therapeutic intervention in colorectal cancer

Introduction: MicroRNAs (miRNAs) are small (19 – 22 nucleotide), non-protein-coding RNA segments that function as master regulators of hundreds of genes simultaneously in both normal and malignant cells. In colorectal cancer (CRC) miRNAs are deregulated and have critical roles in initiation and progression of CRC by interacting with various oncogenes and tumor suppressor genes including APC, KRAS and p53, or by modulating downstream signal transduction pathways. Numerous promising miRNAs have emerged as potential drug targets for therapeutic intervention and possible candidates for replacement therapy in CRC.

Areas covered: In this review the authors summarize the available information on miRNAs and their role in CRC. The authors point out specific miRNAs as potential drug targets and those having a significant role in gene activation and gene silencing during the process of CRC development, to highlight their importance as possible therapeutic candidates for the treatment of CRC.

Expert opinion: Targeting miRNAs provides an emerging opportunity to develop effective miRNA-based replacement therapy or antagonists to alter expression in colon cancer patient tumors. However, the biggest challenge is to overcome obstacles associated with pharmacokinetics, delivery and toxicity in order to translate the potential of miRNAs into efficacious anticancer drugs.     

Let-7 microRNA as a potential therapeutic target with implications for immunotherapy

ABSTRACT

Introduction: MicroRNAs (miRNA) are a class of small non-coding RNA that play a major role in various cellular processes by negatively regulating gene expression. In the past decade, miRNA dysregulation has been reported to be closely linked to inflammatory diseases. The immune response modulates cancer initiation and progression; miRNAs including let-7 family members have been shown to act as key regulators of the immune responses in various diseases and cancers. Notably, the let-7 miRNA has been reported to be closely associated with immunity, specifically with Toll-like receptors that mediate cytokine expression during pathogen infection and with the regulation of various other immune effectors.

Areas covered: In this review, the authors describe the discovery of let-7 as the starting point of the RNA revolution and highlight let-7 as an efficient tool for cancer and immune therapy.

Expert opinion: let-7 miRNA has emerged as a key player in cancer therapy and immune responses and it has potential role as a new immunotherapeutic target. However, while there are challenges regarding miRNA delivery, the exciting emergence of personalized medicine for cancer and immunotherapy could be beneficial for the development of let-7 therapeutics.     

Drug delivery/imaging multifunctionality of mesoporous silica-based composite nanostructures

Introduction: Biocompatible mesoporous silica nanoparticles (MSNs) are regarded as one of the most promising inorganic drug delivery systems (DDSs) to concurrently enhance the therapeutic efficiency and mitigate the side effects of anticancer drugs. Elaborately combining multicomponents with MSNs will endow them with specific functionalities for cancer therapy and diagnosis, such as targeted drug delivery, intelligent on-demand drug releasing, synergistic therapy, diagnostic imaging and so on.

Areas covered: This review discusses the state-of-the-art potential obstacles and further perspectives of the chemical design/synthesis, in vitro/in vivo pharmaceutical evaluations and potential clinical translations of multifunctional mesoporous silica-based nanomaterials for biotechnological and biomedical applications, especially against cancer. These topics cover the years from 2001 to 2013.

Expert opinion: Through the comprehensive evaluations of the biosafety and pharmaceutical efficiency, elaborately designed/fabricated mesoporous silica-based composite nanoparticles show great potentials in clinical applications for efficient diagnostic imaging and chemotherapy of cancer.     

Targeting miR-375 in gastric cancer

Introduction: Gastric cancer remains a major cancer burden in the world, with a poor 5-year survival rate. It is necessary to develop new effective therapeutic strategies to improve the long-term clinical outcome. MicroRNA (miRNA), a class of small non-coding RNA, has been identified as a key regulator of gene expression, and is implicated in the pathogenesis of gastric cancer.

Areas covered: This review summarizes the role of miRNAs in gastric carcinogenesis, with an emphasis on the expression and function of miR-375 in gastric cancer and beyond. It also discusses the opportunities and challenges of miR-375 as a potential therapeutic target for gastric cancer. The genes targeted by miR-375, including JAK2 and 3′-phosphoinositide dependent protein kinase-1 (PDK1), are also candidates for gastric cancer therapy.

Expert opinion: Although radical surgery and rational chemotherapy are still the main treatment for gastric cancer, targeting miRNAs, in combination with other conventional therapies, may serve as a promising therapy strategy to improve the clinical outcome.     

Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer

Introduction: Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer.

Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications.

Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.     

Recent progress in microRNA delivery for cancer therapy by non-viral synthetic vectors

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Because of significant changes in their expression in cancer, miRNAs are believed to be key factors in cancer genetics and to have potential as anticancer drugs. However, the delivery of miRNAs is limited by many barriers, such as low cellular uptake, immunogenicity, renal clearance, degradation by nucleases, elimination by phagocytic immune cells, poor endosomal release, and untoward side effects. Nonviral delivery systems have been developed to overcome these obstacles. In this review, we provide insights into the development of non-viral synthetic miRNA vectors and the promise of miRNA-based anticancer therapies, including therapeutic applications of miRNAs, challenges of vector design to overcome the delivery obstacles, and the development of miRNA delivery systems for cancer therapy. Additionally, we highlight some representative examples that give a glimpse into the current trends into the design and application of efficient synthetic systems for miRNA delivery. Overall, a better understanding of the rational design of miRNA delivery systems will promote their translation into effective clinical treatments.     

The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas

Introduction: Many RNA species have been identified as important players in the development of chronic diseases including cancer. Certain classes of regulatory RNAs such as microRNAs (miRNAs) have been investigated in such detail that bona fide tumor suppressive and oncogenic miRNAs have been identified. Because of this, there has been a major effort to therapeutically target these small RNAs. One in particular, a liposomal formulation of miR-34a (MRX34), has entered Phase I trials.

Areas covered: This review aims to summarize miRNA biology, its regulation within normal versus disease states and how it can be targeted therapeutically, with a particular emphasis on miR-34a. Understanding the complexity of a single miRNA will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases.

Expert opinion: The potential of miRNAs to be developed into anti-cancer therapeutics has become an increasingly important area of research. miR-34a is a tumor suppressive miRNA across many tumor types through its ability to inhibit cellular proliferation, invasion and tumor sphere formation. miR-34a also shows promise within certain in vivo solid tumor models. Finally, as miR-34a moves into clinical trials it will be important to determine if it can further sensitize tumors to certain chemotherapeutic agents.     

Reversing epigenetic mechanisms of drug resistance in solid tumors using targeted microRNA delivery

ABSTRACT

Introduction: Tumor cells utilize many different mechanisms to desensitize themselves to the cytotoxic effects of drugs, but it has recently been recognized that alterations in epigenetic control of gene expression underly many of them. As master regulators of gene expression, microRNAs (miRNAs) present a promising therapeutic strategy for the reversal of epigenetic changes that lead to drug resistance phenotypes in tumor cells.

Areas covered: Effects of epigenetic changes on drug resistance in a variety of solid tumors are discussed. Specific miRNAs that are involved with the regulation of epigenetic machinery are highlighted. Further, we consider how delivery of miRNA or antagomirs may be utilized to resensitize drug-resistant tumor cells.

Expert opinion: Reversal of epigenetically controlled tumor drug resistance mechanisms via miRNA delivery presents a novel strategy for enhancing the efficacy of chemotherapeutics. Further, the ability to target delivery of miRNAs may provide the opportunity to go beyond reversal of resistance to hyper-sensitization of tumor cells to the cytotoxic effects of drugs. However, understanding of the role of miRNA in epigenetic regulation is still in its early stages and further research is critical for potential utility in improving therapeutic efficacy in cancer patients.     

MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1

Objectives: We aimed to analyze the differentially-expressed miRNAs in colon cancer cells in order to identify novel potential biomarkers involved in cancer cell resistance.

Design and methods: We investigated the miRNA expression profile of GEO human colon carcinoma cells, sensitive to the EGFR inhibitor Cetuximab (CTX) and their CTX-resistant counterpart (GEO CR) by using a miRNA chip.

Results: We found 27 upregulated and 10 downregulated miRNAs in GEO CR compared with GEO cells with a fold change ≥ 2. Among the upregulated miRNAs, we focused on miR-199a-5p and miR-375. We report that their enforced expression promotes CTX resistance, whereas their silencing sensitizes to the same drug. The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Conclusion: This study proposes miR-199a-5p and miR-375 as contributors to CTX resistance in colon cancer and suggests a novel approach based on miRNAs as tools for the therapy of this tumor.     

Targeting miRNAs in osteoblast differentiation and bone formation

Importance of the field: Bone tissue arises from mesenchymal stromal cells (MSCs) differentiated into the osteoblast lineage by genetic and epigenetic mechanisms. Emerging evidence indicates that the class of small non-coding single-stranded RNAs known as “microRNAs (miRNAs)” also plays a critical role in this process.

Areas covered in this review: In this short review, we summarize the biology and functional mechanisms of miRNAs. Importantly, we discuss miRNA expression, miRNA function, miRNA target prediction, miRNA overexpression and inhibition methods applied in osteoblastogenesis.

What the reader will gain: We discuss the potential therapeutic opportunities and challenges for improving the treatment of bone-related diseases by using miRNAs as a therapeutic target.

Take home message: Although various microRNAs regulate cell proliferation and differentiation, only a few miRNAs has been reported so far to play a key role in the regulation of osteoblast differentiation and bone formation.     

Electrostatic surface modifications to improve gene delivery

Importance of the field: Gene therapy has the potential to treat a wide variety of diseases, including genetic diseases and cancer.

Areas covered in this review: This review introduces biomaterials used for gene delivery and then focuses on the use of electrostatic surface modifications to improve gene delivery materials. These modifications have been used to stabilize therapeutics in vivo, add cell-specific targeting ligands, and promote controlled release. Coatings of nanoparticles and microparticles as well as non-particulate surface coatings are covered in this review. Electrostatic principles are crucial for the development of multilayer delivery structures fabricated by the layer-by-layer method.

What the reader will gain: The reader will gain knowledge about the composition of biomaterials used for surface modifications and how these coatings and multilayers can be utilized to improve spatial control and efficiency of delivery. Examples are shown for the delivery of nucleic acids, including DNA and siRNA, to in vitro and in vivo systems.

Take home message: The versatile and powerful approach of electrostatic coatings and multilayers will lead to the development of enhanced gene therapies.     

Strategies to deliver microRNAs as potential therapeutics in the treatment of cardiovascular pathology

Context: MicroRNAs (miRNAs) are important and powerful mediators in a variety of diseases including cardiovascular pathology. Thus, they emerged as interesting new drug targets. However, it is important to develop efficient transfer tools to successfully deliver miRNAs or antisense oligonucleotides (antagomirs) to the target tissue.

Objective: The aim of this study was to review the scientific literature on delivery techniques currently used for transfer of miRNAs and antagomirs to animal models of cardiovascular disease and those that are likely to be used for therapeutic miRNA transport in the nearest future.

Methods: The research was carried out by consulting the following medical websites: Medicus Medline Index, PubMed (National Library of Medicine), and a registry database of clinical trials conducted in USA (www.clinicaltrials.gov). The selection gathers articles written in English, published from January 2012.

Results: A current delivery technique includes chemical modification of antagomirs with 2-O-methyl-group or 2-O-methyoxyethyl or using locked nucleic acids to increase drug stability and affinity. Development of miRNA sponges/decoys aims to target all members of a miRNA seed family of interest. A further strategy to augment miRNA levels is to use miRNA delivery through viral-based vectors including adenoviruses, adeno-associated viruses, and lentiviruses. To date, a variety of nanocarriers is available for efficient delivery of miRNAs. Microvesicles, and apoptotic bodies that contain circulating miRNAs could be also used as therapeutic transport systems in the nearest future.

Conclusion: Development of new miRNA carrier systems with advanced properties and large animal data in the cardiovascular field is highly recommended.     

Glycogen phosphorylase inhibitors: a patent review (2013 - 2015)

Introduction: Control of glycemia is crucial in the treatment of type 2 diabetes complications. Glycogen phosphorylase (GP) releases glucose from the liver into the blood stream. Design of potent GP inhibitors is a therapeutic strategy in the context of type 2 diabetes.

Areas covered: Glucose-based inhibitors have found potential applications since they now reach low nanomolar K_i values. Another set of patents disclose cholic acid/7-aza-indole conjugates for targeted drug delivery to the liver. A series of benzazepinones have also been reported as potent GP inhibitors. In vitro data are reported for GP inhibition but the in vivo biological data at the cellular or animal levels are often missing, even though the literature reported for these molecules is also discussed.

Expert opinion: A structural analogy between glucose-based GP inhibitors and C-glucosides targeting sodium glucose co-transporter 2 (SGLT2) is intriguing. Cholic acid/7-aza-indole conjugates are promising in vivo drug delivery systems to the liver. Benzazepinones were very recently described and no associated literature is available, making it very difficult to comment at present. While industry has slowed down on GP inhibitors design, academic groups are pursuing investigations and have provided potential drug candidates which will resuscitate the interest for GP, including its potential for targeting cancer.     

Cationic nanoparticles for cancer therapy

Importance of the field: The lack of selective delivery of therapeutic molecules to cancer cells remains a problem in cancer therapy. As a result of this non-selectivity, cytotoxic agents are delivered to both healthy and cancerous cells, resulting in severe side effects for the patient, eventually causing termination of therapy or ineffective therapy resulting in progression or recurrence of the disease. In this context, cationic polymers with net positive surface charge emerge as a promising option owing to their very strong cellular interaction properties and good cellular uptake.

Areas covered in this review: In this review, the structure, characteristics and preparation techniques for cationic nanoparticulate drug delivery systems are discussed in the light of cytotoxicity associated with cationic polymers and strong complement activation properties of cationic carrier systems on injection. In vivo behavior and biodistribution of cationic nanoparticles are also reviewed for a better understanding of biological interaction of cationic nanoparticles.

What the reader will gain: This review will give an insight to the properties of cationic polymers, including their advantages and drawbacks and drug/gene delivery systems based on cationic polymers intended for cancer therapy.

Take home message: Cationic polymer-based nanoparticles emerge as a promising group of nanosize carrier systems to the tumor cell level with a wide range of modification and application possibilities.     

Utilizing adenovirus vectors for gene delivery in cancer

Introduction: Adenovirus (Ad) is a promising candidate vector for cancer gene therapy because of its unique characteristics, which include efficient infection, high loading capacity and lack of insertional mutagenesis. However, systemic administration of Ad is hampered by the host's immune response, hepatocytoxicity, short half-life of the vector and low accumulation at the target site. For these reasons, clinical applications of Ad are currently restricted.

Areas covered: In this review, we focus on recent developments in Ad nanocomplex systems that improve the transduction and targeting efficacy of Ad vectors in cancer gene therapy. We discuss the development of different Ad delivery systems, including surface modification of Ad, smart Ad/nanohybrid systems and hydrogels for sustained release of Ad.

Expert opinion: The fusion of bioengineering and biopharmaceutical technologies can provide solutions to the obstacles encountered during systemic delivery of Ads. The in vivo transgene expression efficiency of Ad nanocomplex systems is typically high, and animal tumor models demonstrate that systemic administration of these Ad complexes can arrest tumor growth. However, further optimization of these smart Ad nanocomplex systems is needed to increase their effectiveness and safety for clinical application in cancer gene therapy.