Current Pharmaceutical Design - Volume 24, Issue 23, 2018

RNA interference (RNAi), as a novel technique in which RNA molecules limit or silence the gene expression, is currently a hot research topic for producing novel therapeutic materials for challenging diseases. In the development of RNAi-based therapies, nanoscale particles, with a varying diameter along with facile modification methods that can mediate effective RNAi with targeting potential, are gaining wide interest. The nanotechnology itself has tremendous potential in the field of healthcare, especially for the development of better pharmaceuticals. Nano-enabled delivery has shown great success in the delivery of RNAi based therapeutics to specific locations in the body. Especially, siRNAs show great potential for use in nucleic acid therapeutics because of their potent and specific RNAi-triggering activity. This review summarizes the advanced nanocarriers such as solid lipid nanoparticles, gold nanoparticles, silver nanoparticles, iron oxide nanoparticles, polymeric nanoparticles, nanotransformers and curdlan nanoparticles with special emphasis on various aspects of siRNA-based therapeutics.

Background: Gene therapy is a new approach to discover and treat many diseases. It has attracted considerable attention from researchers in the last decades. The gene therapy through RNA interference has been considered one of the most recent and revolutionary approaches used in individualized therapy. In the last years, we have witnessed the rapid development in the field of the gene silencing and knockdown by topical siRNA. Its application in gene therapy has become an attractive alternative for drug development. Methods: This article will address topical delivery of siRNA as a promising treatment for skin disorders. An update on the advances in siRNA-based nanocarriers as a powerful therapeutic strategy for several skin diseases will be discussed giving emphasis on in vitro evaluations. Results: Through the in-depth review of the literature on the use of siRNAs for skin diseases we realize how widespread this use is. We have also realized that nanoparticles as non-viral vectors are increasingly being explored. Skin diseases where the use of siRNA has been explored most are skin cancer (melanoma and nonmelanoma), psoriasis, vitiligo, dermatitis and leprosy. But we also report here other diseases where the use of siRNA has been growing as acne, alopecia areata, cutaneous leishmaniasis, mycoses, herpes, epidermolysis bullosa and oculocutaneous albinism. Also highlighted, the first clinical trial of siRNA for cutaneous diseases, aimed at Pathyounychia Congenita. Conclusion: The treatment of skin diseases based on topical delivery of siRNA, which act by inhibiting the expression of target transcripts, offers many potential therapeutic advantages for suppressing genes into the skin.

Background: RNA interference is a promising therapeutic tool for the treatment of a variety of diseases, with great potential for cancer therapy. Small interfering RNA (siRNA), however, presents several drawbacks that hamper its therapeutic application. Lipid nanoparticles, including liposomes, are delivery systems with great potential for siRNA delivery, protecting it from degradation, enhancing its cell uptake with the ability of controlled release. However, non-specific delivery and side effects could potentially limit the in vivo application. Therefore, targeting lipid nanoparticles to overexpressed receptors of cancer cells represents a strategy for better therapeutic outcome, with improved efficacy and reduced toxicity. For this purpose, lipid nanoparticles could be functionalized with several moieties that can be recognized by cancer cells more than by normal cells. These ligands include folate, transferrin, peptides, oligosaccharides, monoclonal antibodies and aptamers. Methods: In this paper, we reviewed functionalization strategies and addressed the major in vitro and in vivo findings in the field of cancer treatment with siRNA. Results: Many papers showed enhanced siRNA delivery by targeted liposomes, resulting in enhanced drug uptake and better cytotoxicity, with consequent better tumor growth control in xenograft studies. Conclusion: siRNA delivery mediated by functionalized liposomes is promising, but clinical trials need to be conducted.

Background: RNA interference (RNAi)-based therapy has gained attention because of its potent genesilencing effect and high specificity. However, the efficient delivery of nucleic acids to the target site is a major challenge to the clinical implementation. Recently, ultrasound-mediated gene delivery systems have been developed and attracted interest due to its safety and site-specificity. By the combination with contrast agents, called microbubbles, not only the delivery effects but also the imaging effects are significantly enhanced. We developed lipid bubbles (LBs) entrapping an ultrasound contrast gas to enhance the efficacy of ultrasound-mediated delivery and imaging. In this review, we summarize ultrasound-mediated nucleic acid delivery systems and discuss the possibility of combining LBs and ultrasound for RNAi-based therapies. Methods: We prepared polyethylene glycol-modified liposomes and entrapped an echo-contrast gas within the liposomes. Small interfering RNA (siRNA) were transfected into cells and muscles using LBs and ultrasound. Moreover, we also developed nucleic acid-loaded LBs using cholesterol-conjugated siRNA or positively-charged lipid for an efficient systemic delivery of siRNA and microRNA. The usability of LBs for RNA delivery system was evaluated by the silencing effects of target genes and the therapeutic effects on ischemia hind limb. Results: A combination of LBs and therapeutic ultrasound was able to enhance the gene silencing effects by siRNA. Nucleic acid-loaded LBs were able to efficiently deliver siRNA or microRNA by systemic administration. A combination of LBs and diagnostic ultrasound also enhanced the imaging efficiency. Using a hindlimb ischemia mouse model, microRNA-loaded LBs could lead to increased angiogenic factors and improved blood flow. Conclusion: Ultrasound technology is widely used in clinical settings not only for diagnosis but also for therapy. Ultrasonic devices are being actively developed. Computer-controlled ultrasound systems can provide precise exposure to the target site. The combination of precise ultrasound exposure and LBs might be useful for target site-specific nucleic acids delivery, and holds potential to be developed into a beneficial therapeutic and diagnostic system for various diseases.

Background: The search for the effective treatment strategies to combat a disease that is characterized by abnormal cell growth and known as cancer is still required to reach its destiny. To address the problem, recently several gene therapies based on novel RNA interference (RNAi) have been proposed such as siRNA, micro RNA, shRNA, etc. out of which, siRNAs (silencing RNA) promises to show significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility of treating cancer. Methods: This review aims to uncover the hyaluronic acid (HA) and HA-hybridized nanoplatforms for siRNA delivery systems with a particular focus on the discussion of available reports while addressing the future potential of HA-based treatment strategies. Results: HA modified siRNA delivery, as promised, provided better targeting potential in many types of cancers. In addition, it was able to modify the release of siRNA as well. Toxicity of HA is well mentioned however, the loophole is yet to be filled by exploring various remedies for overcoming toxicity. Conclusion: To overcome the problems associated with these emerging genetic tools, investigators have employed glycosaminoglycan HA-based biopolymers. This biopolymer offers a variety of properties such as biodegradability, biocompatibility, aqueous solubility, viscoelasticity, and non-immunogenicity.

Background: Ischaemia-reperfusion injury (IRI), a major complication occurring during organ transplantation, involves an initial ischemia insult, due to loss of blood supply, followed by an inflammation-mediated reperfusion injury. A variety of molecular targets and pathways involved in liver IRI have been identified. Gene silencing through RNA interference (RNAi) by means of small interference RNA (siRNA) targeting mediators of IRI is a promising therapeutic approach. Objective: This study aims at reviewing the use of siRNAs as therapeutic agents to prevent IRI during liver transplantation. Method: We review the crucial choice of siRNA targets and the advantages and problems of the use of siRNAs. Results: We propose possible targets for siRNA therapy during liver IRI. Moreover, we discuss how drug delivery systems, namely liposomes, may improve siRNA therapy by increasing siRNA stability in vivo and avoiding siRNA off-target effects. Conclusion: siRNA therapeutic potential to preclude liver IRI can be improved by a better knowledge of what molecules to target and by using more efficient delivery strategies.

Colorectal Cancer (CRC) is one of the most common cancers with a high rate of morbidity and mortality worldwide. It has been demonstrated that epigenetic alterations which may cause changes in the expression of microRNA, DNA methylation and histone acetylation that results in inheritable modifications in gene expression in colorectal epithelial cells, plays a crucial role in the development of CRC. Recently, targeting epigenetic modification has emerged as a potentially important treatment approach in CRC. The US Food and Drug Association has approved the use of some epigenetic drugs that may be able to inhibit or reverse these alterations and also enhance sensitivity to chemotherapeutic agents and radiotherapy in CRC. In this review we have summarized the recent pre-clinical and clinical trial studies investigating the therapeutic value of using epigenetic drugs as novel therapeutic approach in CRC treatment.

Inter-individual differences in drug response are an important cause of failure in anticancer treatment and adverse drug events in cancer patients. Gene polymorphisms related to these outcomes have been investigated in an effort to find new genetic biomarkers to predict toxicity and response to anticancer drugs. Evaluating the value single nucleotide polymorphisms (SNPs) in the genes involved in transportation, activation and metabolism of anticancer drugs provides a promising approach to select the appropriate therapeutic regimes with at least adverse reactions. This review summarizes the current knowledge about the relationship between of SNPs involved in the transportation, activation and metabolism of anticancer drugs and treatment outcomes in colorectal cancer (CRC) patients.

Gold nanoparticles (AuNPs) are promising biomedical agents in terms of both imaging and therapy, exhibiting excellent physical and chemical characteristics. The actions of AuNPs can be remotely controlled using strong near-infrared (NIR) light, associated with minimal lateral invasion. Employing the photoacoustic (PA) principle, AuNPs integrate imaging and temperature control, affording both diagnosis and treatment mediated by NIR light. We here review recent progress in the theranostic field employing AuNPs to both PA and photothermal ends.

Background and objective: Oxidative stress and inflammation are key parameters in developing metabolic disorders. Hence, antioxidant intake might be an appropriate approach. Several studies have evaluated the effect of coenzyme Q10 (CoQ10) supplementation on lipid profile among patients with metabolic diseases, though findings are controversial. The aim of this systematic review and meta-analysis was to determine the effects of CoQ10 supplementation on lipid profile in patients with metabolic disorders. Methods: We searched PubMed, EMBASE, Web of Science and Cochrane Library databases until July 2017. Prospective clinical trials were selected assessing the effect of CoQ10 supplementation on different biomarkers. Two reviewers independently assessed the eligibility of studies, extracted data, and evaluated the risk of bias of included studies. A fixed- or random-effects model was used to pool the data, which expressed as a standardized mean difference with 95% confidence interval. Heterogeneity was measured using a Q-test and with I2 statistics. Results: A total of twenty-one controlled trials (514 patients and 525 controls) were included. The meta-analysis indicated a significant reduction in serum triglycerides levels (SMD -0.28; 95% CI, -0.56, -0.005). CoQ10 supplementation also decreased total-cholesterol (SMD -0.07; 95% CI, -0.45, 0.31), increased LDL- (SMD 0.04; 95% CI, -0.27, 0.36), and HDL-cholesterol levels (SMD 0.10; 95% CI, -0.32, 0.51), not statistically significant. Conclusion: CoQ10 supplementation may significantly reduce serum triglycerides levels, and help to improve lipid profiles in patients with metabolic disorders. Additional prospective studies are recommended using higher supplementation doses and longer intervention period.

Background: Patients treated with antithrombotic therapy that require abdominal surgical procedures have progressively increased over time. The management of antithrombotics during both the peri- and postoperative period is of crucial importance. Methods: The goal of this review is to present current data concerning the management of antiplatelets in patients with coronary artery disease and of anticoagulants in patients with atrial fibrillation who had to undergo abdominal surgical operations. For this purpose, the incidence of major adverse cardiovascular events (MACE) and risk of antithrombotic use during surgical procedures, as well as the recommendations based on recent guidelines were reported. A thorough search of PubMed, Scopus and the Cochrane Databases was conducted to identify randomized controlled trials, observational studies, novel current reviews, as well as ESC and ACC/AHA guidelines on the subject. Results: Antithrombotic use in daily clinical practice leads to two different pathways: reduction of thromboembolic risk, but a simultaneous increase of bleeding risk. This may cause a therapeutic dilemma during the perioperative period. Nevertheless, careless cessation of antithrombotics can increase MACE and thromboembolic events. However, maintenance of antithrombotic therapy may increase bleeding complications. Studies and current guidelines can help clinicians in making decisions for the treatment of patients that undergo abdominal surgical operations while on antithrombotic therapy. Aspirin should not be stopped perioperatively in the majority of surgical operations. Determining whether to discontinue the use of anticoagulants before surgery depends on the surgical procedure. In surgical operations with a low risk for bleeding, oral anticoagulants should not be discontinued. Bridging therapy should only be considered in patients with a high risk of thromboembolism. Finally, in patients with an intermediate risk for thromboembolism, management should be individualized according to patient's thrombotic and bleeding risk. Conclusion: Management of antithrombotics therapy during the perioperative period in patients undergoing abdominal surgery should follow a patient-centered approach according to a patient's medical history and thrombotic risk weighted for bleeding risk.