Avanti Mini-Extruder (A), Avanti Mini-Extruder internal schematic (B),... | Download Scientific DiagramFig 4 - uploaded by Susanne R Youngren-OrtizContent may be subject to copyright.DownloadView publicationCopy referenceCopy captionEmbed figureAvanti Mini-Extruder (A), Avanti Mini-Extruder internal schematic (B), and Nano DeBEE high-pressure homogenizer (C).  Source publication+2 Aerosol Delivery of siRNA to the Lungs. Part 2: Nanocarrier-based Delivery SystemsArticleFull-text availableJan 2017 Susanne R Youngren-Ortiz Nishant Gandhi Laura España Serrano Mahavir ChouguleIn this article, applications of engineered nanoparticles containing siRNA for inhalation delivery are reviewed and discussed. Diseases with identified protein malfunctions may be mitigated through the use of well-designed siRNA therapeutics. The inhalation route of administration provides local delivery of siRNA therapeutics to the lungs for vario...CiteDownload full-textContext in source publicationContext 1... pressure through dimensionally defined pores, (2) fractionation of a heterogeneous popu- lation by centrifugation or size-exclusion chromatogra- phy, and (3) homogenization to obtain smaller sized liposomes (Bochicchio S. et al., 2014). Examples of extru- sion devices are the Avanti Mini-Extruder and Nano DeBEE high pressure homogenizer shown in Fig. 4. Other mechanical dispersion methods include sonication, freeze-thawed liposomes, lipid-film hydration by shaking or freeze drying, or dried reconstituted vesicles (Çağdaş M. et al., 2014). The non-encapsulated siRNA can be removed by dialysis, ultrafiltration via ultracentrifugation, gel chromatography, and ionic-exchange resins ...View in full-textCitations... The siRNA effi cacy may also be improved via conjugation of small molecules or peptides to the sense strand of siRNA. Many other modifi cations have been revealed to minimize off-target effects, like phosphorothioate or boranophosphate introduction (38,39). ...... This way of delivery has many advantages including ease of preparation and facility of delivery by inhalation, intranasal or intratracheal routes. However, it faces a major problem in cell targeting and uptake and it can be degraded within the airways (39). Lipid-based delivery systems like liposomes or lipid nanoparticles are favored methods especially for inhaled pulmonary delivery. ...... Naked siRNA delivery hav-ing low clinical effi ciency and bioavailability is enhanced with peptide-based delivery vectors. Inorganic-based delivery systems allow for the unique delivery of siRNAs via direct conjugation or non-covalent encapsulation (39). ...Potential therapeutic road for targeting the SARS-CoV-2 at throatArticleFull-text availableJan 2021M. KayaA. M. Abuaisha N. Serakinci S. OzturkIntroduction: Coronavirus disease 2019 (COVID-19) has become a serious public health problem for 183 out of 197 countries in the world. Understanding the routes and pathogenesis of the coronavirus is important and it is considered that the studies on host cell receptor Angiotensin Converting Enzyme 2 (ACE2) may be valuable for the treatment and prevention of the disease.Aim: To evaluate the possibility of inhibition of SARS-CoV-2 at throat.Methods: A comprehensive literature search was conducted.Conclusion: In view of the fact that the mouth and nose have higher number of ACE2 expressed cells, they serve as a gateway for the virus to enter. Thus, blocking the gate could be a good choice to reduce or even prevent the transmission. Small interfering RNAs (siRNAs) are double-stranded RNA molecules and could be designed easily and directed against many strains of a virus. Due to their features, siRNAs can provide a potential strategy to interfere with the replication of viral diseases. We think that since oral and nasal epithelial cells are relatively easily accessible it may allow to develop siRNA molecules to inhibit SARS-CoV-2 already at the entry where it continues to replicate for a period (Fig. 1, Ref. 50).View... Challenges with the development of inhaled RNA therapeutics demonstrate how challenging it is to use this route to effectively deliver RNA molecules in humans. Some recent inhaled RNA therapeutic studies have shown advances in the delivery of RNAi-based drugs to the lungs (reviewed by Youngren-Ortiz et al., 2017;Thanki et al., 2018). However, a common conclusion across these studies is the requirement of the design and development of specifically engineered formulations to safely and effectively deliver the RNAi-based drug. ...... However, a common conclusion across these studies is the requirement of the design and development of specifically engineered formulations to safely and effectively deliver the RNAi-based drug. The engineered molecules must overcome the existing biological barriers, such as degradation by RNase, mucociliary clearance, clearance by impaction and coughing, and alveolar macrophage clearance (Youngren-Ortiz et al., 2017). Adding to that, there is the challenge of developing suitable devices for pulmonary administration of inhalable RNAi-based therapeutic formulations (Thanki et al., 2018). ...Safety Considerations for Humans and Other Vertebrates Regarding Agricultural Uses of Externally Applied RNA MoleculesArticleFull-text availableApr 2020 Thais B. Rodrigues Jay S. PetrickThe potential of double-stranded RNAs (dsRNAs) for use as topical biopesticides in agriculture was recently discussed during an OECD (Organisation for Economic Co-operation and Development) Conference on RNA interference (RNAi)-based pesticides. Several topics were presented and these covered different aspects of RNAi technology, its application, and its potential effects on target and non-target organisms (including both mammals and non-mammals). This review presents information relating to RNAi mechanisms in vertebrates, the history of safe RNA consumption, the biological barriers that contribute to the safety of its consumption, and effects related to humans and other vertebrates as discussed during the conference. We also review literature related to vertebrates exposed to RNA molecules and further consider human health safety assessments of RNAi-based biopesticides. This includes possible routes of exposure other than the ingestion of potential residual material in food and water (such as dermal and inhalation exposures during application in the field), the implications of different types of formulations and RNA structures, and the possibility of non-specific effects such as the activation of the innate immune system or saturation of the RNAi machinery.View... Direct pulmonary delivery also provides a large surface area for medication absorption via alveolar epithelial cells, and size variations in specific nanoparticles can allow for retention in pulmonary alveoli if indicated [75]. Although promising, remaining concerns include potential lung toxicity, decreased absorption by injured lungs, potential removal by lung defense mechanisms, or variable drug stability in aerosolized form [77]. Studies have investigated the effect of inhaled nanotherapy in inflammatory disease [78] pulmonary hypertension [79, 80,] lung infection [81] and lung cancer [82][83][84][85] and the potential benefit of nanotherapy drug administration may be translatable to a model of smoke inhalation injury to improve therapeutic specificity. Recently, Carvalho et al. administered carvacrol, a natural oxyreducing compound, to the lungs after smoke inhalation injury in rats using a solid lipid nanoparticle (SLN) [86]. ...Emerging therapies for smoke inhalation injury: a reviewArticleFull-text availableMar 2020J TRANSL MEDAlexandra Mercel Nick D. Tsihlis Rob MaileMelina R. KibbeBackground: Smoke inhalation injury increases overall burn mortality by up to 20 times. Current therapy remains supportive with a failure to identify an optimal or targeted treatment protocol for smoke inhalation injury. The goal of this review is to describe emerging therapies that are being developed to treat the pulmonary pathology induced by smoke inhalation injury with or without concurrent burn injury.Main body: A comprehensive literature search was performed using PubMed (1995-present) for therapies not approved by the U.S. Food and Drug Administration (FDA) for smoke inhalation injury with or without concurrent burn injury. Therapies were divided based on therapeutic strategy. Models included inhalation alone with or without concurrent burn injury. Specific animal model, mechanism of action of medication, route of administration, therapeutic benefit, safety, mortality benefit, and efficacy were reviewed. Multiple potential therapies for smoke inhalation injury with or without burn injury are currently under investigation. These include stem cell therapy, anticoagulation therapy, selectin inhibition, inflammatory pathway modulation, superoxide and peroxynitrite decomposition, selective nitric oxide synthase inhibition, hydrogen sulfide, HMG-CoA reductase inhibition, proton pump inhibition, and targeted nanotherapies. While each of these approaches shows a potential therapeutic benefit to treating inhalation injury in animal models, further research including mortality benefit is needed to ensure safety and efficacy in humans.Conclusions: Multiple novel therapies currently under active investigation to treat smoke inhalation injury show promising results. Much research remains to be conducted before these emerging therapies can be translated to the clinical arena.View... The most common routes of administration for vaccines are parenteral, notably intra-muscular, intra-dermal or sub-cutaneous. However, there is increasing interest in mucosal routes of administration (Youngren-Ortiz, S.R. et al., 2017). Targeting of M-cells in the nasal mucosa, macrophages and dendritic cells in the lungs, and Peyer s patches in the gastro-intestinal tract have been studied extensively in the last 25 years (Calderon-Nieva D. et al., 2017;Jia Y. et al., 2015;Padilla-Carlin D.J. et al., 2008). ...Nanoparticle Technology for Respiratory Tract Mucosal Vaccine DeliveryArticleJan 2020KONA Leah M. Johnson Jeffrey B. MechamFrederick QuinnAnthony J. HickeyImmunization can be traced back to classical China. Modern immunization reduces the risk of infection by attenuating or killing the pathogen or using non-infectious antigens to elicit the immune response. The challenge of immunization is to raise a robust protective response without infecting the individual or overstimulating the immune response, and this can be achieved by using nanoparticle delivery systems to specifically target the innate immune system with known antigens and where necessary include an adjuvant to enhance the efficacy. These systems can be targeted to mucosal sites that are located throughout the body with the nasal and pulmonary routes of administration allowing ease of access. Macrophages are the first line of defense of the innate immune system and are the host cell for primary intracellular infection by several respiratory pathogens notably mycobacteria and streptococci. The breadth of nanoparticle technology available to deliver vaccines has been explored and consideration of its value in nasal and pulmonary delivery is addressed specifically.Fullsize ImageView... Non-viral vectors used for siRNA complexation.(adapted from409 ) ...Design and direct synthesis of peptide-branched polysiloxane. Towards new generation of hybrid biomaterialsThesisNov 2019Julie MartinThe purpose of this PhD work was the design and synthesis of new hybrid biomaterials based on a polysiloxane backbone. To do so, several biomolecules were silylated, in order to be incorporated in a multifunctional silicone backbone by a bottom-up strategy. Indeed, in contrast to post-grafting approaches, we set up the direct copolymerization of hybrid biomolecule macromonomers presenting a methyldihydroxysilyl moiety, with the dichlorodimethylsilane (DCDMS). Different types of biomolecules have been silylated: peptides, drugs and imaging probes, each of them affording specific properties to the final bioorganic silicone material. Three main applications are described: (i) the design and synthesis of bioactive PDMS cross-linked materials, (ii) silicone-based nanoparticules (NPs) and (iii) silicone-based polyplexes. PDMS materials with biological properties, either antimicrobial or cell adhesion, were obtained by copolymerization of hybrid peptide macromonomer with DCDMS, vinyl and silane reagents followed by hydrosilylation. Silicone-based NPs resulted from the introduction of several hydrophilic macromonomers at 0.5 to 1 mol% compared to DCDMS. Hybrid peptide ligands targeting cancer cell receptors, PEG and a drug model (Methotrexate) were prepared and copolymerized. At last, we investigated the preparation of siRNA polyplexes involving LysHis-based hybrid peptide macromonomers by an in situ polymerization method.View... siRNA contains a sequence that is complementary to a specific protein-coding mRNA and may induce site-specific cleavage, resulting in the inhibition of protein synthesis and suppression of protein expression. 17,18 In addition, the synthesis of siRNA is relatively simple without any necessity of cell expression systems. Therefore, siRNA has important applications to tumor-targeting therapies. ...Antitumor effect of hyaluronic-acid-modified chitosan nanoparticles loaded with siRNA for targeted therapy for non-small cell lung cancerArticleFull-text availableJul 2019Wenhua ZhangWenhua XuYu LanXuliang He Ye LiangWenhua Zhang,1,2,* Wenhua Xu,1,* Yu Lan,3 Xuliang He,1 Kaibin Liu,4 Ye Liang21Department of Inspection, Medical Faculty, Qingdao University, Qingdao 266003, People’s Republic of China; 2Key Laboratory, Department of Urology and Andrology, Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China; 3Department of Inspection, Weihai Central Hospital, Weihai 264400, People’s Republic of China; 4Department of Clinical Medicine, Second Military Medical University, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workPurpose: Nanoparticle (NP)-mediated targeted delivery of therapeutic genes or siRNAs to tumors has potential advantages. In this study, hyaluronic acid (HA)-modified chitosan nanoparticles (CS NPs-HA) loaded with cyanine 3 (Cy3)-labeled siRNA (sCS NPs-HA) were prepared and characterized.Methods: Human non-small cell lung cancer (NSCLC) A549 cells expressing receptor CD44 and tumor-bearing mice were used to evaluate the cytotoxic and antitumor effects of sCS NPs-HA in vitro and in vivo.Results: The results showed that noncytotoxic CS NPs-HA of small size (100–200 nm) effectively delivered the Cy3-labeled siRNA to A549 cells via receptor CD44 and inhibited cell proliferation by downregulating the target gene BCL2. In vivo experiment results revealed that sCS NPs-HA directly delivered greater amounts of Cy3-labeled siRNA to the tumor sites, resulting in the inhibition of tumor growth by downregulating BCL2, as compared to unmodified NPs loaded with siRNA (sCS NPs) and to naked Cy3-labeled siRNA.Conclusion: The HA-modified NPs based on chitosan could serve as a promising carrier for siRNA delivery and targeted therapy for NSCLC expressing CD44.Keywords: nanoparticle, siRNA, CD44, hyaluronic acid, cancerView... Due to the concentration dependent effect of some antibiotics, it is important to have targeted delivery to ensure high concentration only at the affected sites to ensure optimum effects while avoiding side effects. Although small molecules such as antibiotics and airway therapeutics make up the majority of the delivered material, macromolecules such as siRNA have been heavily considered for pulmonary delivery [73]. ...... Antimicrobial delivery via liposomes to the lungs has been shown to be beneficial in the case of cystic fibrosis and exhibits a controlled and sustained release, and some are currently in phase II clinical trials [78]. Studies involving the delivery of macromolecules such as siRNA have also been conducted using nanocarriers, as summarized more in depth elsewhere [73]. ...Carriers for the Targeted Delivery of Aerosolized Macromolecules for Pulmonary PathologiesArticleFull-text availableJul 2018EXPERT OPIN DRUG DEL Nashwa Osman Kan Kaneko Valeria Carini Imran SaleemIntroduction: Macromolecules with unique effects and potency are increasingly being considered for application in lung pathologies. Numerous delivery strategies for these macromolecules through the lung, have been investigated to improve the targeting and overall efficacy.Areas covered: Targeting approaches from delivery devices, formulation strategies and specific targets are discussed.Expert opinion: Although macromolecules are a heterogeneous group of molecules, a number of strategies have been investigated at the macro, micro and nanoscopic scale for the delivery of macromolecules to specific sites and cells of lung tissues. Targeted approaches are already in use at the macroscopic scale through inhalation devices and formulations, but targeting strategies at the micro and nanoscopic scale are still in the laboratory stage. The combination of controlling lung deposition and targeting after deposition, through a combination of targeting strategies could be the future direction for the treatment of lung pathologies through the pulmonary route.View... A delivery vector or carrier is generally necessary to overcome the aforementioned barriers by promoting cellular uptake and offering protection to the RNAi molecules. RNAi delivery system can be categorized into viral and non-viral vectors according to their nature, and these delivery systems have been extensively reviewed [63][64][65][66][67]. ...Delivery of RNAi Therapeutics to the Airways—From Bench to BedsideArticleFull-text availableSep 2016MOLECULES Yingshan Qiu Jenny K W LamSusan W S Leung Wanling LiangRNA interference (RNAi) is a potent and specific post-transcriptional gene silencing process. Since its discovery, tremendous efforts have been made to translate RNAi technology into therapeutic applications for the treatment of different human diseases including respiratory diseases, by manipulating the expression of disease-associated gene(s). Similar to other nucleic acid-based therapeutics, the major hurdle of RNAi therapy is delivery. Pulmonary delivery is a promising approach of delivering RNAi therapeutics directly to the airways for treating local conditions and minimizing systemic side effects. It is a non-invasive route of administration that is generally well accepted by patients. However, pulmonary drug delivery is a challenge as the lungs pose a series of anatomical, physiological and immunological barriers to drug delivery. Understanding these barriers is essential for the development an effective RNA delivery system. In this review, the different barriers to pulmonary drug delivery are introduced. The potential of RNAi molecules as new class of therapeutics, and the latest preclinical and clinical studies of using RNAi therapeutics in different respiratory conditions are discussed in details. We hope this review can provide some useful insights for moving inhaled RNAi therapeutics from bench to bedside.ViewFuture of nanomedicines for treating respiratory diseasesArticleJan 2019EXPERT OPIN DRUG DEL Regina ScherließIntroduction: Nanoparticles are under discussion in drug delivery for more than 20 years now, but examples for nanoparticulate formulations in the treatment of respiratory diseases are rare and mostly limited to the administration of sub-micron drug particles (ultrafine particles). However, nanoparticles may also carry specific benefits for respiratory treatment. Are nanoparticles the next-generation drug carrier system to facilitate systemic delivery, sustained release and cancer treatment in the lungs?Areas covered: This review will look into the promises and opportunities of the use of nanoparticles in the treatment of respiratory diseases. Important aspects to discuss are the fate of nanoparticles in the lung and mechanisms for reproducible delivery of nanoparticulate formulations to the lungs. Examples are given where nanoparticles may be advantageous over for traditional formulations and further aspects to explore are mentioned.Expert opinion: The benefit of nanoparticulate systems for respiratory delivery adds to the portfolio of possible formulation strategies, depends on the intended functionality and needs more exploration. Advantages of such systems are only seen in special cases.ViewThe potential of siRNA based drug delivery in respiratory disorders: Recent advances and progressArticleMar 2019DRUG DEVELOP RES Kamal Dua Ridhima WadhwaGautam SinghviVamshikrishna RapalliChellappanLung diseases are the leading cause of mortality worldwide. The currently available therapies are not sufficient, leading to the urgent need for new therapies with sustained anti‐inflammatory effects. Small/short or silencing interfering RNA (siRNA) has potential therapeutic implications through post‐transcriptional downregulation of the target gene expression. siRNA is essential in gene regulation, so is more favorable over other gene therapies due to its small size, high specificity, potency, and no or low immune response. In chronic respiratory diseases, local and targeted delivery of siRNA is achieved via inhalation. The effectual delivery can be attained by the generation of aerosols via inhalers and nebulizers, which overcomes anatomical barriers, alveolar macrophage clearance and mucociliary clearance. In this review, we discuss the different siRNA nanocarrier systems for chronic respiratory diseases, for safe and effective delivery. siRNA mediated pro‐inflammatory gene or miRNA targeting approach can be a useful approach in combating chronic respiratory inflammatory conditions and thus providing sustained drug delivery, reduced therapeutic dose, and improved patient compliance. This review will be of high relevance to the formulation, biological and translational scientists working in the area of respiratory diseases.ViewShow moreGet access to 30 million figuresJoin ResearchGate to access over 30 million figures and 135+ million publications – all in one place.Join for freeAdvertisementJoin ResearchGate to find the people and research you need to help your work.20+ million members135+ million publications700k+ research projectsJoin for free orDiscover by subject areaRecruit researchersJoin for freeLoginEmail Tip: Most researchers use their institutional email address as their ResearchGate loginPasswordForgot password? Keep me logged inLog inorContinue with GoogleWelcome back! Please log in.Email · HintTip: Most researchers use their institutional email address as their ResearchGate loginPasswordForgot password? Keep me logged inLog inorContinue with GoogleNo account? 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