RNA Nanotechnology for Next Generation Targeted Drug Delivery

The emerging field of RNA nanotechnology is developing into a promising platform for therapeutically application. Utilizing the state-of-art RNA nanotechnology, RNA nanoparticles can be designed and constructed with controllable shape, size for both RNA therapeutics and chemical drug delivery. The high homogeneity in particle size and ease for RNA therapeutic module conjugation, made it feasible to explore versatile RNA nanoparticle designs for preclinical studies. One vital module for therapeutic RNA nanoparticle design is RNA aptamer, which can enable the RNA nanoparticles find its specific target for targeted drug delivery. A system of screening divalent RNA aptamers for cancer cell targeting was developed. The system utilized a highly stable three way junction (3WJ) derived from phi29 bacteriophage packing RNA (pRNA). Instead of using one random loop for aptamer SELEX as traditionally, the divalent RNA nanoparticle library contains two variable loops for substrate binding, similar to protein antibodies. The presence of two binding sites on one aptamer greatly enhanced its affinity, and the thermodynamically stability of pRNA-3WJ motif enables controllable RNA folding of each loop. The selected RNA antibody against epithelial adhesion molecule (EpCAM) A9-8 can deliver therapeutic anti-miR21 to EpCAM positive cancer cells in vitro. The feasibility of using RNA aptamer for targeted chemical drug delivery is explored. A phosphorothioate bond modified DNA (thio-DNA) aptamer targeting annexin A2 was utilized as ligand to build nucleic acid nanoparticles for ovarian cancer targeted drug delivery. A DNA/RNA hybrid nanoparticle was generated by conjugating the thio-DNA aptamer to pRNA-3WJ motif. The DNA/RNA hybrid nanoparticles showed favorable property for delivering doxorubicin to ovarian cancer cells in vitro, also targeted to ovarian cancer xenograft in bio-distribution study in vivo. Utilizing the spatial orientation of pRNA-3WJ, cholesterol modification on the arrow tail of pRNA-3WJ can display RNA nanoparticle on the surface of exosomes/extracellular vesicles (EV) for active targeting. Taking the advantage of RNA ligand for specific targeting; and exosome for efficient membrane fusion, cytosol homing and functional siRNA delivery; the RNA ligand decorated exosomes were constructed for specific delivery of siRNA to cancer cells. PSMA aptamer-displaying exosomes and encapsulated survivin siRNA (PSMAapt/EV/siSurvivin) showed efficient gene silencing both in cell culture and animal trials. After systemically injection of PSMAapt/EV/siSurvivin to prostate cancer xenograft mice, cancer growth was almost completely blocked. These results suggest the advance of RNA nanotechnology can further drive its way towards clinical application as a novel next generation drug delivery system

New Approach to Develop Ultra-High Inhibitory Drug Using the Power Function of the Stoichiometry of the Targeted Nanomachine or Biocomplex

AIMS: To find methods for potent drug development by targeting to biocomplex with high copy number. METHODS: Phi29 DNA packaging motor components with different stoichiometries were used as model to assay virion assembly with Yang Hui\u27s Triangle [Formula: see text], where Z = stoichiometry, M = drugged subunits per biocomplex, p and q are the fraction of drugged and undrugged subunits in the population. RESULTS: Inhibition efficiency follows a power function. When number of drugged subunits to block the function of the complex K = 1, the uninhibited biocomplex equals q(z), demonstrating the multiplicative effect of stoichiometry on inhibition with stoichiometry 1000 \u3e 6 \u3e 1. Complete inhibition of virus replication was found when Z = 6. CONCLUSION: Drug inhibition potency depends on the stoichiometry of the targeted components of the biocomplex or nanomachine. The inhibition effect follows a power function of the stoichiometry of the target biocomplex

Nanoparticle Orientation to Control RNA Loading and Ligand Display on Extracellular Vesicles for Cancer Regression

Nanotechnology offers many benefits, and here we report an advantage of applying RNA nanotechnology for directional control. The orientation of arrow-shaped RNA was altered to control ligand display on extracellular vesicle membranes for specific cell targeting, or to regulate intracellular trafficking of small interfering RNA (siRNA) or microRNA (miRNA). Placing membrane-anchoring cholesterol at the tail of the arrow results in display of RNA aptamer or folate on the outer surface of the extracellular vesicle. In contrast, placing the cholesterol at the arrowhead results in partial loading of RNA nanoparticles into the extracellular vesicles. Taking advantage of the RNA ligand for specific targeting and extracellular vesicles for efficient membrane fusion, the resulting ligand-displaying extracellular vesicles were capable of specific delivery of siRNA to cells, and efficiently blocked tumour growth in three cancer models. Extracellular vesicles displaying an aptamer that binds to prostate-specific membrane antigen, and loaded with survivin siRNA, inhibited prostate cancer xenograft. The same extracellular vesicle instead displaying epidermal growth-factor receptor aptamer inhibited orthotopic breast cancer models. Likewise, survivin siRNA-loaded and folate-displaying extracellular vesicles inhibited patient-derived colorectal cancer xenograft

Design Strategy of Elastoplastic Dampers for Seismic Protection of Structures

A new methodology for seismic control design of MDOF structures is put forward.The methodology is developed for shear-type building frames with supplemental system of braces with dampers. Hysteretic dampers are modelled to be elasto-perfectly plastic. The mechanical parameters of the damper, the supplemental system (damper + brace) and the controlled structure are first defined. Next, based on modal analysis method, the controlled MDOF structure is converted to the equivalent SDOF structure, and the distribution of elastic stiffness of damper on the MDOF structure is derived. Then, a procedure is compiled to achieve the elastic stiffness, the yielding drift and the ductility factor of the damper on each story of the MDOF structure. Finally, the procedure is used for seismic control design of three example structures. Time history analyses show that the proposed methodology is feasible

Theoretical Analysis of Household Heat Metering of Central Heating and Its Application

Central heating medium heat metering is principle of thermodynamics, drawing on some European the experiences of developed countries, and in China's cities such as Beijing, tianjin, the pilot work has achieved great results. The heat enterprises establishing market economy ideas primary, grades have improved significantly in quality and services for heating. Heat supply system in heat supplying enterprises toward the market, users become God, this makes heating enterprises and consciously shift attitudes and take the initiative to improve the quality of service. KEYWORD: Central heating, Metering, Thermodynamics, application International Conference on Industrial Technology and Management Science (ITMS 2015) © 2015. The authors Published by Atlantis Press 1860 As shown in Figure 1, heat metering principle is by measuring the heat pipes to the housing of the thermal value of Q1 and outflow of heat from the heating pipelines of housing poor value for Q3, resulting in users actually use heat value of Q

Development of potent antiviral drugs inspired by viral hexameric DNA-packaging motors with revolving mechanism

The intracellular parasitic nature of viruses and the emergence of antiviral drug resistance necessitate the development of new potent antiviral drugs. Recently, a method for developing potent inhibitory drugs by targeting biological machines with high stoichiometry and a sequential-action mechanism was described. Inspired by this finding, we reviewed the development of anti-viral drugs targeting viral DNA-packaging motors. Inhibiting multisubunit targets with sequential actions resembles breaking one bulb in a series of Christmas lights, which turns off the entire string. Indeed, studies on viral DNA packaging might lead to the development of new antiviral drugs. Recent elucidation of the mechanism of the viral double-stranded DNA (dsDNA)-packaging motor with sequential one-way revolving motion will promote the development of potent antiviral drugs with high specificity and efficiency. Traditionally, biomotors have been classified into two categories: linear and rotation motors. Recently dis- covered was a third type of biomotor, including the viral DNA-packaging motor, beside the bacterial DNA translocases, that uses a revolving mechanism without rotation. By analogy, rotation resembles the Earth’s rotation on its own axis, while revolving resembles the Earth’s revolving around the Sun (see animations at http://rnanano.osu.edu/movie.html). Herein, we review the structures of viral dsDNA-packaging motors, the stoichiometries of motor components, and the motion mechanisms of the motors. All viral dsDNA-packaging motors, including those of dsDNA/dsRNA bacteriophages, adenoviruses, poxviruses, herpesviruses, mimiviruses, megaviruses, pandoraviruses, and pithoviruses, contain a high-stoichiometry machine composed of multiple components that work cooperatively and sequentially. Thus, it is an ideal target for potent drug development based on the power function of the stoichiometries of target complexes that work sequentially

Construction of RNA–Quantum Dot Chimera for Nanoscale Resistive Biomemory Application

RNA nanotechnology offers advantages to construct thermally and chemically stable nanoparticles with well-defined shape and structure. Here we report the development of an RNA–QD (quantum dot) chimera for resistive biomolecular memory application. Each QD holds two copies of the pRNA three-way junction (pRNA-3WJ) of the bacteriophage phi29 DNA packaging motor. The fixed quantity of two RNAs per QD was achieved by immobilizing the pRNA-3WJ with a Sephadex aptamer for resin binding. Two thiolated pRNA-3WJ serve as two feet of the chimera that stand on the gold plate. The RNA nanostructure served as both an insulator and a mediator to provide defined distance between the QD and gold. Immobilization of the chimera nanoparticle was confirmed with scanning tunneling microscopy. As revealed by scanning tunneling spectroscopy, the conjugated pRNA-3WJ–QD chimera exhibited an excellent electrical bistability signal for biomolecular memory function, demonstrating great potential for the development of resistive biomolecular memory and a nano-bio-inspired electronic device for information processing and computing

Land Subsidence in a Coastal City Based on SBAS-InSAR Monitoring: A Case Study of Zhuhai, China

The superimposed effects of sea level rise caused by global warming and land subsidence seriously threaten the sustainable development of coastal cities. In recent years, an important coastal city in China, Zhuhai, has been suffering from severe and widespread land subsidence; however, the characteristics, triggers, and vulnerability assessment of ground subsidence in Zhuhai are still unclear. Therefore, we used the SBAS-InSAR technique to process 51 Sentinel-1A images to monitor the land subsidence in Zhuhai during the period from August 2016 to June 2019. The results showed that there was extensive land subsidence in the study area, with a maximum rate of −109.75 mm/yr. The surface had sequentially undergone a process of minor uplift and decline fluctuation, sharp settlement, and stable subsidence. The distribution and evolution of land subsidence were controlled by tectonic fractures and triggered by the thickness of soft soil, the intensity of groundwater development, and the seasonal changes of atmospheric precipitation. The comprehensive index method and the analytic hierarchy process were applied to derive extremely high subsidence vulnerability in several village communities and some traffic arteries in Zhuhai. Our research provides a theoretical basis for urban disaster prevention in Zhuhai and the construction planning of coastal cities around the world