Multistage nanovectors: from concept to novel imaging contrast agents and therapeutics

Over the last few decades a great variety of nanotechnology based platforms have been synthesized and fabricated to improve the delivery of active compounds to a disease site. Nanoparticles currently used in the clinic, and the majority of nanotherapeutics/nanodiagnostics under investigation, accommodate single- or multiple- functionalities on the same entity. Because many heterogeneous biological barriers can prevent therapeutic and imaging agents from reaching their intended targets in sufficient concentrations, there is an emerging requirement to develop a multimodular nanoassembly, in which different components with individual specific functions act in a synergistic manner. The multistage nanovectors (MSVs) were introduced in 2008 as the first system of this type. It comprises several nanocomponents or "stages", each of which is designed to negotiate one or more biological barriers. Stage 1 mesoporous silicon particles (S1MPs) were rationally designed and fabricated in a nonspherical geometry to enable superior blood margination and to increase cell surface adhesion. The main task of S1MPs is to efficiently transport nanoparticles that are loaded into their porous structure and to protect them during transport from the administration site to the disease lesion. Semiconductor fabrication techniques including photolithography and electrochemical etching allow for the exquisite control and precise reproducibility of S1MP physical characteristics such as geometry and porosity. Furthermore, S1MPs can be chemically modified with negatively/positively charged groups, PEG and other polymers, fluorescent probes, contrast agents, and biologically active targeting moieties including antibodies, peptides, aptamers, and phage. The payload nanoparticles, termed stage 2 nanoparticles (S2NPs), can be any currently available nanoparticles such as liposomes, micelles, inorganic/metallic nanoparticles, dendrimers, and carbon structures, within the approximate size range of 5-100 nm in diameter. Depending upon the physicochemical features of the S1MP (geometry, porosity, and surface modifications), a variety of S2NPs or nanoparticle "cocktails" can be loaded and efficiently delivered to the disease site. As demonstrated in the studies reviewed here, once the S2NPs are loaded into the S1MPs, a variety of novel properties emerge, which enable the design of new and improved imaging contrast agents and therapeutics. For example, the loading of the MRI Gd-based contrast agents onto hemispherical and discoidal S1MPs significantly increased the longitudal relaxivity (r1) to values of up to 50 times larger than those of clinically available gadolinium-based agents (~4 mM(-1) s(-1)/Gd(3+) ion). Furthermore, administration of a single dose of MSVs loaded with neutral nanoliposomes containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein enabled sustained EphA2 gene silencing for at least 21 days. As a result, the tumor burden was reduced in an orthotopic mouse model of ovarian cancer. We envision that the versatility of the MSV platform and its emerging properties will enable the creation of personalized solutions with broad clinical implications within and beyond the realm of cancer theranostics.     

Effect of a dispersed immiscible liquid phase on the hydrodynamics of a bubble column and ebullated bed

Secondary undesired reactions in ebullated bed resid hydroprocessors can generate an additional dispersed liquid phase, referred as mesophase, which is denser and more viscous than the continuous liquid phase and affects the operation and transport phenomena of the fluidized bed. This study investigates the effect of a dispersed immiscible liquid phase on the overall phase holdups, bubble properties, and fluidization behavior in a bubble column and ebullated bed. The experimental system consisted of biodiesel as the continuous liquid phase, glycerol as the dispersed liquid phase, 1.3 mm diameter glass beads, and nitrogen. The addition of dispersed glycerol reduced the gas holdups in the bubble column for the studied gas and liquid superficial velocities. Dynamic gas disengagement profiles reveal a rise in the large bubble population and reductions to the small and micro bubble holdups when increasing the glycerol concentration. Liquid–liquid–solid bed expansions at various liquid flowrates confirm particle agglomeration in the presence of a more viscous dispersed liquid phase. Overall phase holdups in a gas–liquid–liquid–solid ebullated bed were obtained while varying the gas and liquid flowrates as well as the glycerol concentration. A coalesced bubble flow regime was observed in the bed region without glycerol whereas the addition of glycerol resulted in the dispersed bubble flow regime due to particle clustering and a greater apparent particle size. The resulting bubble flow regime increased the bed and freeboard region gas holdups due to enhanced bubble break-up. Observations of the fluidized bed behavior following the addition of the dispersed glycerol are also discussed.     

Matching economical, energetic and environmental benefits: An analysis for hybrid CHCP-heat pump systems

The optimization of design and operation of combined heat, cooling and power systems usually leads to select different plant lay-outs and size of components, depending on the adopted optimization criterion (maximum profit or energy saving or minimum environmental impact). This occurs when the current energy prices and the normative provisions supporting cogeneration are not able to coincide with the specific customer’s interest and the overall “social interest” for a reduction in energy consumption and in pollutants’ emissions. At EU level, polygeneration is considered to have a large potential for residential and commercial buildings district network, for the tertiary sector and for industrial applications. In such applications, it is often convenient to integrate the trigeneration system with a reversible heat pump, because of a low ratio between electric demand and that for heating and cooling. In this paper, the design and operation of such hybrid systems is discussed. The results achievable through different operation modes are compared and, with reference to a 600-rooms hotel and a 300-beds hospital in Italy, the effects on plant design from an hour-by-hour optimization of plant operation are assessed. Finally, the need for a flexible support system for cogeneration plants is put into evidence and some criteria are listed for an effective regulation.     

Enhancement of indirect sulphation of limestone by steam addition

The effect of water (H?O(g)) on in situ SO? capture using limestone injection under (FBC) conditions was studied using a thermobalance and tube furnace. The indirect sulphation reaction was found to be greatly enhanced in the presence of H?O(g). Stoichiometric conversion of samples occurred when sulphated with a synthetic flue gas containing 15% H?O(g) in under 10 h, which is equivalent to a 45% increase in conversion as compared to sulphation without H?O(g). Using gas pycnometry and nitrogen adsorption methods, it was shown that limestone samples sulphated in the presence of H?O(g) undergo increased particle densification without any significant changes to pore area or volume. The microstructural changes and observed increase in conversion were attributed to enhanced solid-state diffusion in CaO/CaSO? in the presence of H?O(g). Given steam has been shown to have such a strong influence on sulphation, whereas it had been previously regarded as inert, may prompt a revisiting of the classically accepted sulphation models and phenomena. These findings also suggest that steam injection may be used to enhance sulfur capture performance in fluidized beds firing low-moisture fuels such as petroleum coke.     

Tailings-nonwoven geotextile filter compatibility in mining applications

Nonwoven geotextiles have been commonly used in filtration and drainage of geotechnical engineering works. This paper presents a study on the use of such materials in drainage and filtration systems of tailings dams. Different combinations of tailings and geotextiles were submitted to gradient ratio (GR) tests under confinement in the laboratory with varying values of stress levels and hydraulic gradients. The results of GR tests under confining stresses up to 2000 kPa are presented and discussed. The dimensions of the tailings particles entrapped in the geotextile specimens and those that piped through the geotextile were also assessed. Geotextile specimens from the drainage system of a tailings dam were exhumed for analyses, as part of the research programme. The results obtained showed that stress levels and the hydraulic gradients used in the tests influenced the behaviour of the system. Physical and microscopic analyses of the specimens tested showed greater geotextile impregnation by tailings particles in the field than in the laboratory. The overall performance of the geotextiles tested under laboratory conditions was satisfactory. However, in the field segregation of tailings particles and transport of fines in suspension can subject the filter to more complex and severe clogging mechanisms, not properly simulated in current standard testing procedures.     

Mesenchymal Stromal Cell-Mediated Treatment of Local and Systemic Inflammation through the Triggering of an Anti-Inflammatory Response

The emergence of cell-based therapeutics, specifically the use of mesenchymal stromal/stem cells (MSCs), stands to significantly affect the future of targeted drug delivery technologies. MSCs represent a unique cell type, offering more than only regenerative potential but also site-specific inflammatory targeting and tissue infiltration. In this study, a versatile multicomponent delivery platform, combining MSC tropism with multistage nanovector (MSV)-mediated payload delivery, is debuted. It is demonstrated that the incorporation of drug-loaded MSVs bestows MSCs with the ability to transport anti-inflammatory payloads, achieving a fivefold increase in payload release without negatively impacting cellular functions, viability, extravasation, and inflammatory homing. When incorporated within MSCs, MSVs avoid rapid sequestration by filtering organs and conserve a 15-fold increase in local inflammatory targeting compared to healthy ears. Furthermore, this MSC-mediated MSV platform (M&Ms) rapidly triggers a 4.5-fold reduction of local inflammation compared to free drug and extends survival to 100% of treated mice in a lethal model of systemic inflammation.     

Technical and economical analysis of a solar–geothermal hybrid plant based on an Organic Rankine Cycle

A combined concentrating solar power system and a geothermal binary plant based on an Organic Rankine Cycle (ORC) is analyzed. Given a supercritical ORC, designed for the optimal utilization of an intermediate enthalpy geothermal source, a solar parabolic trough field was included in the plant, introducing an additional high temperature heat source for the cycle and increasing power production. The off-design performance analysis of the power cycle was performed first. An hour-by-hour simulation was then carried out to estimate the yearly production using a detailed solar field model. Finally, a differential economic analysis was performed to determine the cost of the additional electricity generated with the solar source. On the basis of the current cost of solar collectors, levelized costs of electricity of 145-280 €/MWh were obtained depending on the location of the plant: a competitive value with respect to large, stand-alone concentrating solar power plants.