Venezuelan equine encephalitis virus (VEEV) poses a major public health risk due to its amenability for use as a bioterrorism agent and its severe health consequences in humans. ML336 is a recently developed chemical inhibitor of VEEV, shown to effectively reduce VEEV infection in vitro and in vivo. However, its limited solubility and stability could hinder its clinical translation. To overcome these limitations, lipid-coated mesoporous silica nanoparticles (LC-MSNs) were employed. The large surface area of the MSN core promotes hydrophobic drug loading while the liposome coating retains the drug and enables enhanced circulation time and biocompatibility, providing an ideal ML336 delivery platform. LC-MSNs loaded 20 ± 3.4 μg ML336/mg LC-MSN and released 6.6 ± 1.3 μg/mg ML336 over 24 hours. ML336-loaded LC-MSNs significantly inhibited VEEV in vitro in a dose-dependent manner as compared to unloaded LC-MSNs controls. Moreover, cell-based studies suggested that additional release of ML336 occurs after endocytosis. In vivo safety studies were conducted in mice, and LC-MSNs were not toxic when dosed at 0.11 g LC-MSNs/kg/day for four days. ML336-loaded LC-MSNs showed significant reduction of brain viral titer in VEEV infected mice compared to PBS controls. Overall, these results highlight the utility of LC-MSNs as drug delivery vehicles to treat VEEV.
The limited flux and selectivities of current carbon dioxide membranes and the high costs associated with conventional absorption-based CO2 sequestration call for alternative CO2 separation approaches. Here we describe an enzymatically active, ultra-thin, biomimetic membrane enabling CO2 capture and separation under ambient pressure and temperature conditions. The membrane comprises a ~18-nm-thick close-packed array of 8 nm diameter hydrophilic pores that stabilize water by capillary condensation and precisely accommodate the metalloenzyme carbonic anhydrase (CA). CA catalyzes the rapid interconversion of CO2 and water into carbonic acid. By minimizing diffusional constraints, stabilizing and concentrating CA within the nanopore array to a concentration 10× greater than achievable in solution, our enzymatic liquid membrane separates CO2 at room temperature and atmospheric pressure at a rate of 2600 GPU with CO2/N2 and CO2/H2 selectivities as high as 788 and 1500, respectively, the highest combined flux and selectivity yet reported for ambient condition operation.
The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability to establish structure-activity relationships in vivo. Here, using stable, monosized, radiolabeled, mesoporous silica nanoparticles (MSNs), we apply an integrated SPECT/CT imaging and mathematical modeling approach to understand the combined effects of MSN size, surface chemistry and routes of administration on biodistribution and clearance kinetics in healthy rats. We show that increased particle size from ~32- to ~142-nm results in a monotonic decrease in systemic bioavailability, irrespective of route of administration, with corresponding accumulation in liver and spleen. Cationic MSNs with surface exposed amines (PEI) have reduced circulation, compared to MSNs of identical size and charge but with shielded amines (QA), due to rapid sequestration into liver and spleen. However, QA show greater total excretion than PEI and their size-matched neutral counterparts (TMS). Overall, we provide important predictive functional correlations to support the rational design of nanomedicines.
Lipid-coated mesoporous silica nanoparticles (LC-MSNs) have recently emerged as a next-generation cargo delivery nanosystem combining the unique attributes of both the organic and inorganic components. The high surface area biodegradable inorganic mesoporous silica core can accommodate multiple classes of bio-relevant cargos in large amounts, while the supported lipid bilayer coating retains the cargo and increases the stability of the nanocarrier in bio-relevant media which should promote greater bio-accumulation of LC-MSNs in cancer sites. In this paper, we report on the optimization of various sol–gel synthesis (pH, stirring speed) and post-synthesis (hydrothermal treatment) procedures to enlarge the MSN pore size and tune the surface chemistry so as to enable loading and delivery of large biomolecules. Finally, the proof of concept of the dual cargo-loaded nanocarrier has been demonstrated in immortalized cervical cancer HeLa cells using MSNs of various fine-tuned pore sizes.
Zhu, Wei; Shang, Jin; Guo, Jimin; Motevalli, Benyamin; Durfee, Paul; Agola, Jacob O.; Coker, Eric N.; Brinker, C.J.
Abstract
A novel strategy for the versatile functionalization of the external surface of metal‐organic frameworks (MOFs) has been developed based on the direct coordination of a phenolic‐inspired lipid molecule DPGG (1,2‐dipalmitoyl‐sn‐glycero‐3‐galloyl) with metal nodes/sites surrounding MOF surface. X‐ray diffraction and Argon sorption analysis prove that the modified MOF particles retain their structural integrity and porosity after surface modification. Density functional theory calculations reveal that strong chelation strength between the metal sites and the galloyl head group of DPGG is the basic prerequisite for successful coating. Due to the pH‐responsive nature of metal‐phenol complexation, the modification process is reversible by simple washing in weak acidic water, showing an excellent regeneration ability for water‐stable MOFs. Moreover, the colloidal stability of the modified MOFs in the nonpolar solvent allows them to be further organized into 2 dimensional MOF or MOF/polymer monolayers by evaporation‐induced interfacial assembly conducted on an air/water interface. Finally, the easy fusion of a second functional layer onto DPGG‐modified MOF cores, enabled a series of MOF‐based functional nanoarchitectures, such as MOFs encapsulated within hybrid supported lipid bilayers (so‐called protocells ), polyhedral core‐shell structures, hybrid lipid‐modified‐plasmonic vesicles and multicomponent supraparticles with target functionalities, to be generated. for a wide range of applications.
Silsesquioxane nanoparticles are composed of repetitive organosilica fragments in their frameworks and are now recognized to have outstanding functional fertility. Depending on the organosilane and the synthetic pathways, silsesquioxane NPs can be pendant, bridged, dense or porous. Recently the diverse functionalities of mesoporous silsesquioxane nanoparticles have been exploited for the sake of drug-related biomedicine. Fine-tuning the silsesquioxane nanoparticles characteristics allow not only a superior retention capacity of therapeutics without the need of any further modification, but also a controlled release through various environmentally-stimulated triggers. Furthermore, the main focus of the present review is to highlight the different types of silsesquioxane nanoparticles and their exceptional features focused on controlled delivery of drugs, proteins, antibodies and DNA through pH, redox or light stimuli.
Villegas, Maria R.; Baeza, Alejandro; Noureddine, Achraf; Durfee, Paul N.; Butler, Kimberly B.; Agola, Jacob O.; Brinker, C.J.; Vallet-Regi, Maria
The high density of the extracellular matrix in solid tumors is an important obstacle to nanocarriers for reaching deep tumor regions and has severely limited the efficacy of administrated nanotherapeutics. The use of proteolytic enzymes prior to nanoparticle administration or directly attached to the nanocarrier surface has been proposed to enhance their penetration, but the low in vivo stability of these macromolecules compromises their efficacy and strongly limits their application. Herein, we have designed a multifunctional nanocarrier able to transport cytotoxic drugs to deep areas of solid tumors and once there, to be engulfed by tumoral cells causing their destruction. This system is based on mesoporous silica nanocarriers encapsulated within supported lipid bilayers (SLBs). The SLB avoids premature release of the housed drug while providing high colloidal stability and an easy to functionalize surface. The tumor penetration property is provided by attachment of engineered polymeric nanocapsules that transport and controllably unveil and release the proteolytic enzymes that in turn digest the extracellular matrix, facilitating the nanocarrier diffusion through the matrix. Additionally, targeting properties were endowed by conjugating an antibody specific to the investigated tumoral cells to enhance binding, internalization, and drug delivery. This multifunctional design improves the therapeutic efficacy of the transported drug as a consequence of its more homogeneous distribution throughout the tumoral tissue.
Sun, Bingbing; Wang, Xiang; Liao, Yu P.; Ji, Zhaoxia; Chang, Chong H.; Pokhrel, Suman; Ku, Justine; Liu, Xiangsheng; Wang, Meiying; Dunphy, Darren R.; Li, Ruibin; Meng, Huan; Brinker, C.J.; Nel, Andre E.; Xia, Tian
Contrary to the notion that the use of fumed silica in consumer products can "generally (be) regarded as safe" (GRAS), the high surface reactivity of pyrogenic silica differs from other forms of synthetic amorphous silica (SAS), including the capacity to induce membrane damage and acute proinflammatory changes in the murine lung. In addition, the chain-like structure and reactive surface silanols also allow fumed silica to activate the NLRP3 inflammasome, leading to IL-1β production. This pathway is known to be associated with subchronic inflammation and profibrogenic effects in the lung by α-quartz and carbon nanotubes. However, different from the latter materials, bolus dose instillation of 21 mg/kg fumed silica did not induce sustained IL-1β production or subchronic pulmonary effects. In contrast, the NLRP3 inflammasome pathway was continuously activated by repetitive-dose administration of 3 × 7 mg/kg fumed silica, 1 week apart. We also found that while single-dose exposure failed to induce profibrotic effects in the lung, repetitive dosing can trigger increased collagen production, even at 3 × 3 mg/kg. The change between bolus and repetitive dosing was due to a change in lung clearance, with recurrent dosing leading to fumed silica biopersistence, sustained macrophage recruitment, and activation of the NLRP3 pathway. These subchronic proinflammatory effects disappeared when less surface-reactive titanium-doped fumed silica was used for recurrent administration. All considered, these data indicate that while fumed silica may be regarded as safe for some applications, we should reconsider the GRAS label during repetitive or chronic inhalation exposure conditions.