Search

Samantha A Meenach,1,2 Frederick G Vogt,3 Kimberly W Anderson,2,4 J Zach Hilt,2,4 Ronald C McGarry,5Heidi M Mansour1,41Department of Pharmaceutical Sciences-Drug Development Division, University of Kentucky College of Pharmacy, Lexington, KY; 2Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY, USA; 3Analytical Sciences, Product Development, GlaxoSmithKline, King of Prussia, PA; 4Center of Membrane Sciences, University of Kentucky, Lexington, KY, 5Department of Radiation Medicine, University of Kentucky College of Medicine, Lexington, KY, USAAbstract: Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray-drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan® software and were determined to be 600 nm to 1.2 μm in diameter, which is optimal for deep-lung alveolar penetration. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were performed to analyze solid-state transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers in the solid state of the particles. The residual water content of the particles was very low, as quantified analytically via Karl Fischer titration. The composition of the particles was confirmed using attenuated total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and confocal Raman microscopy (CRM), and chemical imaging confirmed the chemical homogeneity of the particles. The dry powder aerosol dispersion properties were evaluated using the Next Generation Impactor™ (NGI™) coupled with the HandiHaler® dry powder inhaler device, where the mass median aerodynamic diameter from 2.6 to 4.3 μm with excellent aerosol dispersion performance, as exemplified by high values of emitted dose, fine particle fraction, and respirable fraction. Overall, it was determined that the pump rates defined in the spray-drying process had a significant effect on the solid-state particle properties and that a higher pump rate produced the most optimal system. Advanced dry powder inhalers of inhalable lipopolymers for targeted dry powder inhalation delivery were successfully achieved.Keywords: biocompatible biodegradable lipopolymers, lung surfactant, pulmonary delivery, self-assemblies, solid-state, lipospheres

Per- and polyfluoroalkyl substances (PFAS) are anthropogenic compounds developed for various applications; some are connected to adverse health impacts including immunosuppression and higher susceptibility to some cancers. Current PFAS remediation treatments from aqueous sources include granular activated carbon (GAC) adsorption, membrane separation, and anion-exchange resin (AER) removal. Each has specific disadvantages, hence the need for a new and efficient technology. Herein, acrylamide-based hydrogel composites were synthesized with powdered activated carbon (PAC) and characterized to determine their affinity for PFAS. Physicochemical characterization included Fourier-Transform infrared spectroscopy (FTIR) to identify chemical composition, thermogravimetric analysis (TGA) to confirm PAC loading percentage, and aqueous swelling studies to measure the effect of crosslinking density. FTIR showed successful conversion of carbonyl and amine groups, and TGA analysis confirmed the presence of PAC within the network. Surface characterization also confirmed carbon-rich areas within composite networks, and the swelling ratio decreased with increasing crosslinking density. Finally, sorption of PFAS was detected via liquid chromatography with tandem mass spectrometry (LC-MS/MS), with removal efficiencies of up to 98% for perfluorooctanoic sulfonic acid (PFOS) and 96% for perfluorooctanoic acid (PFOA). The developed hydrogel composites exhibited great potential as advanced materials with tunable levers that can increase affinity towards specific compounds in water.

Environmental conditions of groundwater and surface water greatly vary as a function of location. Factors such as ionic strength, water hardness, and solution pH can change the physical and chemical properties of the nanocomposites used in remediation and the pollutants of interest. In this work, magnetic nanocomposite microparticle (MNM) gels are used as sorbents for remediation of PCB 126 as model organic contaminant. Three MNM systems are used: curcumin multiacrylate MNMs (CMA MNMs), quercetin multiacrylate MNMs (QMA MNMs), and polyethylene glycol-400-dimethacrylate MNMs (PEG MNMs). The effect of ionic strength, water hardness, and pH were studied on the sorption efficiency of the MNMs for PCB 126 by performing equilibrium binding studies. It is seen that the ionic strength and water hardness have a minimal effect on the MNM gel system sorption of PCB 126. However, a decrease in binding was observed when the pH increased from 6.5 to 8.5, attributed to anion-π interactions between the buffer ions in solution and the PCB molecules as well as with the aromatic rings of the MNM gel systems. Overall, the results indicate that the developed MNM gels can be used as magnetic sorbents for polychlorinated biphenyls in groundwater and surface water remediation, provided that the solution pH is controlled.

Traditional chemotherapies target rapidly developing cells in the human body resulting in harsh side effects including fatigue, immune system suppression, and nausea, among others. Delivery systems to focus the active pharmaceutical ingredients (APIs) to the diseased tissue can diminish the negative side effects while improving treatment outcomes. Gold nanoparticles (AuNP) offer many unique advantages as drug delivery vehicles, including being biologically inert, easily adaptable to various shapes and sizes, able to create a strong Au-thiol bond, and able to generate heat upon the absorption of near-infrared light. To this end, a AuNP delivery vehicle was engineered to load and release two DNA binding anti-cancer drugs, mithramycin and doxorubicin, in a controlled fashion. The drugs were loaded onto the surface of the AuNP with temperature sensitive linkages. The amount of heat generated, and subsequent release of the drugs was controlled by the irradiation time with a near-infrared laser. By modulating the linkage used to load the drugs three different release profiles were able to be achieved, indicating the feasibility of such a system for combinational therapy requiring sequential release of APIs., Competing Interests: Declarations of Competing Interest None., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The widespread presence of numerous organic contaminants in water poses a threat to the ecological environment and human health. Magnetic nanocomposites exposed to an alternating magnetic field (AMF) have a unique ability for magnetically mediated energy delivery (MagMED) resulting from the embedded magnetic nanoparticles; this localized energy delivery and associated chemical and thermal effects are a potential method for removing contaminants from water. This work developed a novel magnetic nanocomposite-a polyacrylamide-based hydrogel loaded with iron oxide nanoparticles. For this magnetic nanocomposite, persulfate activation and the contamination removal in water were investigated. Magnetic nanocomposites were exposed to AMF with a model organic contaminant, rhodamine B (RhB) dye, with or without sodium persulfate (SPS). The removal of RhB by the nanocomposite without SPS as a sorbent was found to be proportional to the concentration of magnetic nanoparticles (MNPs) in the nanocomposite. With the addition of SPS, approximately 100% of RhB was removed within 20 min. This removal was attributed primarily to the activation of sulfate radicals, triggered by MNPs, and the localized heating resulted from the MNPs when exposed to AMF. This suggests that this magnetic nanocomposite and an AMF could be a unique environmental remediation technique for hazardous contaminants.

Given their versatility and formability, polymers have proven to be a viable platform facilitating a controlled and tuned release for a variety of therapeutic agents. One growing area of polymer drug delivery is polymeric prodrugs, which covalently link active pharmaceutical ingredients to a polymeric form to enhance stability, delivery, and pharmacology. One such class of polymeric prodrugs, poly(beta amino esters) (PβAEs) can be synthesized into crosslinked, or "thermoset," networks which greatly limits their processability. An antioxidant-PβAE polymer prodrug that is soluble in organic solutions would permit enhanced processability, increasing their utility and manufacturability. Curcumin PβAEs were synthesized to be soluble in organic solvents while retaining the release and activity properties. To demonstrate the polymer processability, curcumin PβAEs were further synthesized into nanoparticles and thin films. Control over nanoparticle size and film thickness was established through variance of dope solution concentration and withdrawal speed, respectively. Layering of polymeric films was demonstrated through inkjet printing of thin films. Polymer function was characterized through curcumin release and antioxidant activity. The processing of the polymer had a drastic impact on the curcumin release profiles indicating the polymer degradation was influenced by surface area and porosity of the final product. Previously, release was controlled primarily through the hydrophobicity of the polymer. Here, we demonstrate a novel method for further tuning the degradation by processing the polymer., (© 2022 Wiley Periodicals LLC.)

Severe acute respiratory syndrome coronavirus 2's (SARS-CoV-2) rapid global spread has posed a significant threat to human health, and similar outbreaks could occur in the future. Developing effective virus inactivation technologies is critical to preventing and overcoming pandemics. The infection of SARS-CoV-2 depends on the binding of the spike glycoprotein (S) receptor binding domain (RBD) to the host cellular surface receptor angiotensin-converting enzyme 2 (ACE2). If this interaction is disrupted, SARS-CoV-2 infection could be inhibited. Magnetic nanoparticle (MNP) dispersions exposed to an alternating magnetic field (AMF) possess the unique ability for magnetically mediated energy delivery (MagMED); this localized energy delivery and associated mechanical, chemical, and thermal effects are a possible technique for inactivating viruses. This study investigates the MNPs' effect on vesicular stomatitis virus pseudoparticles containing the SARS-CoV-2 S protein when exposed to AMF or a water bath (WB) with varying target steady-state temperatures (45, 50, and 55 °C) for different exposure times (5, 15, and 30 min). In comparison to WB exposures at the same temperatures, AMF exposures resulted in significantly greater inactivation in multiple cases. This is likely due to AMF-induced localized heating and rotation of MNPs. In brief, our findings demonstrate a potential strategy for combating the SARS-CoV-2 pandemic or future ones.

The versatility and unique qualities of thermoresponsive polymeric systems have led to the application of these materials in a multitude of fields. One such field that can significantly benefit from the use of innovative, smart materials is environmental remediation. Of particular significance, multifunctional poly(N-isopropylacrylamide) (PNIPAAm) systems based on PNIPAAm copolymerized with various cationic comonomers have the opportunity to target and attract negatively charged pollutants such as perfluorooctanoic acid (PFOA). The thermoresponsive cationic PNIPAAm systems developed in this work were functionalized with cationic monomers N -[3-(dimethylamino)propyl]acrylamide (DMAPA) and (3-acrylamidopropyl)trimethylammonium chloride (DMAPAQ). The polymers were examined for swelling capacity behavior and PFOA binding potential when exposed to aqueous environments with varying pH and temperature. Comonomer loading percentages had the most significant effect on polymer swelling behavior and temperature responsiveness as compared to aqueous pH. PFOA removal efficiency was greatly improved with the addition of DMAPA and DMAPAQ monomers. Aqueous pH and buffer selection were important factors when examining binding potential of the polymers, as buffered aqueous environments altered polymer PFOA removal quite drastically. The role of temperature on binding potential was not as expected and had no discernible effect on the ability of DMAPAQ polymers to remove PFOA. Overall, the cationic systems show interesting swelling behavior and significant PFOA removal results that can be explored further for potential environmental remediation applications.

Oral drug delivery remains the most common and well tolerated method for drug administration. However, its applicability is often limited due to low drug solubility and stability. One approach to overcome the solubility and stability limitations is the use of amorphous polymeric prodrug formulations, such as poly(β-amino ester) (PBAE). PBAE hydrogels, which are biodegradable and pH responsive, have shown promising results for the controlled release of drugs by improving the stability and increasing the solubility of these drugs. In this work, we have evaluated the potential use of PBAE prodrugs in an oral tablet formulation, studying their sustained drug release potential and storage stability. Curcumin, a low solubility, low stability antioxidant drug was used as a model compound. Poly(curcumin β-amino ester) (PCBAE), a crosslinked amorphous network, was synthesized by a previously published method using a commercial diacrylate and a primary diamine, in combination with acrylate-functionalized curcumin. PCBAE-based tablets were made and exhibited a sustained release for 16 h, following the hydrolytic degradation of PCBAE particles into native curcumin. In addition to the release studies, preliminary storage stability was assessed using standard and accelerated stability conditions. As PCBAE degradation is hydrolysis driven, tablet stability was found to be sensitive to moisture.

Humans are constantly exposed to exogenous chemicals throughout their life, which can lead to a multitude of negative health impacts. Advanced materials can play a key role in preventing or mitigating these impacts through a wide variety of applications. The tunable properties of hydrogels and hydrogel nanocomposites (e.g., swelling behavior, biocompatibility, stimuli responsiveness, functionality, etc.) have deemed them ideal platforms for removal of environmental contaminants, detoxification, and reduction of body burden from exogenous chemical exposures for prevention of disease initiation, and advanced treatment of chronic diseases, including cancer, diabetes, and cardiovascular disease. In this review, three main junctures where the use of hydrogel and hydrogel nanocomposite materials can intervene to positively impact human health are highlighted: 1) preventing exposures to environmental contaminants, 2) prophylactic treatments to prevent chronic disease initiation, and 3) treating chronic diseases after they have developed., (© 2021 Wiley-VCH GmbH.)

Water pollution continues to be one of the greatest challenges humankind faces worldwide. Increasing population growth, fast industrialization and modernization risk the worsening of water accessibility and quality in the coming years. Nanoadsorbents have steadily gained attention as remediation technologies that can meet stringent water quality demands. In this work, core-shell magnetic nanoparticles (MNPs) comprised of an iron oxide magnetic core and a styrene based polymer shell were synthesized via surface initiated atom transfer radical polymerization (SI-ATRP), and characterized them for their binding of polychlorinated biphenyls (PCBs), as model organic contaminants. Acrylated plant derived polyphenols, curcumin multiacrylate (CMA) and quercetin multiacrylate (QMA), and divinylbenzene (DVB) were incorporated into the polymeric shell to create high affinity binding sites for PCBs. The affinity of these novel materials for PCB 126 was evaluated and fitted to the nonlinear Langmuir model to determine binding affinities (K D ). The K D values obtained for all the MNP systems showed higher binding affinities for PCB 126 that carbonaceous materials, like activated carbon and graphene oxide, the most widely used adsorption materials for water remediation today. The effect of increasing ATRP reaction time on the binding affinity of MNPs demonstrated the ability to tune polymer shell thickness by modifying the reaction extent and initial crosslinker concentrations in order to maximize pollutant binding. The enhancement in binding affinity and capacity for PCB 126 was demonstrated by the use of hydrophobic, aromatic rich molecules like styrene, CMA, QMA and DVB, within the polymeric shell provides more sites for π-π interactions to occur between the MNP surface and the PCB molecules. Overall, the high affinities for PCBs, as model organic pollutants, and magnetic capabilities of the core-shell MNPs synthesized provide a strong rationale for their application as nanoadsorbents in the environmental remediation of specific harmful contaminants., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Poly(N-isopropylacrylamide) PNIPAAm was polymerized with co-monomers containing a biphenyl moiety to create a unique thermoresponsive physically crosslinked system due to the presence of pi-pi interactions between the biphenyl moieties. The biphenyl monomers used were 2-phenylphenol monoacrylate (2PPMA) and 4-phenylphenol monoacrylate (4PPMA). These monomers were utilized to synthesize a set of polymers with biphenyl monomer (2PPMA/4PPMA) content from 2.5 to 7.5 mole percent and with initiator concentrations from 0.1 and 1.0 weight percent. The resulting polymers were characterized by various techniques, such as gel permeation chromatography (GPC), swelling studies and mechanical testing. The decrease in the average molecular weight of the polymers due to the increase in the concentration of initiator was confirmed by GPC results. Swelling studies confirmed the expected temperature dependent swelling properties and explored the impact of the biphenyl comonomers. These studies indicated that with the increase in biphenyl comonomers, the physical crosslinking increases which leads to decrease in the swelling ratio. The results from the mechanical tests also depict the effect of the concentration of biphenyl comonomers. These physically crosslinked polymeric systems with their unique properties have potential applications spanning environmental remediation/sensing, biomedicine, etc.

Reduction of airborne viral particles in enclosed spaces is critical in controlling pandemics. Three different hollow fiber membrane (HFM) modules were investigated for viral aerosol separation in enclosed spaces. Pore structures were characterized by scanning electron microscopy, and air transport properties were measured. Particle removal efficiency was characterized using aerosols generated by a collision atomizer from a defined mixture of synthetic nanoparticles including SARS-CoV-2 mimics (protein-coated 100 nm polystyrene). HFM1 (polyvinylidene fluoride, ~50-1300 nm pores) demonstrated 96.5-100% efficiency for aerosols in the size range of 0.3-3 μ m at a flow rate of 18.6 ± 0.3 SLPM (~1650 LMH), whereas HFM2 (polypropylene, ~40 nm pores) and HFM3 (hydrophilized polyether sulfone, ~140-750 nm pores) demonstrated 99.65-100% and 98.8-100% efficiency at flow rates of 19.7 ± 0.3 SLPM (~820 LMH) and 19.4 ± 0.2 SLPM (~4455 LMH), respectively. Additionally, lasting filtration with minimal fouling was demonstrated using ambient aerosols over 2 days. Finally, each module was evaluated with pseudovirus (vesicular stomatitis virus) aerosol, demonstrating 99.3% (HFM1), >99.8% (HFM2), and >99.8% (HFM3) reduction in active pseudovirus titer as a direct measure of viral particle removal. These results quantified the aerosol separation efficiency of HFMs and highlight the need for further development of this technology to aid the fight against airborne viruses and particulate matter concerning human health., Competing Interests: The authors declare no competing financial interest.

As a method to combat the extensive contamination of poly- and perfluoroalkyl substances (PFAS) in water supplies, poly( N -isopropylacrylamide) (PNIPAM) microgels copolymerized with 2,2,2-trifluoroethylacrylate (TFEA) represent a potential sensing tool for recognizing PFAS at dilute aqueous concentrations. The microgels exhibit exceptional temperature responsiveness, transitioning from a swollen z -average diameter of 890.8 ± 19.8 nm to a collapsed diameter of 246.4 ± 10.3 nm below and above their lower critical solution temperature, respectively, for non-fluorinated gels, offering broad size fluctuations that are susceptible to coadded contaminants. Monitoring size perturbations as a function of analyte concentration, the polymers were observed to deswell in the presence of perfluorooctanoic acid, octanoic acid, phenol, and sodium 1-octane sulfonate while tetraethylammonium perfluorooctane sulfonate (TPFOS) augmented swelling. Adding up to 40 mol% TFEA to the networks lowered the concentration at which the microgels' normalized z -average diameter demonstrated a significant deviation from 0.25 mM to 0.1 mM for TPFOS, indicating fluorophilicity as a key contributor to the copolymers' associative capacity. Implanting Förster resonance energy transfer-compatible dyes, cyanine 3 and cyanine 5, into non-fluorinated microgels largely reiterated results from light scattering, as expected for the size-dependent energy transfer mechanism. Including dyes did, however, reinforce the customizability of this system, leaving windows open for functionalization with other signal transduction motifs to lower the detection limits of the polymer further. The swelling changes for PNIPAM microgels stimulated by the acidic constituents of PFAS highlight the polymer as a candidate for detecting the substances following additional development.

Due to mounting evidence of the negative health effects of persistent perfluoroalkyl acids (PFAAs) with long (i.e., >C 7 ) tails, there is a need for convenient systems capable of sensing these contaminants at dilute aqueous concentrations. To address this concern, a thermoresponsive polymeric network composed of poly(N-isopropylacrylamide) copolymerized with fluorinated comonomers was studied to characterize the gel's physical response to fluorosurfactants in solution. Incorporating fluorinated comonomers into the polymer backbone raised their swelling in fluorocontaminant solutions relative to water - gels synthesized with 10.0 mol% 2,2,2-trifluoroethyl acrylate (TFEA) displayed a heightened maximum water-analyte swelling difference of 3761 ± 147% compared to 3201 ± 466% for non-fluorinated gels in the presence of 1 mM tetraethylammonium perfluorooctane sulfonate (TPFOS). The normalized area under the curve for gels with 12.5 mol% TFEA was further raised to 1.77 ± 0.09, indicating a broadened response window for the contaminant, but at the cost of reducing the overall swelling ratio to 3227 ± 166% and elongating the time required to reach swelling equilibrium. Overall, a copolymer fed with 10.7 mol% TFEA was predicted to maximize both the swelling and response window of the polymer toward TPFOS. Equilibration times followed a logarithmic increase as the percentage of comonomer was raised, noting gradual fluorosurfactant penetration into the gels impeded by initial gel compaction caused by the addition of fluorinated comonomers. Comparative study of gels containing 1H,1H,7H-dodecafluoroheptyl acrylate, TFEA, or 1,1,1,3,3,3-hexafluoroisopropyl acrylate identified careful selection of fluorinated comonomers and their feed ratios as useful tools for tailoring the network's swelling response to TPFOS.

Monomers containing biphenyl moieties were employed to create two sets of covalently crosslinked polymers that displayed noncovalent interactions in their 3-dimensional network. The biphenyls (precursors) used were 2-phenylphenol, 4-phenylphenol and 4,4'-dihydroxybiphenyl, and their acrylated forms were synthesized and named as 2-phenylphenolmonoacrylate (2PPMA), 4-phenylphenolmonoacrylate (4PPMA), and 4,4'-dihydroxybiphenyldiacrylate (44BDA), respectively. These were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR) to confirm the successful acrylation reaction. Polymers were synthesized via free radical polymerization reactions with varying crosslinker contents, and their network properties were characterized using swelling studies and compressive modulus tests. Interestingly, swelling studies did not show the expected decreasing swelling ratio with increasing crosslinker content, while compression testing indicated the expected trend of increasing modulus with increasing crosslinking density. The unexpected swelling results are hypothesized to result from the intramolecular interactions between the biphenyl side groups that result in noncovalent crosslinks.

Per- and polyfluoroalkyl substances (PFAS) have rapidly accumulated in the environment due to their widespread use prior to commercial discussion in the early 21st century, and their slow degradation has magnified concerns of their potential toxicity. Monitoring their distribution is, therefore, necessary to evaluate and control their impact on the health of exposed populations. This investigation evaluates the capability of a simple polymeric detection scheme for PFAS based on crosslinked, thermoresponsive poly( N -isopropylacrylamide) (PNIPAM) hydrogels. Surveying swelling perturbations induced by several hydrotropes and comparable hydrocarbon analogs, tetraethylammonium perfluorooctane sulfonate (TPFOS) showed a significantly higher swelling ratio on a mass basis (65.5 ± 8.8 at 15°C) than any of the other analytes tested. Combining swelling with the fluorimetric response of a solvachromatic dye, nile red, revealed the fluorosurfactant to initiate observable aggregation (i.e., its critical aggregation concentration) at 0.05 mM and reach saturation (i.e., its charge neutralization concentration) at 0.5 mM. The fluorosurfactant was found to homogeneously distribute throughout the polymer matrix with energy dispersive X-ray spectroscopy, marking the swelling response as a peculiar nexus of fluorinated interfacial positioning and delocalized electrostatic repulsion. Results from the current study hold promise for exploiting the physiochemical response of PNIPAM to assess TPFOS's concentration.

Translational animal models for oral mucositis (OM) are necessary to simulate and assess the bioclinical effects and response in humans. These models should simulate high levels of radiation exposure that leads to oxidative stress and inflammatory-initiated tissue changes. Hamster models have been extensively studied to observe pathological effects of radiation exposure and help in the development of effective treatments. To successfully evaluate the potential for treatment regimens with consistency and relevance, a radiation-induced OM hamster model was developed using a clinical linear accelerator utilized by cancer patients daily. The dose exposure to the isolated, everted cheek pouch of a hamster, as well as the progression of injury, pro-inflammatory marker, histological, and elasticity analyses of the buccal pouch were conducted to verify replicability and reproducibility of the injury model. The findings from this model demonstrated its ability to consistently induce injury and resolution over 28 days using an acute dose of 60 Gy. This model was developed to enhance clinical relevance when evaluating potential efficacious treatments and can now be utilized in efficacy studies to better evaluate developed therapeutics in a preclinical model that is easy to translate to clinical studies.., Competing Interests: The authors of this work have equity, ownership in, and serve as advisors for Bluegrass Advanced Materials, LLC which is currently developing products related to the research being reported. The terms of this arrangement have been reviewed and approved by the University of Kentucky in accordance with its responsible conduct of research policies., (© 2021 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Bionanotechnology is an ever-expanding field as innovations in nanotechnology continue to be developed based on biological systems or to be applied to address unmet needs in biology, biomedicine, etc ., including various sensor and drug delivery solutions. Amidst the wide range of bionanomaterials that have been developed, stimuli responsive bionanomaterials are of particular interest and are thus emphasized within this review. Here, we have highlighted the most recent advances for stimuli responsive bionanomaterials with focus on those possessing responses based on activation, expansion/contraction and self-assembly/disassembly. The aim of this review is to bring attention to some of the most current bionanotechnology research and the interesting applications within this field., Competing Interests: Conflict of interest statement Nothing declared.

In this work, the development of novel magnetic nanocomposite microparticles (MNMs) via free radical polymerization for their application in the remediation of contaminated water is presented. Acrylated plant-based polyphenols, curcumin multiacrylate (CMA) and quercetin multiacrylate (QMA), were incorporated as functional monomers to create high affinity binding sites for the capture of polychlorinated biphenyls (PCBs), as a model pollutant. The MNMs were characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, dynamic light scattering, and UV-visible spectroscopy. The affinity of these novel materials for PCB 126 was evaluated and fitted to the nonlinear Langmuir model to determine binding affinities ( K D ). The results suggest the presence of the polyphenolic moieties enhances the binding affinity for PCB 126, with K D values comparable to that of antibodies. This demonstrates that these nanocomposite materials have promising potential as environmental remediation adsorbents for harmful contaminants.

The versatility and applicability of thermoresponsive polymeric systems have led to great interest and a multitude of publications. Of particular significance, multifunctional poly( N -isopropylacrylamide) (PNIPAAm) systems based on PNIPAAm copolymerized with various functional comonomers or based on PNIPAAm combined with nanomaterials exhibiting unique properties. These multifunctional PNIPAAm systems have revolutionized several biomedical fields such as controlled drug delivery, tissue engineering, self-healing materials, and beyond (e.g., environmental treatment applications). Here, we review these multifunctional PNIPAAm-based systems with various cofunctionalities, as well as highlight their unique applications. For instance, addition of hydrophilic or hydrophobic comonomers can allow for polymer lower critical solution temperature modification, which is especially helpful for physiological applications. Natural comonomers with desirable functionalities have also drawn significant attention as pressure surmounts to develop greener, more sustainable materials. Typically, these systems also tend to be more biocompatible and biodegradable and can be advantageous for use in biopharmaceutical and environmental applications. PNIPAAm-based polymeric nanocomposites are reviewed as well, where incorporation of inorganic or carbon nanomaterials creates synergistic systems that tend to be more robust and widely applicable than the individual components.

[This corrects the article DOI: 10.1093/rb/rbz002.][This corrects the article DOI: 10.1093/rb/rbz002.]., (© The Author(s) 2019. Published by Oxford University Press.)

Despite the promise of its therapeutic benefits, curcumin as a free molecule has failed to demonstrate significant clinical success. Arguably, its inherently poor stability and rapid clearance is a significant reason for these negative outcomes. The incorporation of curcumin into the backbone of a crosslinked hydrogel that utilizes poly(beta-amino ester) (PBAE) chemistry can provide a tunable protective network with the ability to release at a controlled rate while improving its therapeutic potential. Kinetics of curcumin conjugated PBAE microparticles controlled release delivery system in the presence of oxidative environments was studied for the first time, where consumption rates of active curcumin and release products were obtained. The constituent amount of curcumin present in solution was improved by incorporating the active into the network in comparison to curcumin as a free drug. Modeling curcumin conjugated PBAE microparticles will provide a design platform to improve translation and overall success in delivering a therapeutic agent that matches levels of oxidative stress.

In this work, we developed novel core-shell nanoparticle systems with magnetic core and polymer shell via atom transfer radical polymerization for use as high affinity nanoadsorbents for organic contaminants in water and wastewater treatment. Polyphenolic-based moieties, curcumin multiacrylate (CMA) and quercetin multiacrylate (QMA), were incorporated into poly(ethylene glycol) (PEG) based polymeric shells to create high affinity binding sites for the capture of polychlorinated biphenyls (PCBs) as a model pollutant. The resulting magnetic nanoparticles (MNPs) were characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), X-ray diffraction (XRD), dynamic light scattering (DLS), and UV-visible spectroscopy. The affinity of these novel materials for PCB 126 was evaluated and fitted to the nonlinear Langmuir model to determine binding affinities (KD). The KD values obtained were: PEG MNPs (8.42 nM) < IO MNPs (8.23nM) < QMA MNPs (5.88 nM) < CMA MNPs (2.72 nM), demonstrating that the presence of polyphenolic-based moieties enhanced PCB 126 binding affinity, which is hypothesized to be a result of π - π stacking interactions. These values are lower that KD values for activated carbon, providing strong evidence that these novel core-shell nanoparticles have a promising application as nanoadsorbents for specific organic contaminants offering a cost effective alternative to current remediation approaches.

Despite increasing controls in their production and disposal, persistent organic pollutants in water, even at concentrations below parts per million, represent an ongoing environmental health risk. Despite this concern, the detection of these compounds in water sources rely upon expensive, time consuming approaches that do not permit frequent monitoring and evaluation. In this work, a new fluorescence-based technique is presented for the detection of polychlorinated biphenyls (PCBs) in water. Benzopyrene (BaP) fluorescence was shown to increase with trace concentrations of aromatic organic pollutants. BaP forms a hydrophobic complex with PCBs, which has allowed for the successful detection of pollutants including PCB-126, PCB-153 and PCB-118. To determine the selectivity and robustness of this response, the impact of pH, ionic strength and humic acid to mimic surface water conditions is explored. While suppression of the signal was seen, these factors' impact on the detection of PCBs was minor, suggesting that a potential sensing strategy can be developed through this interaction. It is seen that the number and location of chlorine atoms are important along with the geometric orientation of molecule's structure.

As a consequence of their increase in annual production and widespread distribution in the environment, nanoparticles potentially pose a significant public health risk. The sought-after catalytic activity granted by their physiochemical properties doubles as a hazard to physiological processes following exposure through inhalation, oral, transdermal, subcutaneous, and intravenous uptake. Upon uptake into the body, their size, morphology, surface charge, coating, and chemical composition augment the response of biological systems to the materials and enhance their toxicity. Identification of each property is necessary to predict the harm imposed by foreign nanomaterials in the body. Assay methods ranging from endotoxin and lactate dehydrogenase (LDH) signaling to apoptosis and oxidative stress detection supply valuable techniques for exposing biomarkers of nanoparticle-induced cellular damage. Spectroscopic investigation of epithelial barrier permeation and distribution within living cells reveals the proclivity of nanoparticles to penetrate the body's natural defensive boundaries and deposit themselves in cytotoxic locations. Combination of the various characterization methodologies and assays is required for every new nanoparticulate system despite preexisting data for similar systems due to the lack of deterministic trends among investigated nanoparticles. The propensity of nanomaterials to denature proteins and oxidize substrates in their local environment generates significant concern for the applicability of several traditional in vitro assays, and the modification of susceptible approaches into novel methods suitable for the evaluation of nanoparticles comprises the focus of future work centered on nanoparticle toxicity analysis.

Disulfides are used extensively in reversible cross-linking because of the ease of reduction into click-reactive thiols. However, the free-radical scavenging properties upon reduction are often under-considered. The free thiols produced upon reduction of this disulfide material mimic the cellular reducing chemistry (glutathione) that serves as a buffer against acute oxidative stress. A nanoparticle formulation producing biologically relevant concentrations of thiols may not only provide ample chemical conjugation sites, but potentially be useful against severe acute oxidative stress exposure, such as in targeted radioprotection. In this work, we describe the synthesis and characterization of highly thiolated poly (β-amino ester) (PBAE) nanoparticles formed from the reduction of bulk disulfide cross-linked PBAE hydrogels. Degradation-tunable PBAE hydrogels were initially synthesized containing up to 26 wt % cystamine, which were reduced into soluble thiolated oligomers and formulated into nanoparticles upon single emulsion. These thiolated nanoparticles were size-stable in phosphate buffered saline consisting of up to 11.0 ± 1.1 mM (3.7 ± 0.3 mmol thiol/g, n = 3 M ± SD), which is an antioxidant concentration within the order of magnitude of cellular glutathione (1⁻10 mM).

Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g. glutathione/glutathione disulfide), if these biomaterials modify the cellular redox environment, they may inadvertently affect cellular compatibility and/or oxidative stress defenses. In this work, we hypothesize that the degradation products of a poly(β-amino ester) (PBAE) hydrogel formed with redox sensitive disulfide (cystamine) crosslinking could serve as a supplement to the environmental cellular antioxidant defenses. Upon introduction into a reducing environment, these disulfide-containing hydrogels cleave to present bound-thiol groups, yet remain in the bulk form at up to 66 mol% cystamine of the total amines. By controlling the molar fraction of cystamine, it was apparent that the thiol content varied human umbilical vein endothelial cell (HUVEC) viability IC 50 values across an order of magnitude. Further, upon introduction of an enzymatic oxidative stress generator to the cell culture (HX/XO), pre-incubated thiolated hydrogel degradation products conferred cellular and mitochondrial protection from acute oxidative stress, whereas non-reduced disulfide-containing degradation products offered no protection. This polymer may be an advantageous implantable drug delivery system for use in acute oxidative stress prophylaxis and/or chronic oxidative stress cell therapies due to its solid/liquid reversibility in a redox environment, controlled thiolation, high loading capacity through covalent drug-addition, and simple post-synthesis modification which bound-thiols introduce., Statement of Significance: In this work, we demonstrate a unique property of disulfide containing degradable biomaterials. By changing the redox state of the degradation products (from oxidized to reduced), it is possible to increase the IC 50 of the material by an order of magnitude. This dramatic shift is linked directly to the oxidative stress response of the cells and suggests a possible mechanism by which one can tune the cellular response to degradable biomaterials., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

A novel crosslinker [4,4'-dihydroxybiphenyl diacrylate (44BDA)] was developed, and a series of temperature-responsive hydrogels were synthesized through free radical polymerization of N -isopropylacrylamide (NIPAAm) with 44BDA. The temperature-responsive behavior of the resulting gels was characterized by swelling studies, and the lower critical solution temperature (LCST) of the hydrogels was characterized through differential scanning calorimetry. Increased content of 44BDA led to a decreased swelling ratio and shifted the LCST to lower temperatures. These novel hydrogels also displayed resiliency through multiple swelling-deswelling cycles, and their temperature responsiveness was reversible. The successful synthesis of NIPAAm-based hydrogels crosslinked with 44BDA has led to a new class of temperature-responsive hydrogel systems with a variety of potential applications., Competing Interests: The authors declare no competing financial interest.

Curcumin has recently gained interest for use in drug delivery, chemical sensing, and environmental applications. As a result, the development of synthesis strategies for the incorporation of curcumin into novel materials has become a priority. One such strategy, curcumin acrylation, involves the introduction of acrylate functional groups to the curcumin scaffold, with the potential generation of mono-, di-, and triacrylate curcumin species. The relative populations of these species in the resulting multiacrylate mixture can be controlled by the ratio of curcumin to acryloyl chloride in the initial reaction formulation. Characterization of the acrylation reaction and the resulting curcumin multiacrylate product is essential for the effective preparation of new curcumin-containing materials. In this work, a synthesis method for curcumin acrylation is presented and the resulting curcumin multiacrylate product is characterized via various techniques, i.e., HPLC, LCMS, and NMR, as a basis to establish the relationship between synthesis conditions and the extent of acrylation that is achieved.

Poly(β amino ester) polymers have received growing attention in the literature, owing to their ease of synthesis, versatile co-monomer selection, and highly tunable degradation kinetics. As such, they have shown extensive potential in many biomedical applications as well. In this work, it is demonstrated for the first time that PβAE polymers containing primary and secondary amine groups can undergo degradation by primary alcohols via transesterification mechanism. While this work emphasizes an important aspect of solvent compatibility of these networks, it also represents an interesting, simple mechanism for post synthesis drug incorporation, with riboflavin conjugation being demonstrated as a model compound.

Two series of thermosensitive hydrogels were synthesized by copolymerizing N-isopropylacrylamide (NIPAAm) with various contents of novel hydrophobic crosslinkers, curcumin multiacrylate (CMA) and quercetin multiacrylate (QMA). The compositions of the resulting hydrogels were characterized using solid state-NMR (ss-NMR), and the temperature dependent swelling behavior and lower critical solution temperature (LCST) were characterized using swelling studies and differential scanning calorimetry (DSC). Increasing the crosslinker content resulted in a significant decrease in the LCST and swelling ratio of hydrogels, which could be attributed to the increased hydrophobicity introduced by CMA or QMA. All of the hydrogels demonstrated temperature responsive swelling with the extent of swelling decreasing with increasing crosslinker content. The lower crosslinker content gels displayed sharper phase transitions, while the high crosslinker content gels had broader phase transitions.

The constant growth in population worldwide over the past decades continues to put forward the need to provide access to safe, clean water to meet human needs. There is a need for cost-effective technologies for water and wastewater treatment that can meet the global demands and the rigorous water quality standards and at the same maximizing pollutant efficiency removal. Current remediation technologies have failed in keeping up with these factors without becoming cost-prohibitive. Most recently, nanotechnology has been sought as the best alternative to increase access to water supplies by remediating those already contaminated and offering ways to access unconventional sources. The use of iron oxide magnetic nanoparticles as nanoadsorbents has led way to a new class of magnetic separation strategies for water treatment. This review focuses on highlighting some of the most recent advances in core-shell iron oxide magnetic nanoparticles and nanocomposites containing iron oxide nanoparticles currently being developed for water and wastewater treatment of organic pollutants. We discuss the novelty of these novel materials and the insight gained from their advances that can help develop cost-effective reusable technologies for scale-up and commercial use.

Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP). The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. While application of inhalable magnetic nanocomposite microparticles or magnetic nanocomposites (MnMs) to the micrometastatic TNBC model comprised of TTA generated from cancer and stromal cells, showed no measureable adverse effects in the absence of AMF-exposure, magnetic hyperthermia generated under the influence of an AMF in TTA incubated in a high concentration of MNP (1 mg/mL) caused significant increase in cellular death/damage with mechanical disintegration and release of cell debris indicating the potential of these inhalable composites as a promising approach for thermal treatment of diseased lungs. The novelty and significance of this study lies in the development of methods to evaluate in vitro the application of inhalable composites containing MNPs in thermal therapy using a physiologically relevant metastatic TNBC model representative of the microenvironmental characteristics in secondary lung malignancies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of novel temperature responsive hydrogels were synthesized by free radical polymerization with varying content of chrysin multiacrylate (ChryMA). The goal was to study the impact of this novel polyphenolic-based multiacrylate on the properties of N -isopropylacrylamide (NIPAAm) hydrogels. The temperature responsive behavior of the copolymerized gels was characterized by swelling studies, and their lower critical solution temperature (LCST) was characterized through differential scanning calorimetry (DSC). It was shown that the incorporation of ChryMA decreased the swelling ratios of the hydrogels and shifted their LCSTs to a lower temperature. Gels with different ChryMA content showed different levels of response to temperature change. Higher content gels had a broader phase transition and smaller temperature response, which could be attributed to the increased hydrophobicity being introduced by the ChryMA., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Magnetic iron oxide nanoparticles have been well known for their applications in magnetic resonance imaging (MRI), hyperthermia, targeted drug delivery, etc. The surface modification of these magnetic nanoparticles has been explored extensively to achieve functionalized materials with potential application in biomedical, environmental and catalysis field. Herein, we report a novel and versatile single step methodology for developing curcumin functionalized magnetic Fe3O4 nanoparticles without any additional linkers, using a simple coprecipitation technique. The magnetic nanoparticles (MNPs) were characterized using transmission electron microscopy, X-ray diffraction, fourier transform infrared spectroscopy and thermogravimetric analysis. The developed MNPs were employed in a cellular application for protection against an inflammatory agent, a polychlorinated biphenyl (PCB) molecule., (Copyright © 2016. Published by Elsevier B.V.)

To increase the efficacy of radiation, iron oxide nanoparticles can be utilized for their ability to produce reactive oxygen species (ROS). Radiation therapy promotes leakage of electrons from the electron transport chain and leads to an increase in mitochondrial production of the superoxide anion which is converted to hydrogen peroxide by superoxide dismutase. Iron oxide nanoparticles can then catalyze the reaction from hydrogen peroxide to the highly reactive hydroxyl radical. Therefore, the overall aim of this project was to utilize iron oxide nanoparticles conjugated to a cell penetrating peptide, TAT, to escape lysosomal encapsulation after internalization by cancer cells and catalyze hydroxyl radical formation. It was determined that TAT functionalized iron oxide nanoparticles and uncoated iron oxide nanoparticles resulted in permeabilization of the lysosomal membranes. Additionally, mitochondrial integrity was compromised when A549 cells were treated with both TAT-functionalized nanoparticles and radiation. Pre-treatment with TAT-functionalized nanoparticles also significantly increased the ROS generation associated with radiation. A long term viability study showed that TAT-functionalized nanoparticles combined with radiation resulted in a synergistic combination treatment. This is likely due to the TAT-functionalized nanoparticles sensitizing the cells to subsequent radiation therapy, because the nanoparticles alone did not result in significant toxicities., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Mitochondria are considered to be the "power plants" of the cell, but can also initiate and execute cell death, stimulated by oxidative stress (OS). OS induced mitochondrial dysfunction is characterized by a loss in oxygen consumption and reduced ATP production. Curcumin, as a potential therapeutic, has been explored as a candidate for mitochondrial OS suppression, but rapid metabolism and aqueous insolubility has prevented it from being effective. Further, efficient delivery of curcumin via the incorporation into nanocarriers has again been limited due to low drug loading capacities and/or significant burst release, resulting in acute cytotoxicity. Hence, to increase the therapeutic potential and reduce the toxic effects of curcumin, curcumin conjugated poly(β-amino ester) nanogels (CNGs) were synthesized using Michael addition chemistry. This approach provided easy control over the nanogel size, with CNGs showing a uniform release of active curcumin over 48h with no burst release. This controlled release system significantly increased the safety limit for curcumin, with a ten fold increase in the cytotoxic threshold, as compared to free curcumin. Further, real-time mitochondrial response analysis with the Seahorse XF96 showed effective and prolonged suppression of H2O2 induced mitochondrial oxidative stress upon pre-treating endothelial cells with CNGs and this potential of nanogels was studied at different pre-treatment times prior to H2O2 exposure., Competing Interests: The authors have no potential conflicts of interest., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aim: In the present study, we examine the effects of internalized peptide-conjugated iron oxide nanoparticles and their ability to locally convert alternating magnetic field (AMF) energy into other forms of energy (e.g., heat and rotational work)., Materials & Methods: Dextran-coated iron oxide nanoparticles were functionalized with a cell penetrating peptide and after internalization by A549 and H358 cells were activated by an AMF., Results: TAT-functionalized nanoparticles and AMF exposure increased reactive oxygen species generation compared with the nanoparticle system alone. The TAT-functionalized nanoparticles induced lysosomal membrane permeability and mitochondrial membrane depolarization, but these effects were not further enhanced by AMF treatment. Although not statistically significant, there are trends suggesting an increase in apoptosis via the Caspase 3/7 pathways when cells are exposed to TAT-functionalized nanoparticles combined with AMF., Conclusion: Our results indicate that internalized TAT-functionalized iron oxide nanoparticles activated by an AMF elicit cellular responses without a measurable temperature rise.

Three-dimensional (3D) lung multicellular spheroids (MCS) in liquid-covered culture (LCC) and air-interface culture (AIC) conditions have both been developed for the evaluation of aerosol anticancer therapeutics in solution and aerosols, respectively. The MCS were formed by seeding lung cancer cells on top of collagen where they formed spheroids due to the prevalence of cell-to-cell interactions. LCC MCS were exposed to paclitaxel (PTX) in media whereas AIC MCS were exposed to dry powder PEGylated phospholipid aerosol microparticles containing paclitaxel. The difference in viability for 2D versus 3D culture for both LCC and AIC was evaluated along with the effects of the particles on lung epithelium via transepithelial electrical resistance (TEER) measurements. For LCC and AIC conditions, the 3D spheroids were more resistant to treatment with higher IC50 values for A549 and H358 cell lines. TEER results initially indicated a decrease in resistance upon drug or particle exposure, however, these values increased over the course of several days indicating the ability of the cells to recover. Overall, these studies offer a comprehensive in vitro evaluation of aerosol particles used in the treatment of lung cancer while introducing a new method for culturing lung cancer MCS in both LCC and AIC conditions.

This review highlights the state-of-the-art in the application of magnetic nanoparticles (MNPs) and their composites for remote controlled therapies. Novel macro- to nano-scale systems that utilize remote controlled drug release due to actuation of MNPs by static or alternating magnetic fields and magnetic field guidance of MNPs for drug delivery applications are summarized. Recent advances in controlled energy release for thermal therapy and nanoscale energy therapy are addressed as well. Additionally, studies that utilize MNP-based thermal therapy in combination with other treatments such as chemotherapy or radiation to enhance the efficacy of the conventional treatment are discussed.

PβAE polymers have emerged as highly promising candidates for biomedical and drug delivery applications owing to their tunable, degradable and pH sensitive properties. These polymeric systems can serve as prodrug carriers for the delivery of bioactive compounds which suffer from poor aqueous solubility, low bioavailability and are biologically unstable, such as the antioxidant, quercetin. Using acrylate functionalized quercetin, it is possible to incorporate the polyphenol into the backbone of the polymer matrix, permitting slow release of the intact molecule which is perfectly timed with the polymer degradation. While formulating these quercetin conjugated PβAE matrix into nanocarriers would allow for multiple delivery routes (oral, intravenous, inhalation etc.), well known oil-water nano-emulsion formulation methods are not amenable to the crosslinked hydrolytically sensitive nanoparticle/nanogel. In this work, a single-phase reaction-precipitation method was developed to formulate quercetin conjugated PβAE nanogels (QNG) via reaction of acrylated quercetin (4-5 acrylate groups) with a secondary diamine under dilute conditions using acetonitrile as the reaction medium, resulting in a self-stabilized suspension. The proposed approach permits the post synthesis modification of the spherical nanogels with a PEGylated coating, enhancing their aqueous stability and stealth characteristics. Nanogel size was controlled by varying feed reactant concentrations, achieving drug loadings of 25-38wt%. Uniform release of quercetin over 45-48h was observed upon PβAE ester hydrolysis under physiological conditions with its retained antioxidant activity over the extended times., Statement of Significance: Here we present the first demonstration of using poly(beta amino ester) chemistry to form nanogels composed of a bioactive polyphenol for the control of cellular oxidative stress. Previous nanogel and nanoparticle approaches, which use a water phase, are not readily amenable to PBAE chemistry due to their hydrolytic sensitivity. Here we demonstrate a simple approach to control particle size, modify surface chemistry and achieve highly regulated controlled release of active antioxidants, which can protect cells against external oxidative stress signals. This work has importance in the area of controlling material biocompatibility through augmenting the antioxidant status of cells., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Monosaccharide coated iron oxide nanoparticles were developed to selectively target colon cancer cell lines for magnetically mediated energy delivery therapy. The nanoparticles were prepared using a coupling reaction to attach the glucose functional group to the iron oxide core, and functionality was confirmed with physicochemical characterization techniques. The targeted nanoparticles were internalized into CT26 cells at a greater extent than non-targeted nanoparticles, and the nanoparticles were shown to be localized within lysosomes. Cells with internalized nanoparticles were exposed to an AMF to determine the potential to delivery therapy. Cellular ROS generation and apoptotic cell death was enhanced with field exposure. The nanoparticle coatings inhibit the Fenton-like surface generation of ROS suggesting a thermal or mechanical effect is more likely the source of the intracellular effect, unless the nanoparticle coating is unstable in the cellular environment., Statement of Significance: This is the first study to assess glucose coated MNPs for the delivery of MagMED therapy. With exposure of an AMF, the glucose-coated nanoparticles displayed a significant increase in cellular ROS and apoptotic cell death with no measurable increase in media temperature. To determine the mechanism of toxicity, we investigated the surface generation of ROS through Fenton-like chemistry. The coated systems displayed negligible ROS generation compared to uncoated nanoparticles. These observations suggest the cellular ROS measured is attributed to a thermal or mechanical effect of the internalized nanoparticles. In summary, this manuscript reports on some new insights as to the mechanism of MagMED therapies, which are of high interest to the biomaterials and cancer nanomedicine fields., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Nanoparticles represent one of the most widely studied classes of advanced drug delivery platforms in recent years due to a wide range of unique properties and capabilities that can be utilized to improve upon traditional drug administration. Conversely, hydrogel nanoparticles (HNPs) - also called nanogels - represent a unique class of materials that combine the intrinsic advantages of nanotechnology with the inherent capabilities of hydrogels. Responsive hydrogels pose a particularly interesting class of materials that can sense and respond to external stimuli and previous reports of inhalable hydrogel particles have highlighted their potential in pulmonary delivery. Here, we synthesized two different pH-responsive HNPs, designated HNP120 and HNP270, by incorporating functional monomers with a common crosslinker and characterized their physicochemical properties. One of the HNP systems was selected for incorporation into a composite dry powder by spray drying, and the aerodynamic performance of the resulting powder was evaluated. The HNP120s displayed a hydrodynamic diameter of approximately 120 nm in their fully swollen state and a minimal diameter of around 80 nm while the HNP270s were approximately 270 nm and 115 nm, respectively. Electron microscopy confirmed particle size- and morphological uniformity of the HNPs. The HNP120s were spray dried into composite dry powders for inhalation and cascade impaction studies showed good aerosol performance with a mass median aerosol diameter (MMAD) of 4.82 ± 0.37 and a fine particle fraction > 30%. The HNPs released from the spray dried composites retained their responsive behavior thereby illustrating the potential for these materials as intelligent drug delivery systems that combine the advantages of nanotechnology, lung targeting through pulmonary delivery, and stimuli-responsive hydrogels.

In situ forming poly(lactic-co-glycolic acid) (PLGA) implants have not been strongly considered for bone applications because of their poor mechanical properties. Here, in situ forming scaffolds containing hydroxyapatite micro- and nanoparticles were characterized to determine their mechanical properties, injectability, and microarchitecture. Scaffolds were prepared with various concentrations of hydroxyapatite, as well as poly(β-amino ester) microparticles that facilitate drug delivery. Strength was increased threefold, from 2 to 6 MPa, while compressive modulus was improved sixfold, from 24 to 141 MPa, via the addition of 30% nanohydroxyapatite, which provided greater benefits at equivalent concentrations compared to micro-hydroxyapatite. Scaffolds retained a uniformly porous microarchitecture, and hydroxyapatite particles were distributed evenly throughout the PLGA phase. Injectability, determined by the force required to inject 0.5 mL of material within 60 s, remained clinically acceptable at <50 N at 30% w/w hydroxyapatite and up to 10% w/w PBAE microparticles. Ex vivo injections into intact porcine femoral heads increased compressive modulus of trabecular bone from 81 to 180 MPa and strength from 3.5 to 5.9 MPa. This injectable scaffold offers mechanical reinforcement coupled with previously demonstrated drug delivery potential in a single injection for bone-weakening conditions, such as osteonecrosis or osteoporosis., (© 2014 Wiley Periodicals, Inc.)

Iron oxide nanoparticles coated with dextran were synthesized via four variations on the co-precipitation method. The methods ranged from in situ formation of the nanoparticles within the dextran solution to the adsorption of dextran to the nanoparticle surface following nucleation and extensive washing. The timing of the addition of dextran into the reaction mixture was found to greatly influence the physical and chemical properties of the magnetic nanoparticles. Batches of dextran coated iron oxide nanoparticles were synthesized by each method in triplicate, and the nanoparticles were further crosslinked with epichlorohydrin. The properties of the nanoparticles such as size, percentage of dextran coating, stability in solution, crystallinity, and magnetic properties were evaluated. The simultaneous semi-two-step method injected the reducing agent and the dextran solution into the reaction vessel at the same time. This method resulted in the greatest batch-to-batch reproducibility of nanoparticle properties and the least variation in nanoparticles synthesized in the same batch. The two-step method resulted in the greatest variation of the characteristics examined between batches. The one-step method was synthesized with both five grams and one gram of dextran to investigate the effects of solution viscosity on the resulting nanoparticle characteristics. The one-step method with five grams of dextran resulted in nanoparticles with significantly smaller crystal sizes (5.4 ± 1.9 nm) and lower specific adsorption rate (SAR) values (138.4 ± 13.6 W/g) in an alternating magnetic field (58 kA/m, 292 kHz). However, this method resulted in nanoparticles that were very stable in PBS over 12 hours, which is most likely due to the greater dextran coating (60.0 ± 2.7 weight percent). For comparison, the simultaneous semi-two-step method generated nanoparticles 179.2 ± 18.3 nm in diameter (crystal size 12.1 ± 0.2 nm) containing 18.3 ± 1.2 weight percent dextran with a SAR value of 321.1 ± 137.3 W/g.

Targeted pulmonary delivery facilitates the direct application of bioactive materials to the lungs in a controlled manner and provides an exciting platform for targeting magnetic nanoparticles (MNPs) to the lungs. Iron oxide MNPs remotely heat in the presence of an alternating magnetic field (AMF) providing unique opportunities for therapeutic applications such as hyperthermia. In this study, spray drying was used to formulate magnetic nanocomposite microparticles (MnMs) consisting of iron oxide MNPs and d-mannitol. The physicochemical properties of these MnMs were evaluated and the in vitro aerosol dispersion performance of the dry powders was measured by the Next Generation Impactor(®). For all powders, the mass median aerosol diameter (MMAD) was <5μm and deposition patterns revealed that MnMs could deposit throughout the lungs. Heating studies with a custom AMF showed that MNPs retain excellent thermal properties after spray drying into composite dry powders, with specific absorption ratios (SAR)>200W/g, and in vitro studies on a human lung cell line indicated moderate cytotoxicity of these materials. These inhalable composites present a class of materials with many potential applications and pose a promising approach for thermal treatment of the lungs through targeted pulmonary administration of MNPs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

To help reduce the need for autografts, calcium sulfate (CS)-based bone graft substitutes are being developed to provide a stable platform to aid augmentation while having the ability to release a broad range of bioactive agents. CS has an excellent reputation as a biocompatible and osteoconductive substance, but addition of bioactive agents may further enhance these properties. Samples were produced with either directly loaded small, hydrophobic molecule (i.e., simvastatin), directly loaded hydrophilic protein (i.e., lysozyme), or 1 and 10 wt % of fast-degrading poly(β-amino ester) (PBAE) particles containing protein. Although sustained release of directly loaded simvastatin was achieved, direct loading of small amounts of lysozyme resulted in highly variable release. Direct loading of a larger amount of protein generated a large burst, 65% of total loading, followed by sustained release of protein. Release of lysozyme from 1 wt % of PBAE particles embedded into CS was more controllable than when directly loaded, and for 10 wt % of protein-loaded PBAE particles, a higher burst was followed by sustained release, comparable to the results for the high direct loading. Compression testing determined that incorporation of directly loaded drug or drug-loaded PBAE particles weakened CS. In particular, PBAE particles had a significant effect on the strength of the composites, with a 25 and 80% decrease in strength for 1 and 10 wt % particle loadings, respectively. CS-based composites demonstrated the ability to sustainably release both macromolecules and small molecules, supporting the potential for these materials to release a range of therapeutic agents., (© 2014 Wiley Periodicals, Inc.)

The surfaces of iron oxide nanoparticles are capable of catalytically generating reactive oxygen species (ROS) through the Fenton and Haber-Weiss reactions. Fenton chemistry has been shown to be temperature dependent with an increase in activity up to 40 °C and then a decrease above this temperature as the hydrogen peroxide degrades into oxygen and water which limits the reaction. When exposed to an alternating magnetic field (AMF), iron oxide nanoparticles absorb the energy from the magnetic field and convert it into heat. In this study, we observed an increase in the degradation of methylene blue when a suspension of magnetite nanoparticles (Fe 3 O 4 ) was exposed to an AMF indicating there was an increase in the ROS generation in response to the AMF. The increase in ROS generation compared to the Arrhenius prediction was both time and concentration dependent; in which we observed a decrease in ROS enhancement with increased time of exposure and concentration. We postulate that the decrease is due to agglomeration in the presence of the field. As the nanoparticles agglomerate, there is a decrease in surface area per mass limiting the reaction rate.