Simulated Physiological Media Research Articles

Biodegradable silica gated poly (methylacrylate acid) core-shell microspheres for pH and glutathione dual responsive drug delivery

Tumor microenvironment responsive drug delivery system presents great potential in tumor-targeted drug delivery. In this study, a poly (ethylene glycol) (PEG) coated biodegradable core-shell microsphere PMAA@DOX-SiO2-PEG with a poly (methylacrylate acid) (PMAA) core and a biodegradable silica layer was prepared. Doxorubicin (DOX) was effectively loaded into the PMAA core and sealed by the silica layer with a drug loading efficiency of 15.3 %. The PEG-modified drug-loaded microspheres present high stability at simulated physiological media with minimized drug leakage (8 %, 56 h), while 80 % drug could be released within 10 h at simulated tumor environment due to the effective carrier degradation. In vitro cell experiments also confirm the good biocompatibility of the blank carrier and the effective tumor inhibition of the drug-loaded microspheres. The study is expected to further promote the development of tumor microenvironment-responsive drug delivery systems.

Degradation and Erosion of Metal-Organic Frameworks: Comparative Study of a NanoMIL-100 Drug Delivery System.

To make a drug work better, the active substance can be incorporated into a vehicle for optimal protection and control of the drug delivery time and space. For making the drug carrier, the porous metal-organic framework (MOF) can offer high drug-loading capacity and various designs for effective drug delivery performance, biocompatibility, and biodegradability. Nevertheless, its degradation process is complex and not easily predictable, and the toxicity concern related to the MOF degradation products remains a challenge for their clinical translation. Here, we describe an in-depth molecular and nanoscale degradation mechanism of aluminum- and iron-based nanoMIL-100 materials exposed to phosphate-buffered saline. Using a combination of analytical tools, including X-ray photoelectron spectroscopy, nuclear magnetic resonance spectroscopy, small-angle X-ray scattering, and electron microscopy, we demonstrate qualitatively and quantitatively the formation of a new coordination bond between metal(III) and phosphate, trimesate release, and correlation between these two processes. Moreover, the extent of material erosion, i.e., bulk or surface erosion, was examined from the transformation of nanoparticles' surface, morphology, and interaction with water. Similar analyses show the impact of drug loading and surface coating on nanoMIL-100 degradation and drug release as a function of the metal-ligand binding strength. Our results indicate how the chemistry of nanoMIL-100(Al) and nanoMIL-100(Fe) drug carriers affects their degradation behaviors in a simulated physiological medium. This difference in behavior between the two nanoMIL-100s enables us to better correlate the nanoscale and atomic-scale mechanisms of the observed phenomena, thus validating the presented multiscale approach.

Dual Rifampicin and Isoniazid Mannose-Decorated Lipopolysaccharide Nanospheres for Macrophage- Targeted Lung Delivery.

Currently, the treatment protocols for tuberculosis (TB) have several challenges, such as inconsistent oral bioavailability, dose-related adverse effects, and off-target drug toxicity. This research reports the design and characterization of rifampicin (RIF) and isoniazid (INH) loaded hybrid lipid-polysaccharide nanoparticles using the solvent injection method, and demonstrated the influence of conjugated mannosyl residue on macrophage targeting and intracellular drug delivery capacity. The nanospheres, herein called mannose-decorated lipopolysaccharide nanoparticles, were spherical in shape, exhibiting average sizes less than 120 nm (PDI<0.20) and positive zeta potentials. Drug encapsulation was greater than 50% for rifampicin and 60% for isoniazid. The pH-responsive drug release was sustained over a 48-hour period and preferentially released more rifampicin/isoniazid in a simulated acidic phagolysosomal environment (pH 4.8) than in a simulated physiological medium. TGA and FTIR analysis confirmed successful mannose-grafting on nanoparticle surface and optimal degree of mannosylation was achieved within 48-hour mannose-lipopolysaccharide reaction time. The mannosylated nanoparticles were biocompatible and demonstrated a significant improvement towards uptake by RAW 264.7 cells, producing higher intracellular RIF/INH accumulation when compared to the unmannosylated nanocarriers. Overall, the experimental results suggested that mannose-decorated lipopolysaccharide nanosystems hold promise towards safe and efficacious macrophage-targeted delivery of anti-TB therapeutics.

Development of Stable Amino-Pyrimidine-Curcumin Analogs: Synthesis, Equilibria in Solution, and Potential Anti-Proliferative Activity.

With the clear need for better cancer treatment, naturally occurring molecules represent a powerful inspiration. Recently, curcumin has attracted attention for its pleiotropic anticancer activity in vitro, especially against colorectal and prostate cancer cells. Unfortunately, these encouraging results were disappointing in vivo due to curcumin's low stability and poor bioavailability. To overcome these issues, herein, the synthesis of eight new pyrimidine-curcumin derivatives is reported. The compounds were fully characterized (1H/13C NMR (Nuclear Magnetic Resonance), LC-MS (Liquid Chromatography-Mass Spectrometri), UV-Vis spectroscopy), particularly their acid/base behavior; overall protonation constants were estimated, and species distribution, as a function of pH, was predicted, suggesting that all the compounds are in their neutral form at pH 7.4. All the compounds were extremely stable in simulated physiological media (phosphate-buffered saline and simulated plasma). The compounds were tested in vitro (48 h incubation treatment) to assess their effect on cell viability in prostate cancer (LNCaP and PC3) and colorectal cancer (HT29 and HCT116) cell lines. Two compounds showed the same anti-proliferative activity as curcumin against HCT116 cells and improved cytotoxicity against PC3 cells.

Hyperbranched Copolymers of Methacrylic Acid and Lauryl Methacrylate H-P(MAA-co-LMA): Synthetic Aspects and Interactions with Biorelevant Compounds.

The synthesis of novel copolymers using one-step reversible addition-fragmentation chain transfer (RAFT) copolymerization of biocompatible methacrylic acid (MAA), lauryl methacrylate (LMA), and difunctional ethylene glycol dimethacrylate (EGDMA) as a branching agent is reported. The obtained amphiphilic hyperbranched H-P(MAA-co-LMA) copolymers are molecularly characterized by size exclusion chromatography (SEC), FTIR, and 1H-NMR spectroscopy, and subsequently investigated in terms of their self-assembly behavior in aqueous media. The formation of nanoaggregates of varying size, mass, and homogeneity, depending on the copolymer composition and solution conditions such as concentration or pH variation, is demonstrated by light scattering and spectroscopic techniques. Furthermore, drug encapsulation properties are studied by incorporating the low bioavailability drug, curcumin, in the nano-aggregate hydrophobic domains, which can also act as a bioimaging agent. The interaction of polyelectrolyte MAA units with model proteins is described to examine protein complexation capacity relevant to enzyme immobilization strategies, as well as explore copolymer self-assembly in simulated physiological media. The results confirm that these copolymer nanosystems could provide competent biocarriers for imaging and drug or protein delivery/enzyme immobilization applications.

Newly Synthesized Lignin Microparticles as Bioinspired Oral Drug-Delivery Vehicles: Flavonoid-Carrier Potential and In Vitro Radical-Scavenging Activity.

The aim of the present study was to synthesize lignin microparticles, to evaluate their physicochemical, spectral, morphological and structural characteristics, to examine their encapsulation and in vitro release potential and behaviour towards the flavonoid morin in simulated physiological medium and to assess the in vitro radical-scavenging potential of the morin-loaded lignin microcarrier systems. The physicochemical, structural and morphological characteristics of alkali lignin, lignin particles (LP) and morin-encapsulated lignin microparticles (LMP) were determined based on particle size distribution, SEM, UV/Vis spectrophotometric, FTIR and potentiometric titration analyses. The encapsulation efficiency of LMP was 98.1%. The FTIR analyses proved that morin was successfully encapsulated in the LP without unexpected chemical reactions between the flavonoid and the heteropolymer. The in vitro release performance of the microcarrier system was successfully mathematically described by Korsmeyer-Peppas and the sigmoidal models outlining the general role of diffusion during the initial stages of the in vitro release process in simulated gastric fluid (SGF), and the predominant contribution of biopolymer relaxation and erosion was determined in simulated intestinal medium (SIF). The higher radical-scavenging potential of LMP, as compared to that of LP, was proven via DPPH and ABTS assays. The synthesis of lignin microcarriers not only provides a facile approach for the utilization of the heteropolymer but also determines its potential for the design of drug-delivery matrices.

Oxime@Zirconium-Metal–Organic Framework Hybrid Material as a Potential Antidote for Organophosphate Poisoning

A novel material with dual activity toward organophosphate (OP) poisoning, based on Zr-MOF-808 and neutral oxime RS69N, has been prepared. The hybrid material has a significant drug payload (5.2 ± 0.9 oxime to MOF-808 molar ratio) and shows a sustained oxime release in simulated physiological media, leading to the successful reactivation of OP-inhibited acetylcholinesterase. At the same time, the hybrid system presents an efficient and moderately fast removal rate of a toxic organophosphorus model compound (diisopropylfluorophosphate) from simulated physiological media (t1/2 = 183 min; 95% removal rate after 24 h).

Mechanical, tribological and electrochemical behavior of Zr-based ceramic thin films for dental implants

To determine the possibility of using new thin films architectures as biocompatible materials, an experimental and computational study was performed to evaluate the mechanical, tribological, and corrosion properties in simulated physiological media (saliva and blood plasma) of Zr, ZrN, and ZrN/Zr coatings, deposited by PVD magnetron sputtering. The crystalline structure and chemical composition were well correlated with high resistance to plastic deformation, wear, and corrosion, making these materials excellent candidates for functionalizing and protecting dental prostheses. The predominant wear mechanism under consideration was abrasion, which was reduced when using ceramic ZrN coating as a base for the superficial Zr thin film. When exposed to simulated body fluids, these materials exhibited high corrosion resistance, which was demonstrated by potentiodynamic measurements. These results are consistent with those predicted by Density Functional Theory computational models, which showed that electron transfer associated with the wear mechanism is kinetically impeded, as a consequence of the large energy barriers for this process associated with the adsorption of the molecular species on the ZrN surface. Additionally, calculated adsorption energies indicated that urea (from the simulated saliva solution) interacts strongly with the surface. This interaction was associated to the formation of passivating protective layers, which is a key mechanism to protect against corrosion, acting in synergy with the kinetic barriers.

Indium-gallium-zinc oxide Schottky diodes on softening substrates for rectifying bioelectronic circuits

Incorporating electronic components onto soft materials facilitates the development of compliant electronics suited for bioelectronic applications. In this work, we present indium-gallium-zinc-oxide (IGZO) Schottky diodes fabricated on a stimuli-responsive polymer that undergoes softening (i.e. orders-of-magnitude drop in modulus) upon exposure to physiological stimuli. These diodes rectify megahertz radio-frequency (RF) signals in half-wave rectification circuits across the softening of the polymer substrate and withstand mechanical and chemical stresses such as repeated folding up to 10 000 cycles and aging in a simulated physiological medium for up to two weeks. The effects of thermal annealing and ultraviolet-ozone treatment processes are evaluated using dynamic mechanical analysis and x-ray photoelectron spectroscopy techniques, showing that these processes lead to a large improvement in the interface properties of the platinum-IGZO Schottky contact while preserving the thermomechanical properties of the softening polymer substrate. The RF rectification capabilities of these diodes in softened and deformed states are particularly interesting for the next generation of soft wireless bioelectronics.

Cephalexin loading and controlled release studies on mesoporous silica functionalized with amino groups

KIT-6 mesoporous silica has been synthesized using the sol-gel method and functionalized with 3-aminopropyl triethoxysilane by grafting route to obtain KIT-6/NH2. These samples were used as carriers in the loading and controlled release of cephalexin (CFX). The effect of temperature and gastric and intestinal pH on the stability of pure CFX and loaded in KIT-6 and KIT-6/NH2 were investigated. The properties of the synthesized materials and their CFX loading capacity were studied through FTIR, ads-des N2 at 77 K, TEM, SEM, XPS, and TGA. The controlled release tests were carried out in a simulated physiological medium at gastric (1.2) and intestinal pH (6.8). Furthermore, the biocompatibility of both materials was studied through cell viability tests in Caco-2 intestinal cells. The results revealed that KIT-6 and KIT-6/NH2 had similar CFX loading capacities. It was found that CFX degrades at pH 6.8, however, KIT-6 and KIT-6/NH2 were able to protect it from the aforementioned degradation. Moreover, KIT-6 materials presented a good performance as CFX carriers since both materials provided diffusion-controlled release profiles during 24 h, satisfying the Korsmeyer-Peppas kinetic model. Mesoporous silicas presented in this work are promising candidates to be used in CFX controlled release systems due to their chemical interactions, textural properties, and high cell viability.

Highly porous and injectable hydrogels derived from cartilage acellularized matrix exhibit reduction and NIR light dual-responsive drug release properties for application in antitumor therapy

In this work, we developed novel stimuli-responsive injectable hydrogels composed of a highly biocompatible cartilage acellularized matrix (CAM) and a water-soluble cross-linker containing a diselenide bridge by using ultrafast norbornene (Nb)-tetrazine (Tz) click chemistry. The cross-linking reaction between the Nb groups of the CAM and Tz groups of the cross-linker evolved nitrogen gas and resulted in injectable hydrogels with highly porous structures. The synthesized hydrogels demonstrated high drug loading efficiencies (up to 93%), good swelling ratios, and useful mechanical properties. The doxorubicin (DOX)-loaded hydrogels released minimal amounts of DOX in the simulated physiological medium; however, sustained release of DOX was detected under reducing conditions, revealing more than 90% DOX release after 96 h. Interestingly, the indocyanine green (ICG)-incorporated hydrogels produced reactive oxygen species upon exposure to NIR light and exhibited burst release (>50% DOX release) of DOX during the first 4 h, followed by a sustained release phase. In vitro cytocompatibility tests showed that the synthesized CAM-Nb and hydrogels are essentially nontoxic to HFF-1 fibroblast cells and human colorectal adenocarcinoma cells (HT-29), indicating their excellent bioorthogonality and biocompatibility. Furthermore, DOX-loaded and DOX + ICG-loaded hydrogels inhibited the metabolic activities of HT-29 cells after GSH or NIR exposure and induced antitumor effects similar to those of free DOX. Therefore, these biocompatible and reduction-responsive injectable hydrogels, which exhibited on-demand drug release after NIR exposure, could be promising candidates for minimally invasive local delivery of cancer therapeutics.

Nb-60Ta-2Zr alloy exposed to simulated physiological medium: Metallic-ion release behaviour and its correlation with electrochemical properties

In this work, a magnetic-resonance-imaging (MRI) compatible Nb-60Ta-2Zr alloy was selected to investigate the metallic-ion release behaviour exposed to simulated physiological medium. The kinetic processes of metallic-ion release were apparently characterized in two distinct phases. In contrast, electrochemical properties were insensitive to extended exposure times. A well-defined correlation of metallic-ion release with electrochemical properties was absent until the dynamic steady state of ion release was established. XPS analysis indicated that the passive film on the Nb-60Ta-2Zr surface after 21 days of exposure was primarily composed of Nb2O5 and Ta2O5, together with trace amounts of ZrO2 and suboxides of Nb and Ta.

Chitosan-based DDSs for pH/hypoxia dual-triggered DOX delivery: Facile morphology modulation for higher in vitro cytotoxicity

The morphology of the drug delivery systems (DDSs) has been recognized to play an important role in their phagocytosis, cellular interaction and distribution. However, it is a technical challenge to simply prepare the non-spherical nanoscaled DDSs. Here, a facile strategy was developed to fabricate the pH/hypoxia dual-responsive nanowires by adding the maleic acid (MAH) and PEG modified chitosan (PEG-SS-CS-MAH) into aqueous solution of DOX. Compared with the PEG-SS-CS-MAH/DOX nanoparticles (NPs) by adding DOX into the PEG-SS-CS-MAH solution, the PEG-SS-CS-MAH/DOX nanowires (NWs) possessed a higher drug loading capacity of 58% and better pH/hypoxia dual-triggered DOX release performance with higher drug release in the simulated tumor intracellular microenvironment but a much lower premature drug leakage in the simulated normal physiological medium. As a result, higher in vitro anti-tumor efficacy was achieved with the PEG-SS-CS-MAH/DOX NWs, demonstrating their promising potential for tumor chemotherapy.

Co-Crystals of Etravirine by Mechanochemical Activation

The co-crystals formation of etravirine with three carboxylic acids was investigated. New co-crystals of etravirine with adipic acid, benzoic acid, and 4-hydroxybenzoic acid have been synthesized by wet milling of ingredients for 120 min. The novelty of these solid forms was first evidenced by powder X-ray diffraction. Their different morphology was evidenced by SEM microscopy. Spectroscopic analyses (FT-IR, MAS-NMR, and XPS) highlighted the hydrogen bonds between etravirine and co-formers, as a result of the solid-state reaction of the ingredients by wet milling. Thermal analyses pointed out that the milling process caused in co-crystals a reduction in the fusion enthalpy and the melting temperature, compared to the values obtained for etravirine. These co-crystals are stable up to four months on storage under extreme conditions, excepting the co-crystal with benzoic acid which begins to transform into a polymorph of etravirine after 30 days. The UV absorption spectra of the samples tested in three simulated physiological media with pH values of 6, 6.3, and 7 have evidenced the conformation change of etravirine due to hydrogen bonds between etravirine and carboxylic acids.

Structure and Corrosion Behavior of TiO2 Thin Films Deposited by ALD on a Biomedical Magnesium Alloy

Magnesium alloys have been investigated as temporary biomaterials for orthopedic applications. Despite their high osseointegration and mechanical (bone-like) properties, Mg alloys quickly degrade in simulated physiological media. Surface coatings can be deposited onto Mg alloys to slow the corrosion rate of these biomaterials in chloride-rich environments. TiO2 films show high potential for improving the corrosion resistance of magnesium alloys. This article presents the structural observations and corrosion behavior of TiO2 thin films deposited onto a MgCa2Zn1Gd3 alloy using atomic layer deposition (ALD). Surface morphologies were observed using scanning electron microscopy (SEM) and atomic force microscopy (AFM), and Raman analysis of the deposited TiO2 films was also carried out. The corrosion behavior of the uncoated alloy and the alloy coated with TiO2 was measured in Ringer’s solution at 37 °C using electrochemical and immersion tests. The microscopic observations of the TiO2 thin films with a thickness of about 52.5 and 70 nm showed that the surface morphology was homogeneous without visible defects on the TiO2 surface. The electrochemical and immersion test results showed that the thin films decreased the corrosion rate of the studied Mg-based alloy, and the corrosion resistance was higher in the thicker TiO2 film.

Improving drug delivery performance of pH-triggered prodrug nanoparticles with an adaptive polycation block as pH-sensitive gatekeeper.

Efficient approach was established to improve the drug delivery performance of the pH-triggered prodrug nanoparticles by introducing a polycation block as a pH-sensitive gatekeeper. With the help of the poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) block as a pH-sensitive shell gatekeeper, the proposed core-shell-corona PEG43-b-PDPA65-b-PFPMA36-DOX nanoparticles possessed a higher drug release rate in the simulated acidic tumor intracellular micro-environment while a lower premature drug leakage in the simulated weak basic normal physiological medium, compared with the core-shell PEG43-b-PFPMA36-DOX nanoparticles. The proposed strategy is expected to design high-performance drug delivery systems (DDSs) for tumor treatment, with improved anticancer efficacy but minimized toxic side effects.

DOX-conjugated CQD-based nanosponges for tumor intracellular pH-triggered DOX release and imaging

Novel tumor nanotheranostics were designed by conjugating doxorubicin (DOX) onto the hydrazine-functionalized crosslinked carbon quantum dots (CQDs)/polyethylene glycol bisacrylate (PEGBA) (C-CQDPEGBA-Hy) nanosponges via an acid-labile imine bond for the tumor intracellular real-time imaging and pH-triggered DOX release. The proposed prodrug nanotheranostics with a DOX content of 14.57 % and a mean hydrodynamic diameter around 116 nm showed excellent pH-triggered drug release performance, with a cumulative release of 52.71 % in the simulated tumor intracellular microenvironment in 4 days, while a premature drug leakage of 7.09 % in the simulated normal physiological medium. Besides, the fluorescence could be recovered during the drug release, indicating the potential application for tumor intracellular real-time imaging.

Mobility and accessibility of Zn, Pb, and As in abandoned mine tailings of northwestern Mexico.

Generation, storage, and management of waste coming from industrial processes are a growing worldwide problem. One of the main contributors is the mining industry, in particular tailings generated by historical mining, which are barely maintained, especially in developing countries. Assessing the impact of a mining site to surrounding soils and ecosystems can be complex, especially when determining mobility and accessibility of the contaminants is required to perform ecological and human health risk assessment. As an effort to obtain information regarding mobility and accessibility of some potentially toxic elements (Zn, Pb, and As) from an historical mining site of northwestern Mexico, the abandoned mine tailings of San Felipe de Jesús in central Sonora and adjacent agricultural soils were investigated. Mobility and accessibility were assessed by means of sequential extraction procedures and using simulated physiological media. Additionally, an assessment of accidental oral intake was calculated considering the bioaccessible fractions. Results show that higher concentrations of contaminants were found in sulfide-rich tailings (Zn = 92,540; Pb = 21,288; As = 19,740mgkg-1) compared with oxide-rich tailings (Zn = 43,240; Pb = 14,763; As = 13,401mgkg-1). Concentrations in agricultural soils were on average Zn = 4755, Pb = 2840, and As = 103mgkg-1. Zinc was mainly recovered from labile fractions in oxide-rich tailings (~ 60%) and in a lower amount from sulfide-rich tailings (~ 30%). Pb and As were mainly associated with residual fractions (80-95%) in both types of tailings. The percentage of mobile fractions (sum of water-soluble, exchangeable, and bound to carbonate fractions) in agricultural soils was as follows: Zn ~ 60%, Pb ~ 15%, and As ~ 70%. Regarding the phytoaccessible fraction, the studied elements in mine tailings and agricultural soil samples exceeded the threshold limits, except for As in agricultural soils. According to data obtained, toxic effects were also calculated. As for daily oral intake for non-carcinogenic effects in adults and children, only Pb and As exceeded reference dose values, especially in children exposed to sulfide-rich tailings and agricultural soils. Regarding carcinogenic effects of Pb and As, most of the samples were above acceptable risk values.

Acid-labile anhydride-linked doxorubicin-doxorubicin dimer nanoparticles as drug self-delivery system with minimized premature drug leakage and enhanced anti-tumor efficacy

Acid-labile anhydride-linked doxorubicin-doxorubicin dimers (D-DOX) were designed as doxorubicin-doxorubicin conjugate-based drug self-delivery systems (DSDSs) with high drug content for tumor intracellular pH-triggered release, by conjugating doxorubicin (DOX) with various anhydrides, such as maleic anhydride (MAH), succinic anhydride (suc), and 2,3-dimethylmaleic anhydride (DMMAH). With the similar diameter of about 200 nm, the D-DOXMAH showed better pH-triggered DOX release and was thus selected for the further investigation. The D-DOX-5 nanoparticles with desirable average hydrodynamic diameter (Dh) of 162 nm and high drug content of 51.20% were obtained via self-assembly by a facile dialysis technique, with the PEGylated dimer (D-DOXMAH-S-PEG) as surfactant. The cumulative DOX release from the proposed D-DOX nanoparticles reached 40.6% within 36 h in the simulated tumor intracellular acidic micro-environment, while the premature drug leakage was only 4.5% in the simulated normal physiological medium. The MTT results indicated the proposed DSDS possessed an enhanced anti-tumor efficacy for the HepG2 cancer cell than the free DOX.

PH-responsive surface charge reversal carboxymethyl chitosan-based drug delivery system for pH and reduction dual-responsive triggered DOX release

A facile approach was established to fabricate the pH-responsive surface charge reversal carboxymethyl chitosan-based drug delivery system for pH and reduction dual-responsive triggered DOX release, with a reduction responsive sheddable shell via facile organic solvent-free co-precipitation method. In the proposed DDS, DOX was loaded in the pH responsive core of the poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) fragments, which were bioreducibly conjugated onto the PEGylated carboxymethyl chitosan (PEG-CMCS) backbone as reduction responsive sheddable shielding shell. The proposed PEG-CMCS-SS-PDPA/DOX nanoparticles, with a high drug loading capacity of >36 % with drug-loading only in their cores, showed excellent pH and reduction dual-responsive triggered disintegration and DOX release performance with cumulative release >85 % in the simulated tumor intracellular microenvironment but a low drug leakage <8.5 % in the simulated normal physiological medium within 57 h, lower than all the reported CMCS-based DDSs.