Radionuclide 188Re-Loaded Photothermal Hydrogel for Cancer Theranostics

Herein, an injectable photothermal hydrogel system containing a therapeutic radionuclide ¹⁸⁸Re is studied for combined radioisotope therapy and photothermal therapy (PTT) of cancer. A dopamine-conjugated poly(α,β-aspartic acid) copolymer (PDAEA) is used to trigger a sol–gel phase transition in mixture with Fe³⁺ ions, rapidly forming a gel by simply mixing PDAEA and FeCl₃ phosphate buffer saline solutions. The injectable hydrogel exhibits strong near-infrared light absorbance and can efficiently convert light into a heating effect for local PTT treatment. The obtained hydrogel possesses a porous 3D microstructure, and can be utilized for radionuclide loading. After the Na¹⁸⁸ReO₄ loading, the hydrogel is intratumorally injected into the tumor of mice bearing 4T1 murine breast cancer cells for studying the tumor retention and therapeutic efficiency. In vivo results show that Na¹⁸⁸ReO₄-loaded hydrogel exhibits significantly longer time in the tumor sites than that of free Na¹⁸⁸ReO₄. The tumor growth of mice treated with Na¹⁸⁸ReO₄-loaded hydrogel under near-infrared radiation is significantly inhibited compared with control groups. Therefore, the results show that the developed strategy using an injectable and biocompatible hydrogel may promote the applications of radioisotope therapy and photothermal therapy for cancer.     

Upon a magnetic composite preparation based on magnetite and poly(succinimide)-b-poly(ethylene glycol) shell

Taking into account that magnetic particles with suitable surface characteristics have a high potential for the use in a lot of in vitro and in vivo applications, in the study is presented the in situ preparation of a core-shell magnetic composite based on the magnetite core and the shell composed from the poly(succinimide)-b-poly(ethylene glycol) copolymer. The average particle size of the synthesized magnetic microspheres is in the range of 6.5-8.8 μm with a magnetite content of around 11%. The saturation magnetization of the microspheres was found 26.8 emu/g, the magnetic microspheres being characterized by superparamagnetic properties. The particles have combined properties of high magnetic saturation and biocompatibility and interactive functions at the surface through the block copolymer shell. The surface of the magnetic particles has also the possibility for further functionalization or the attachment of various bioactive molecules after the hydrolysis of the succinimide cycle and the resulting carboxylic group.     

Ultrasound-triggered nicotine release from nicotine-loaded cellulose hydrogel

Ultrasound (US)-triggered nicotine release system in a cellulose hydrogel drug carrier was developed with three different cellulose concentrations of 0.45 wt%, 0.9 wt%, and 1.8 wt%. The nicotine-loaded cellulose hydrogels were fabricated by the phase inversion method when the nicotine and cellulose mixture in the 6 wt% LiCl/N, N-dimethylacetamide solvent was exposed to water vapor at room temperature. Nicotine was used as the medicine due to its revealed therapeutic potential for neurodegenerative diseases like Alzheimer's and Parkinson's diseases. The behavior of US-triggered nicotine release from nicotine-cellulose hydrogel was studied at 43 kHz US frequency at the changing US output powers of 0 W, 5 W, 10 W, 20 W, 30 W, and 40 W. The significant US-triggered nicotine release enhancement was noted for the hydrogels made with 0.9 wt% and 1.8 wt% cellulose loading. The matrix made with 0.9 wt% cellulose was exhibited the highest nicotine release at the 40 W US power, and differences in nicotine release at different US powers were noticeable than at 0.45 wt% and 1.8 wt% cellulose loadings. For the three cellulose hydrogel systems, the storage modulus (G′) values at the 0.01 wt% strain rate were dropped from their initial values due to the US irradiation. This reduction was proportionately decreased when the US power was increased. The deconvolution of FTIR spectra of nicotine-loaded cellulose films before and after US exposure was suggested breakage of cellulose-nicotine and cellulose-water in the matrix; thus, the stimulated nicotine release from the cellulose matrix was promoted by the US irradiation.     

Ultrasound stimulated release of mimosa medicine from cellulose hydrogel matrix

Ultrasound (US) drug release system using cellulose based hydrogel films was developed as triggered to mimosa. Here, the mimosa, a fascinating drug to cure injured skin, was employed as the loading drug in cellulose hydrogel films prepared with phase inversion method. The mimosa hydrogels were fabricated from dimethylacetamide (DMAc)/LiCl solution in the presence of mimosa, when the solution was exposed to ethanol vapor. The US triggered release of the mimosa from the hydrogel matrix was carried out under following conditions of US powers (0–30 W) and frequencies (23, 43 and 96 kHz) for different mimosa hydrogel matrix from 0.5 wt% to 2 wt% cellulose solution. To release the drug by US trigger from the matrix, the better medicine release was observed in the matrix prepared from the 0.5 wt% cellulose solution when the 43 kHz US was exposed to the aqueous solution with the hydrogel matrix. The release efficiency increased with the increase of the US power from 5 to 30 W at 43 kHz. Viscoelasticity of the hydrogel matrix showed that the hydrogel became somewhat rigid after the US exposure. FT-IR analysis of the mimosa hydrogel matrixes showed that during the US exposure, hydrogen bonds in the structure of mimosa–water and mimosa–cellulose were broken. This suggested that the enhancement of the mimosa release was caused by the US exposure.     

Structural features of hydroxyapatite and carbonated apatite formed under the influence of ultrasound and microwave radiation and their effect on the bioactivity of the nanomaterials

The samples of hydroxyapatite and carbonate substituted hydroxyapatite (CHA) were obtained under the influence of physical factors, namely ultrasound (US) and microwave (MW) radiations. The results of Fourier transform infrared spectroscopy and X-ray diffraction analysis have proved the formation of the calcium deficient hydroxyapatite and B-type CHA with the Ca/P ratio in the ranges 1.62–1.87. In vitro studies have showed the increased bioactivity of the samples, synthesized under the influence of physical factors as compared to the standard ones. The samples of both groups, synthesized under the influence of 600 W MW, have shown the greatest stability in biological environment. In vivo tests confirm that obtained under US and MW radiations hydroxyapatite-based biomaterials are biocompatible, non-toxic and exhibit osteoconductive properties. The usage of US and MW radiations can significantly shorten the time (up to 5–20 min) of obtaining of calcium deficient hydroxyapatite and B-type CHA in nanopowder form, close in structure and composition to the biological hydroxyapatite.     

Cytotoxicity and drug release behavior of PNIPAM grafted on silica-coated iron oxide nanoparticles

The nanoparticles containing thermosensitive and magnetic properties were investigated for their potential use as a novel drug carrier for targeted and controlled release drug delivery system. These thermosensitive and magnetic nanoparticles were prepared by grafting thermosensitive poly (N-isopropylacrylamide) (PNIPAM) on the surface of silica (SiO₂)-coated Fe₃O₄ nanoparticles with the particle size of 18.8 ± 1.6 nm. Adsorption and desorption behavior of bovine serum albumin (BSA) on the surface of PNIPAM-grafted SiO₂/Fe₃O₄ nanoparticles was studied, and the results indicated that these nanoparticles were able to absorb protein at temperature above the lower critical solution temperature (LCST) and to be desorbed below the LCST. Cytotoxicity studies conducted on Chinese hamster ovary (CHO-K1) cells using methyl tetrazolium (MTT) assays revealed that cell viability of 1 mg/mL PNIPAM-grafted nanoparticles was slightly decreased after 24 h of incubation as compared to the lower concentration of nanoparticles. Furthermore, the concentration of 0.5 mg/mL PNIPAM-grafted nanoparticles was totally biocompatible for 48 h, but had low cytotoxicity after 72 h of incubation. These PNIPAM-grafted nanoparticles did not induce morphological change in their cellularity after exposure for 24 and 108 h. These results demonstrate that PNIPAM-grafted nanoparticles are biocompatible and have potential use as drug carriers.     

Multi-responsive poly(N-isopropylacrylamide) hydrogel with D-π-A type dye

To get a multi-responsive polymer hydrogel, metal sensible and acid/base-switchable D-π-A type dye monomer was synthesized first. The synthesized electron donor-π-conjugated-electron acceptor (D-π-A) type dye monomer 3 was investigated with not only the selective Ni²⁺ and Cu²⁺ metal ion sensing effects, but also an acid/base unit sensing effects in optical properties with UV-vis absorption and fluorescence emission. A thermo-responsive poly(NIPAM-co-dye) copolymer with D-π-A type dye was prepared by typical radical copolymerization. The LCST behavior was investigated by UV-vis spectroscopy, which allows the measurement of the phase transition from 20 to 50 °C in an aqueous solution. The poly(NIPAM-co-dye) copolymer also exhibited color change when not only Ni²⁺ or Cu²⁺ cations were used but also when an acid/base unit was used. The morphology of the internal matrix structure of the poly(NIPAM-co-dye) hydrogel was observed by SEM.     

Temperature-induced phase transition and intramolecular charge-transfer process based on poly(N-isopropylacrylamide) hydrogel with covalently attached D-π-A type dye

A thermoresponsive poly(NIPAM-co-dye) copolymer with covalently attached D-π-A type dye was prepared by typical radical copolymerization. Software was used to calculate the electron density distribution of the push-pull, intramolecular charge transfer (ICT) operating in donor-π-conjugation-acceptor (D-π-A) configurations of dye monomer 3. It can be constructed an acid/base-induced molecular switch by modulation of intramolecular charge transfer with protonation/deprotonation. The lower critical solution temperature (LCST) behavior was investigated by means of UV-vis spectroscopy that allows the measurement of the phase transition from 25 to 40 °C in aqueous solution. The poly(NIPAM-co-dye) copolymer also exhibited color change when used an acid/base-induced molecular switch via control of intramolecular charge transfer (ICT). The morphology of the internal microstructure of the poly(NIPAM-co-dye) hydrogel was observed by scanning electron microscopy (SEM). The reversible switch could be obtained by thermal and acid/base stimuli.     

In vitro application of Fe/MgO nanoparticles as magnetically mediated hyperthermia agents for cancer treatment

In this work we study the heating efficiency of Fe/MgO magnetic core/biocompatible shell nanoparticles and their in vitro application in magnetic hyperthermia on cancer cells. Different human breast cancer cell lines were used to assess the suitability of nanoparticles for in vivo application. The experiments revealed a very good cytotoxicity profile and significant uptake efficiency together with relatively high specific absorption rates and fast thermal response, features that are crucial for adequate thermal efficiency and minimum duration of treatment.     

Encapsulating doxorubicin-intercalated lamellar nanohydroxyapatite into PLGA nanofibers for sustained drug release

In this work, doxorubicin (DOX) was intercalated into layered nanohydroxyapatite (LHAp). The drug loaded LHAp (DOX@LHAp) was then mixed with poly(lactic-co-glycolic acid) (PLGA) and electrospun to yield DOX@LHAp/PLGA composite scaffolds. As control, needle-like nanohydroxyapatite (nHAp) was also used to make an DOX@nHAp/PLGA composite scaffold and bare DOX was used to fabricate DOX/PLGA scaffold. The morphology, release behavior of DOX, and capability to inhibit cancer cells were assessed. The addition of DOX-loaded nHAp to PLGA causes a slight decrease in the average fiber diameter of DOX@LHAp/PLGA as compared to PLGA. The in vitro drug release tests reveal a much faster release of DOX from DOX/PLGA than DOX@LHAp/PLGA. Moreover, DOX@LHAp/PLGA displays a more sustainable release over DOX@nHAp/PLGA due to the storage of DOX in the gallery of LHAp, which is further proved by their cancer cell inhibition results. We believe that the DOX@LHAp/PLGA scaffold has potential as an implantable drug delivery system.     

Quantitative ToF-SIMS studies of protein drug release from biodegradable polymer drug delivery membranes

Biodegradable polymers are of interest in developing strategies to control protein drug delivery. The protein that was used in this study is Keratinocyte Growth Factor (KGF) which is a protein involved in the re-epithelialization process. The protein is stabilized in the biodegradable polymer matrix during formulation and over the course of polymer degradation with the use of an ionic surfactant Aerosol-OT (AOT) which will encapsulate the protein in an aqueous environment. The release kinetics of the protein from the surface of these materials requires precise timing which is a crucial factor in the efficacy of this drug delivery system.Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used in the same capacity to identify the molecular ion peak of the surfactant and polymer and use this to determine surface concentration. In the polymer matrix, the surfactant molecular ion peak was observed in the positive and negative mode at m/z 467 and 421, respectively. These peaks were determined to be [AOT + Na⁺] and [AOT − Na⁺]. These methods are used to identify the surfactant and protein from the polymer matrix and are used to measure the rate of surface accumulation. The second step was to compare this accumulation rate with the release rate of the protein into an aqueous solution during the degradation of the biodegradable film. This rate is compared to that from fluorescence spectroscopy measurements using the protein autofluorescence from that released into aqueous solution [C.M. Mahoney, J. Yu, A. Fahey, J.A.J. Gardella, SIMS depth profiling of polymer blends with protein based drugs, Appl. Surf. Sci. 252 (2006), 6609-6614.].     

Regulating the thermal response of PNIPAM hydrogels by controlling the adsorption of magnetite nanoparticles

Thermoswitchable magnetic hydrogels are being extensively investigated because of their great potential for medical applications. Indeed, they can behave as smart carriers able to transport drugs to a chosen part of the body and release them via magneto-thermal activation by an external alternating magnetic field. We report on the magnetization of the thermosensitive poly(N-isopropylacrylamide) hydrogel through the adsorption of controlled amounts of magnetite nanoparticles. We show that the temperature at which the hydrogel contraction occurs (i.e. the lower critical solution temperature) can be controlled from 32 ^°C to 52 ^°C by varying the concentration of adsorbed nanoparticles. This is clearly shown by photon correlation spectroscopy. The results are an advance in the use of the magnetized poly(N-isopropylacrylamide) hydrogel as a flexible and adjustable nanomaterial and are of great interest in numerous applications which require drug release on demand.     

Synthesis and characterization of Pluronic® grafted chitosan copolymer as a novel injectable biomaterial

Water-soluble thermosensitive chitosan copolymers were prepared by coupling Pluronic^® onto chitosan using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and N-hydroxysuccinimide (NHS) as coupling agents. The physicochemical properties of the resulting copolymers were characterized and they formed thermally reversible hydrogels, which exhibit a lower critical solution temperature (LCST) at 34 °C in aqueous solutions. As a result, chitosan copolymers attest to the usefulness as an injectable material for cell and drug delivery because of their thermally reversible property.     

Controlled release of ketorolac through nanocomposite films of hydrogel and LDH nanoparticles

A novel nanocomposite film for sustained release of anionic ophthalmic drugs through a double-control process has been examined in this study. The film, made as a drug-loaded contact lens, consists principally of a polymer hydrogel of 2-hydroxyethyl methacrylate (HEMA), in whose matrix MgAl-layered double hydroxide (MgAl-LDH) nanoparticles intercalated with the anionic drug are well dispersed. Such nanocomposite films (hydrogel-LDH-drug) contained 0.6–0.8 mg of MgAl-LDH and 0.08–0.09 mg of the ophthalmic drug (ketorolac) in 1.0 g of hydrogel. MgAl-drug-LDH nanoparticles were prepared with the hydrodynamic particle size of 40–200 nm. TEM images show that these nanoparticles are evenly dispersed in the hydrogel matrix. In vitro release tests of hydrogel-LDH-drug in pH 7.4 PBS solution at 32 °C indicate a sustained release profile of the loaded drug for 1 week. The drug release undergoes a rapid initial burst and then a monotonically decreasing rate up to 168 h. The initial burst release is determined by the film thickness and the polymerization conditions, but the following release rate is very similar, with the effective diffusion coefficient being nearly constant (3.0 × 10⁻¹² m²/s). The drug release from the films is mechanistically attributed to anionic exchange and the subsequent diffusion in the hydrogel matrix.     

Multi-time scale characterization of acoustic droplet vaporization and payload release of phase-shift emulsions using high-speed microscopy

Acoustic droplet vaporization (ADV) is the phase-transitioning of perfluorocarbon emulsions, termed phase-shift emulsions, into bubbles using focused ultrasound. ADV has been utilized in many biomedical applications. For localized drug release, phase-shift emulsions with a bioactive payload can be incorporated within a hydrogel to yield an acoustically-responsive scaffold (ARS). The dynamics of ADV and associated drug release within hydrogels are not well understood. Additionally, emulsions used in ARSs often contain high molecular weight perfluorocarbons, which is unique relative to other ADV applications. In this study, we used ultra-high-speed brightfield and fluorescence microscopy, at frame rates up to 30 million and 0.5 million frames per second, respectively, to elucidate ADV dynamics and payload release kinetics in fibrin-based ARSs containing phase-shift emulsions with three different perfluorocarbons: perfluoropentane (PFP), perfluorohexane (PFH), and perfluorooctane (PFO). At an ultrasound excitation frequency of 2.5 MHz, the maximum expansion ratio, defined as the maximum bubble diameter during ADV normalized by the initial emulsion diameter, was 4.3 ± 0.8, 4.1 ± 0.6, and 3.6 ± 0.4, for PFP, PFH, PFO emulsions, respectively. ADV yielded stable bubble formation in PFP and PFH emulsions, though the bubble growth rate post-ADV was three orders of magnitudes slower in the latter emulsion. Comparatively, ADV generated bubbles in PFO emulsions underwent repeated vaporization/recondensation or fragmentation. Different ADV-generated bubble dynamics resulted in distinct release kinetics in phase-shift emulsions carrying fluorescently-labeled payloads. The results provide physical insight enabling the modulation of bubble dynamics with ADV and hence release kinetics, which can be used for both diagnostic and therapeutic applications of ultrasound.     

Stabilizer specific interaction of gold nanoparticles with a thermosensitive polymer hydrogel

We report the experimental results on temperature-dependent studies of interactions between a novel biocompatible thermosensitive polymer hydrogel and different stabilizing agent capped gold nanoparticles (Au NPs) with particle size ranging from 5 to 20 nm. Stabilizing agents such as thioglycolic acid, tryptophan, and phenylalanine have been used as capping agents for Au NPs. The poly-N-isopropyl acrylamide-co-acrylic acid (pNIPAm-AAc) with 3.0 ± 0.7 μm in size was synthesized by radical polymerization of a selected mixture of N-isopropyl acrylamide (NIPAm), methylene-bis-acrylamide and acrylic acid (AAc). The capped Au NPs were mixed with a solution of pNIPAm-AAc hydrogel. The temperature-dependent properties of the mixture were studied by UV–vis spectroscopy, dynamic light scattering based particle size analysis, and transmission electron microscopy (TEM). The observations indicated change in the lower critical solution temperature (LCST) depending on the nature of the stabilizer, with hydrophobic ones lowering the value while hydrophilic stabilizers increasing the same. Also, the optical absorption due to Au NPs, when stabilized with hydrophobic groups, reduced significantly at above LCST along with significant blue shift of wavelength maximum.     

Effect of alkyl chain lengths on the assemblies of magnetic nanoparticles coated with multi-functional thiolactone-containing copolymer

This work presents the synthesis of magnetite nanoparticle (MNP) coated with poly(N,N-diethylaminoethyl methacrylate)-b-poly(N-isopropyl acrylamide-st-thiolactone acrylamide) (PDEAEMA-b-P(NIPAAm-st-TlaAm) copolymer and its use in controlled drug release and bio-conjugation. TlaAm units in the copolymer were ring-opened with various alkyl amines to form thiol groups (-SH), followed by thiol-ene coupling reactions with acrylamide-coated MNP and then quaternized to obtain cationic copolymer-MNP assemblies (the size <?200 nm/cluster). The use of alkyl amines having various chain lengths (e.g., 1-propylamine, 1-octylamine, or 1-dodecylamine) in the nucleophilic ring-opening reactions of the thiolactone rings affected their magnetic separation ability, water dispersibility, and release rate of doxorubicin model drug. In all cases, when increasing the temperature, they showed a thermo-responsive behavior as indicated by the decrease in hydrodynamic size and the accelerated drug release rate. These copolymer-MNP assemblies could be used as a novel platform with thermal-triggering controlled drug release and capability for adsorption with any negatively charged biomolecules.

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Graphical abstract MNP coated with multi-functional PDEAEMA-b-P(NIPAAm-st-TlaAm) copolymer and its proposed drug release

     

Emission characteristics of a barrier discharge in an argon-freon-water vapor mixture in the UV-VUV spectral range

Optical characteristics of an ArCl*-OH* lamp excited by a nanosecond barrier discharge are studied. This discharge is a source of the ArCl (B → X), (D’ → A’), and OH(A → X) molecular band emission with peaks at 175, 258, and 309 nm, respectively. The intensity of the barrier discharge plasma radiation is optimized as a function of the CCl₄ vapor partial pressure at p(Ar) = 24 kPa and p(H₂O) = 10–20 Pa.     

Confocal Raman and electronic microscopy studies on the topotactic conversion of calcium carbonate from Pomacea lineate shells into hydroxyapatite bioceramic materials in phosphate media

Conversion of Pomacea lineate shells into hydroxyapatite (HA) bioceramic materials was investigated by their in vitro treatment with phosphate solutions, at room temperature. Confocal Raman microscopy revealed that the conversion proceeds at distinct rates through the nacreous or periostracum sides of the shell. The conversion can be accelerated using powdered samples, yielding biocompatible materials of great interest in biomedicine.     

Effects of combination treatments of lysozyme and high power ultrasound on the Salmonella typhimurium inactivation and quality of liquid whole egg

An investigation was conducted into the utilization of treatments combining ultrasound and lysozyme (US + Lys) to deactivate Salmonella typhimurium (S. typhimurium) in the liquid whole egg (LWE). Furthermore, US + Lys and heat treatment (HT) with a similar microbial inactivation effect were comparatively evaluated by examining their impact on the quality attributes of LWE. The LWE was treated with US at 35–45 °C and 605–968 W/cm² for 5–35 min, and with HT at 58–64 °C for 3–4 min. Lysozyme (Lys) alone achieved a minimal degree of inactivation in S. typhimurium, while it was enhanced with the application of US alone when the treatment temperature, time, and energy were increased. Furthermore, US and US + Lys caused a reduction of 3.31 and 4.26 log₁₀ cycles in S. typhimurium, respectively at 968 W/cm² and 35 °C for 20 min, indicating a synergistic relationship between US and Lys for the effective inactivation of S. typhimurium. Similarly, HT and HT + Lys achieved a reduction of 4.10 and 4.75 log₁₀ cycles at 64 °C/3 min, respectively. The L* and b* values of the LWE following US and US + Lys application were significantly higher than untreated and heat-treated LWE, indicating that US treated LWE had a brighter and yellower appearance. The protein solubility (PS) slightly decreased after all treatments, while the pH increased. Furthermore, the foaming capacity (FC) and foam stability (FS) were decreased, revealing that LWE had a lower FC and unstable foam after all treatments. Therefore, US and US + Lys could increase the viscosity and gelation temperature (Tg) of LWE, indicating that LWE exhibited higher heat resistance after US treatment. These results indicated that US + Lys might be a promising pasteurization technology in the processing of LWE.