Thermally-responsive and reduced glutathione-sensitive folate-targeted nanocarrier based on alginate and pluronic F127 for on-demand release of methotrexate.

A specific rheumatoid arthritis (RA)-microenvironment-triggered nanocarrier for RA treatment of a first-line antirheumatic drug (Methotrexate, MTX) has been proposed. Reduced glutathione (GSH) responsivity, cystamine, was first introduced on the alginate backbone, which was then used as the bridge to connect pluronic F127 (temperature-responsive factor) and folic acid (targeting factor for active immune cells), resulting in dual-responsive triggered targeting carrier, PCAC-FA. In vitro study demonstrated that PCAC-FA was preferentially taken up by activated macrophage cells rather than normal ones, suggesting the targeting of PCAC-FA to inflamed tissue. The loading capacity of the designed carrier was 21.23 ± 0.91 %. MTX from the PCAC-FA carrier was significantly accelerated release in the presentation of glutathione or in cold shock condition, proposing the efficacy-controlled release. MTX@PCAC-FA showed excellent hemocompatibility, confirming a suitable application with parenteral administration. Notably, the acute and subacute toxicity in the mice model showed that the toxicity of MTX had significantly reduced after encapsulating in the PCAC-FA carrier. These nanoplatforms not only provide an alternative safe strategy for the clinical treatment of rheumatoid arthritis with MTX but also deliver MTX selectively and provide on-demand drug release via external and internal signals, thus emerging as a promising therapeutic option for precise RA therapy.

Injectable thermogel incorporating reactive oxygen species scavenger and nitric oxide donor to accelerate the healing process of diabetic wounds.

The healing of diabetic wounds is challenging due to redox imbalances. Herein, the thermogelling system AR-ACP hydrogel, with encapsulated biosafe nitric oxide (NO) donor L-arginine and resveratrol as an ROS scavenger, is established for sustainable wound therapy in the diabetic state. The innovated AR-ACP hydrogel dressings shows the sol-gel transition at 34 °C, allowing the hydrogel to fully cover wounds. The combination of L-arginine and resveratrol showed a prominent effect on anti-oxidative activity. The elimination of superoxide anions from the activated immune cells/oxidative cells by resveratrol maintained the NO-proangiogenic factors generated from L-arginine. Furthermore, the AR-ACP hydrogel endowed outstanding features such as haemocompatibility, non-skin irradiation as well as antibacterial activity. In the in vivo diabetic mice model, complete epidermal regeneration comparable to undamaged skin was observed with AR-ACP hydrogel. The synergy between L-arginine and resveratrol in the ACP hydrogel facilitated neovascularisation in the early stage, resulting in the higher balance in cellularity growth and collagen deposition in the dermal layer compared to control groups. Taken together, our findings demonstrate that the use of a customised ACP-based hydrogel, with the additional L-arginine and resveratrol, resulted in significant skin regeneration in the diabetic state.

A comparative study on essential oils from the leaves and stems of Vietnamese Mikania micrantha Kunth.

Mikania micrantha Kunth is widely known as potential herbal medicine, although it is an invasive alien species in Southeast Asia. In this study, the essential oils from leaves and stems of M. micrantha were extracted by hydrodistillation method, and the chemical profiles of essential oils were then analysed by gas chromatography (GC) and gas chromatography coupled with mass spectrometry (GC/MS). It was found that there were similarities and differences in chemical compositions and their percentage between the essential oils obtained from these two parts. The dominant components of leaves essential oil are ß-Cubebene, Germacrene D, and α-Zingiberene, accounting for 11.34%, 10.96%, and 10.76%, respectively. Additionally, the major components of stems essential oils are D-Limonene (16.99%), ß-Pinene (7.91%), and α-Zingiberene (7.26%). The research sheds fresh light on the chemical makeup of M. micrantha essential oils, emphasising their potential for the future.

Potential from synergistic effect of quercetin and paclitaxel co-encapsulated in the targeted folic-gelatin-pluronic P123 nanogels for chemotherapy.

Dual-drug delivery systems for anticancer therapy have recently attracted substantial attention due to their potency to overcome limitations of conventional anti-cancer drugs, tackle drug resistance problems, as well as improve the therapeutic efficacy. In this study, we introduced a novel nanogel based on folic acid-gelatin-pluronic P123 (FA-GP-P123) conjugate to simultaneously deliver quercetin (QU) and paclitaxel (PTX) to the targeted tumor. The results indicated that the drug loading capacity of FA-GP-P123 nanogels was significantly higher than that of P123 micelles. The kinetic release profiles of QU and PTX from the nanocarriers were governed by Fickian diffusion and swelling behavior, respectively. Notably, FA-GP-P123/QU/PTX dual-drug delivery system induced higher toxicity to MCF-7 and Hela cancer cells than either QU or PTX individual delivery system, and the non-targeted dug delivery system (GP-P123/QU/PTX), indicating the synergistic combination of dual drugs and FA positive targeting effect. Furthermore, FA-GP-P123 could effectively deliver QU and PTX to tumors in vivo after administration into MCF-7 tumor-bearing mice, which resulted in 94.20 ± 5.90 % of tumor volume reduced at day 14. Moreover, the side effects of the dual-drug delivery system were significantly reduced. Overall, we suggest FA-GP-P123 as potential nanocarrier for dual-drug delivery for targeted chemotherapy.

Curcumin and Paclitaxel Co-loaded Heparin and Poloxamer P403 Hybrid Nanocarrier for Improved Synergistic Efficacy in Breast Cancer.

INTRODUCTION: Multi-drug nanosystem has been employed in several therapeutic models due to the synergistic effect of the drugs and/or bioactive compounds, which help in tumor targeting and limit the usual side effects of chemotherapy. METHODS: In this research, we developed the amphiphilic Heparin-poloxamer P403 (HSP) nanogel that could load curcumin (CUR) and Paclitaxel (PTX) through the hydrophobic core of Poloxamer P403. The features of HSP nanogel were assessed through Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), differential light scattering (DLS), and critical micelle concentration (CMC). Nanogel and its dual drug-loaded platform showed high stability and spherical morphology. RESULTS: The drug release profile indicated fast release at pH 5.5, suggesting effective drug distribution at the tumor site. In vitro research confirms lower cytotoxicity of HSP@CUR@PTX compared to free PTX and higher inhibition effect with MCF-7 than HSP@PTX. These results support the synergism between PTX and CUR. CONCLUSION: HSP@CUR@PTX suggests a prominent strategy for achieving the synergistic effect of PTX and CUR to circumvent undesirable effects in breast cancer treatment.

Curcuminoid Co-Loading Platinum Heparin-Poloxamer P403 Nanogel Increasing Effectiveness in Antitumor Activity.

Nanosized multi-drug delivery systems provide synergistic effects between drugs and bioactive compounds, resulting in increased overall efficiency and restricted side effects compared to conventional single-drug chemotherapy. In this study, we develop an amphiphilic heparin-poloxamer P403 (HP403) nanogel that could effectively co-load curcuminoid (Cur) and cisplatin hydrate (CisOH) (HP403@CisOH@Cur) via two loading mechanisms. The HP403 nanogels and HP403@CisOH@Cur nanogels were closely analyzed with 1H-NMR spectroscopy, FT-IR spectroscopy, TEM, and DLS, exhibiting high stability in spherical forms. In drug release profiles, accelerated behavior of Cur and CisOH at pH 5.5 compared with neutral pH was observed, suggesting effective delivery of the compounds in tumor sites. In vitro studies showed high antitumor activity of HP403@CisOH@Cur nanogels, while in vivo assays showed that the dual-drug platform prolonged the survival time of mice and prevented tail necrosis. In summary, HP403@CisOH@Cur offers an intriguing strategy to achieve the cisplatin and curcumin synergistic effect in a well-designed delivery platform that increases antitumor effectiveness and overcomes undesired consequences caused by cisplatin in breast cancer treatment.

Effect of targeting ligand designation of self-assembly chitosan-poloxamer nanogels loaded Paclitacel on inhibiting MCF-7 cancer cell growth.

In this study, we investigated two formulations of chitosan-Pluronic P123 with different folate ligand designation for targeted delivery of Paclitaxel (PTX), in which folic acid (FA) was directly conjugated to chitosan (FA-Cs-P123) or substituted onto P123 (Cs-P123-FA). The results showed that the FA content of Cs-P123-FA was determined at 0.71 wt/wt% which was significantly higher than that of FA-Cs-P123 (0.31 wt/wt%). Two copolymers were low critical gel concentrations (CGC). FA-Cs-P123 and Cs-P123-FA nanogels performed high PTX encapsulation efficiency reaching 95.57 ± 5.51 and 92.51 ± 6.68 wt/wt%, respectively. Transmission electron microscopy (TEM) and zeta potential analysis indicated that the PTX-loaded nanogels were spherically formed around 60 nm in diameter along with positive charge. Furthermore, the PTX release profile was slow and it was controlled by the pH of the medium. In particular, in vitro biocompatibility assays indicated that both FA-Cs-P123 and Cs-P123-FA exhibited good biological compatibility with a human foreskin fibroblast cell line and well uptake efficiency into MCF-7 cancer cells. Cs-P123-FA nanogel significantly enhanced the cytotoxicity of PTX in comparison with FA-Cs-P123. The result indicates that Cs-P123-FA nanogels with a higher decorated FA content perform a better targeting efficiency; therefore, they could have great potential application towards breast cancer treatment.

Pb(II) adsorption mechanism and capability from aqueous solution using red mud modified by chitosan.

Red mud modified by chitosan (RM/CS) was utilized as an adsorbent to effectively remove Pb(II) from aqueous solution. The surface area of RM/CS was found to significantly increase by more than 50% compared to that of original red mud. Different factors that affected the Pb(II) removal on this material, such as initial Pb(II) concentration, pH, and contact time, were investigated. The pseudo-first-order, pseudo-second-order, and intra-diffusion models were used to fit the experimental data to investigate the Pb(II)'s removal kinetics. The Pb(II) removal followed the intra-diffusion model. Additionally, the non-zero C value obtained from this model indicates that the removal was controlled by many different mechanisms. We also found that the interaction of Pb(II) and carbonate group on the material's surface played a primary role once the adsorption equilibrium was reached. Finally, the maximum adsorptive capacity was found to be about 209 mg/g. This obtained value is higher than those obtained for some other materials. Therefore, the present RM/CS should be a potential material for removing Pb(II) from aqueous solution.

Enhanced Sensitivity and Detection of Near-Infrared Refractive Index Sensor with Plasmonic Multilayers.

In this work, the multilayer of the surface plasmon resonance (SPR) sensor was optimized to achieve the maximum sensor sensitivity. By optimizing the thickness of the silver layer (Ag) and dielectric films (TiO2 and AlAs), the optimum sensitivity of the SPR sensor could be obtained. The performance of the SPR sensor proposed was compared with control simulations utilizing zinc oxide (ZnO) and molybdenum oxide (MoO3). The numerical results indicate that the figure-of-merits (FOM) of the SPR sensor was achieved around 150/RIU, corresponding to the sensor sensitivity of 162.79°/RIU with the optimized thicknesses of the TiO2, Ag, and AlAs layers of 140 nm, 60 nm, and 25 nm, respectively. This refractive index sensor shows the FOM to have high detection accuracy and high sensitivity that lead to finding potential application in bio-chemical detection with a small volume of liquid used in biological diagnosis.

Multifunctional injectable pluronic-cystamine-alginate-based hydrogel as a novel cellular delivery system towards tissue regeneration.

This paper presents a new thermal sensitive hydrogel system based on cystamine-functionalised sodium alginate-g-pluronic F127 (ACP). The introduction of cystamine to the alginate backbone not only creates a covalent bond with pluronic F127 but also provides intrinsic anti-bacterial activity for the resultant hydrogel. The amount of water uptake inside the hydrogel remained ~200% for 6 days and the degradation was completed in 12 days in physiological media. The ACP copolymer solution could form a hydrogel at body temperature (~37 °C) and could return to the solution phase if the temperature decreased below 25o °C. Fibroblast encapsulated in situ in the ACP hydrogel maintained their viability (≥90% based on the live/dead assay) for 7 days, demonstrating the good biocompatibility of the ACP hydrogel for long-term cell cultivation. In addition, three-dimensional (3D) culture showed that fibroblast attached to the hydrogels and successfully mimicked the porous structure of the ACP hydrogel after 5 days of culture. Fibroblast cells could migrate from the cell-ACP clusters and form a confluent cell layer on the surface of the culture dish. Altogether, the obtained results indicate that the thermal-responsive ACP hydrogel synthesised in this study may serve as a cellular delivery platform for diverse tissue engineering applications.

Cytocompatible dendrimer G3.0-hematin nanoparticle with high stability and solubility for mimicking horseradish peroxidase activity in in-situ forming hydrogel.

Hematin has been used as an alternative enzyme catalyst to horseradish peroxidase (HRP) due to its iron-containing activity center. Although hematin and it derivatives have been widely used for polymerization of phenol/analine compounds, it has some drawbacks such as the limited solubility and reaction only at high pH condition. Herein, we report a nanosized biomimetic catalyst, hematin-decorated polyamidoamine dendrimer (G3.0-He) that can effectively catalyze the in situ hydrogelation of phenol-conjugated polymers under neutral pH condition. We demonstrate that G3.0-He particles are smaller than 100 nm and have excellent enzyme-mimetic functions. Interestingly, the nanosized catalyst is not inactivated at high H2O2 concentration. Compared to pure hematin, G3.0-He has significantly higher dispersion in acidic and neutral media, and preserves the percentage of survival of fibroblasts over 90%. Notably, G3.0-He possesses an exquisite HRP-mimicking activity in gelation of gelatin derivative with phenolic hydroxyl (tyamine) moieties under mild physiological conditions. The in vitro study demonstrated that Gel-Tyr hydrogel by G3.0-He catalyzed reaction had excellent cytocompatibility and an excellent scaffold for adhesion to fibroblast cells. Therefore, the designed minimalistic G3.0-He catalyst could serve as an effective catalytic alternative for HRP enzyme in the preparation of biomedical hydrogels.

Morphological dependent effect of cell-free formed supramolecular fibronectin on cellular activities.

Fibrillar fibronectin (FFN), an active form of fibronectin (FN), plays important roles in various cellular processes. Our goal is to investigate effect of FFN morphology on cellular behaviors. Plasma FN at two concentrations was cross-linked into FFN by dialysis against 2 M urea followed by morphological analysis under Scanning Electron Microscopy. To evaluate effect of FFN morphology, fibroblasts were cultured on FN or different FFNs. Fibroblast behaviors including adhesion, spreading, and migration were evaluated. Our data showed that FN fibrillogenesis was dependent on FN concentration. At high concentrations (0.75 mg/mL), large FFN approximately 2.167 + 0.875 µm in diameter were formed with attached nodular structures and rough surface. In contrast, smooth surface FFN fibrils with diameter of 1.886 + 0.412 µm were formed from FN at 0.25 mg/mL. Cellular assays revealed morphological dependent biological effects of different FFNs. Fibroblast separately adhered to native FN and remained spherical while on FFN, cells attached with higher quantity and showed spreading morphology. A synergistic ligand interaction of integrin α5ß1 and αvß3 was observed in cell adhering on FFN. Cell migration results showed that large FFN decreased migration rate while small FFN did not. Taken together, our data draws new attention towards controlling biological function of FN by its fibrillar structure.

Primary biosorption mechanism of lead (II) and cadmium (II) cations from aqueous solution by pomelo (Citrus maxima) fruit peels.

The present work investigates the primary adsorption mechanisms of lead (II) and cadmium (II) cations onto pomelo fruit peel (PFP) from aqueous solution. pH, adsorption time, ion strength, and initial metal cation concentrations, which are factors affecting the uptake of these cations, are investigated. Results show that pH and ion strengths strongly affect the removal of these cations from aqueous solution. Different isotherm adsorption models, such as Langmuir, Freundlich, and Sips, are utilized to fit the experimental data in order to determine the adsorption in nature. The Langmuir monolayer adsorption capacities are found to be 47.18 mg/g for lead (II) and 13.35 mg/g for cadmium (II). Kinetic and thermodynamic studies based on a combination of FT-IR and TG-DSC spectroscopies demonstrate that electrostatic attraction plays a primary adsorption mechanism of lead (II) and cadmium (II) cations onto pomelo fruit peel.

Adsorptive Removal of Iron Using SiO2 Nanoparticles Extracted from Rice Husk Ash.

In this work, SiO2 nanoparticles were prepared by the sol-gel method after sodium silicate was extracted from rice husk ash (RHA) under various experimental conditions such as types of acids, NaOH concentration, dissolved time, and temperature and used for removal of Fe2+ ions from aqueous solutions. The extracted SiO2 was morphologically and chemically characterized and showed a surface area of 78 m2/g and uniform pores of 2.71 nm, offering high adsorption capacity for Fe2+ ions. The influence of pH, contact time, and amount of adsorbent was studied in order to establish the best conditions for the Fe2+ adsorption and removal. Furthermore, the adsorption data were fitted with an exponential shape curve for all the three variable parameters that affect the adsorption process. The best results were obtained for pH 5, 20 min contact time, and 0.5 g adsorbent dose. The loading adsorption capacity was 9 mg of Fe2+ ions/g SiO2 in the concentration range 0.1-1.0 mgL-1. In addition, the synthesized SiO2 with the size of around 50 nm can be used for specific heavy metal removal and drug delivery, after modification of the SiO2 surface with various functional groups.

A dual synergistic of curcumin and gelatin on thermal-responsive hydrogel based on Chitosan-P123 in wound healing application.

This study aimed to fabricate the potential therapeutic scaffold to efficiently and safely fastening skin wound healing. A biocompatible grafting polymer-based thermal sensitive hybrid hydrogel (Chitosan-P123, CP) containing gelatin and curcumin was designed to be suitable stiffness for tissue regeneration. A detailed in the rheological study found that the encapsulated agents induced the change in the stiffness of the hydrogel from the hard to the soft. Especial, the thermally induced phase transition of CP hydrogel was governed by the participant of gelatin rather than curcumin. For example, at 25 wt% gelatin, CP hydrogel exhibited a unique gel-sol-gel transition following the function of temperature. Moreover, in vitro investigation revealed that the hybrid hydrogel provides the capacity of especially induced curcumin release with a sustainable rate as well as the excellent biocompatibility scaffold. Altogether with in vivo study, the hybrid hydrogel highlighted the advance of the dual synergistic of curcumin and gelatin in development of smart scaffold system, which promoted the efficacy in the regeneration of the structure and the barrier's function of damaged skin such as wound or skin cancer.

Dual Interactions of Amphiphilic Gelatin Copolymer and Nanocurcumin Improving the Delivery Efficiency of the Nanogels.

Herein, a new process to manufacture multicore micelles nanoparticles reinforced with co-assembly via hydrophobic interaction and electrostatic interaction under the help of ultrasonication was developed. The precise co-assembly between negative/hydrophobic drug and positive charged amphiphilic copolymer based pluronic platform allows the formation of complex micelles structures as the multicore motif with predefined functions. In this study, curcumin was selected as a drug model while positively charged copolymer was based on a pluronic-conjugated gelatin with different hydrophobicity length of Pluronic F87 and Pluronic F127. Under impact of dual hydrophobic and electrostatic interactions, the nCur-encapsulated core-shell micelles formed ranging from 40 nm to 70 nm and 40-100 nm by transmission electron microscopy (TEM) and Dynamic Light Scattering (DLS), respectively. It is found that the structures emerged depended on the relative lengths of the hydrophobic blocks in pluronic. Regarding g2(τ) behavior from DLS measurement, the nanogels showed a high stability in spherical form. Surprisingly, the release profiles showed a sustainable behavior of Cur from this system for drug delivery approaches. In vitro study exhibited that nCur-encapsulated complex micelles increased inhibitory activity against cancer cells growth with IC50 is 4.02 ± 0.11 mg/L (10.92 ± 0.3 µM) which is higher than of free curcumin at 9.40 ± 0.17 mg/L (25.54 ± 0.18 µM). The results obtained can provide the new method to generate the hierarchical assembly of copolymers with incorporated loading with the same property.

Modified Carboxyl-Terminated PAMAM Dendrimers as Great Cytocompatible Nano-Based Drug Delivery System.

Polyamidoamine (PAMAM) dendrimers are extensively researched as potential drug delivery system thanks to their desirable features such as controlled and stable structures, and ease of functionalization onto their surface active groups. However, there have been concerns about the toxicity of full generation dendrimers and risks of premature clearance from circulation, along with other physical drawbacks presented in previous formulations, including large particle sizes and low drug loading efficiency. In our study, carboxyl-terminated PAMAM dendrimer G3.5 was grafted with poly (ethylene glycol) methyl ether (mPEG) to be employed as a nano-based drug delivery system with great cytocompatibility for the delivery of carboplatin (CPT), a widely prescribed anticancer drug with strong side effects so that the drug will be effectively entrapped and not exhibit uncontrolled outflow from the open structure of unmodified PAMAM G3.5. The particles formed were spherical in shape and had the optimal size range (around 36 nm) that accommodates high drug entrapment efficiency. Surface charge was also determined to be almost neutral and the system was cytocompatible. In vitro release patterns over 24 h showed a prolonged CPT release compared to free drug, which correlated to the cytotoxicity assay on malignant cell lines showing the lack of anticancer effect of CPT/mPEG-G3.5 compared with CPT.

PEGylated PAMAM dendrimers loading oxaliplatin with prolonged release and high payload without burst effect.

Oxaliplatin (OXA) was coupled to PEGylated polyamidoamine dendrimers of fourth generation (G4-PEG@OXA) in the comparison to PEGylated ones of odd generation (G3.5-PEG@OXA). Proton nuclear magnetic resonance and Fourier-transform infrared spectroscopy were used to confirm the successful incorporation of OXA as well as the synthesis of carrier systems. Both two types of carrier systems exhibited in sphere nanoparticle shape with size of less than 100 nm that was in the range being able to cause toxicity on cancer cells. The average drug loading efficiency (DLE) of G4-PEG@OXA was obtained at 84.63% that was higher than DLE of G3.5-PEG of 75.69%. The release kinetic of G4-PEG@OXA and G3.5-PEG@OXA did not show any burst release phenomenon while free OXA was released over 40% at the first hour. The sustainable release of OXA was achieved when it was encapsulated in these carriers, but the G4 generation liberated OXA (3.4%-6.4%) slower than G3.5 one (11.9%-22.8%). The in vitro cytotoxicities of G4-PEG@OXA were evaluated in HeLa cell lines using resazurin assay and live/dead staining test. Although the free OXA showed a rather moderate killing ability, the G4-PEG@OXA still displayed the low viability of HeLa that was better to the result of G3.5-PEG@OXA due to released OXA amount. The benefit of this system was to overcome the burst release phenomenon to minimize OXA toxicity without compromising its efficiency.

Synergic Activity Against MCF-7 Breast Cancer Cell Growth of Nanocurcumin-Encapsulated and Cisplatin-Complexed Nanogels.

Nanogel-based systems loaded with single anticancer drugs display miscellaneous effectiveness in tumor remission, gradually circumventing mutation and resistance in chemotherapy. Hence, the existence of dual-drug delivered nano-sized systems has been contemporaneous with drug development and preceded the conventional-dose chemotherapy. Among outstanding synergistic drug nanoplatforms, thermosensitive copolymer heparin-Pluronic F127 (Hep-F127) co-delivering cisplatin (CDDP) and curcumins (Cur) (Hep-F127/CDDP/Cur) has emerged as a notable candidate for temperature-responsive drug delivery. The procedure was based on the entrapment of curcumin into the hydrophobic core of bio-degradable co-polymer Hep-F127 while the hydrophilic drug CDDP subsequently conjugated to the backbone heparin to form the core-shell structure. The copolymer was characterized by Fourier transform infrared (FT-IR) spectrophotometry, Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS), to corroborate the successful synthesis and via HPLC along with AES-ICP to evaluate the high drug loading along with a controllable release from the nano-gels. A well-defined nano-shell with size in the 129.3 ± 3.8 nm size range could enhance higher the efficacy of the conjugated-CDDP to Hep-F127 than that of single doses. Moreover, the considerable amount of dual-drug released from thermosensitive nanogels between different conditions (pH = 7.4 and pH = 5.5) in comparison to CDDP from Hep-F127 partially indicated the significantly anti-proliferative ability of Hep-F127/CDDP/Cur to the MCF-7 cell line. Remarkably, drug testing in a xenograft model elucidates the intricate synergism of co-delivery in suppressing tumor growth, which remedies some of the problems affecting in cancer chemotherapy.