Next-generation engineered nanogold for multimodal cancer therapy and imaging: a clinical perspectives.

Cancer is one of the significant threats to human life. Although various latest technologies are currently available to treat cancer, it still accounts for millions of death each year worldwide. Thus, creating a need for more developed and novel technologies to combat this deadly condition. Nanoparticles-based cancer therapeutics have offered a promising approach to treat cancer effectively while minimizing adverse events. Among various nanoparticles, nanogold (AuNPs) are biocompatible and have proved their efficiency in treating cancer because they can reach tumors via enhanced permeability and retention effect. The size and shape of the AuNPs are responsible for their diverse therapeutic behavior. Thus, to modulate their therapeutic values, the AuNPs can be synthesized in various shapes, such as spheres, cages, flowers, shells, prisms, rods, clusters, etc. Also, attaching AuNPs with single or multiple targeting agents can facilitate the active targeting of AuNPs to the tumor tissue. The AuNPs have been much explored for photothermal therapy (PTT) to treat cancer. In addition to PTT, AuNPs-based nanoplatforms have been investigated for combinational multimodal therapies in the last few years, including photodynamic therapy, chemotherapy, radiotherapy, immunotherapy, etc., to ablate cancer cells. Thus, the present review focuses on the recent advancements in the functionalization of AuNPs-based nanoconstructs for cancer imaging and therapy using combinatorial multimodal approaches to treat various cancers.

Polyquaternium enhances the colloidal stability of chitosan-capped platinum nanoparticles and their antibacterial activity.

Here, for the first time, we have developed a novel green synthesis method where chitosan acts as a reducing agent and as a colloidal stabilizer, together with polyquaternium for the synthesis of platinum nanoparticles (PtNPs). It was observed that only chitosan-stabilized PtNPs (Ch@PtNPs) were stable up to pH 5, with a diameter of around 89 nm. The diameter of the Ch@PtNPs increased with the increase in pH, indicating the instability of Ch@PtNPs at neutral and alkaline mediums. However, when polyquaternium (PQ) (a cationic polymer) was added as a stabilizer along with chitosan, the diameter of chitosan/polyquaternium stabilized PtNPs (Ch/PQ@PtNPs), i.e. 87 nm, remained almost constant up to pH 9. Similarly, the pH-dependent decrease in the surface charge of Ch@PtNPs was also attenuated with the addition of polyquaternium. This indicates high colloidal stability of Ch/PQ@PtNPs in acidic, neutral, as well as alkaline mediums. It was observed that Ch/PQ@PtNPs exhibited high antibacterial activity againstStaphylococcus aureus, as compared to uncapped PtNPs and Ch@PtNPs. Thus, the addition of PQ increases the antibacterial properties of Ch/PQ@PtNPs againstStaphylococcus aureusby enhancing the stability of PtNPs at neutral pH.

Central composite design for the development of carvedilol-loaded transdermal ethosomal hydrogel for extended and enhanced anti-hypertensive effect.

BACKGROUND: Carvedilol, the anti-hypertensive drug, has poor bioavailability when administered orally. Ethosomes-mediated transdermal delivery is considered a potential route of administration to increase the bioavailability of carvedilol. The central composite design could be used as a tool to optimize ethosomal formulation. Thus, this study aims to optimize carvedilol-loaded ethosomes using central composite design, followed by incorporation of synthesized ethosomes into hydrogels for transdermal delivery of carvedilol. RESULTS: The optimized carvedilol-loaded ethosomes were spherical in shape. The optimized ethosomes had mean particle size of 130 ± 1.72 nm, entrapment efficiency of 99.12 ± 2.96%, cumulative drug release of 97.89 ± 3.7%, zeta potential of - 31 ± 1.8 mV, and polydispersity index of 0.230 ± 0.03. The in-vitro drug release showed sustained release of carvedilol from ethosomes and ethosomal hydrogel. Compared to free carvedilol-loaded hydrogel, the ethosomal gel showed increased penetration of carvedilol through the skin. Moreover, ethosomal hydrogels showed a gradual reduction in blood pressure for 24 h in rats. CONCLUSIONS: Taken together, central composite design can be used for successful optimization of carvedilol-loaded ethosomes formulation, which can serve as the promising transdermal delivery system for carvedilol. Moreover the carvedilol-loaded ethosomal gel can extend the anti-hypertensive effect of carvedilol for a longer time, as compared to free carvedilol, suggesting its therapeutic potential in future clinics.

N-Doped carbon dots with pH-sensitive emission, and their application to simultaneous fluorometric determination of iron(III) and copper(II).

Simultaneous fluorometric determination of iron(III) and copper(II) without the use of any masking agent or additional treatment is achieved by using N-doped carbon dots (NCDs). The NCDs were hydrothermally prepared, have strongest excitation/emission peaks at 320/406 nm and a 47% quantum yield. Excitation-tunable emission is found to depend on solution pH values. This supports the involvement of surface states in the origin of the excitation dependent nature. The NCDs were employed as a fluorescent probe for the simultaneous determination of Fe(III) with a linear response in the 3-60 µM concentration range and a 0.31 µM detection limit (LOD). The probe also responds linearly to Cu(II) in the 0.5-15 µM concentration range and with a 56 nM LOD. With the addition of Cu(II), the absorption spectra of NCDs presented a clear decrease in the intensity at 312 nm followed by an increase at 360 nm. This is not observed in the presence of Fe(III). The fluorescence lifetime of NCDs (5.8 ns) is reduced by Fe(III) but not by Cu(II). Thus, the two metal ions can be simultaneously detected without the need for any reagents. The probe was employed to quantify Fe(III) and Cu(II) in spiked water, serum, and urine samples. Graphical abstract Schematic representation of hydrothermal synthesis of highly fluorescent N-doped carbon dots with novel pH dependent emission and their application for the simultaneous determination of Cu(II) and Fe(III) with individual ion discrimination.

Multiplexed Surface Protein Detection and Cancer Classification Using Gap-Enhanced Magnetic-Plasmonic Core-Shell Raman Nanotags and Machine Learning Algorithm.

Cancer is the second leading cause of death attributed to disease worldwide. Current standard detection methods often rely on a single cancer marker, which can lead to inaccurate results, including false negatives, and an inability to detect multiple cancers simultaneously. Here, we developed a multiplex method that can effectively detect and classify surface proteins associated with three distinct types of breast cancer by utilizing gap-enhanced Raman scattering nanotags and machine learning algorithm. We synthesized anisotropic magnetic core-gold shell gap-enhanced Raman nanotags incorporating three different Raman reporters. These multicolor Raman nanotags were employed to distinguish specific surface protein markers in breast cancer cells. The acquired signals were deconvoluted and analyzed using classical least-squares regression to generate a surface protein profile and characterize the breast cancer cells. Furthermore, computational data obtained via finite-difference time-domain and discrete dipole approximation showed the amplification of the electric fields within the gap region due to plasmonic coupling between the two gold layers. Finally, a random forest classifier achieved an impressive classification and profiling accuracy of 93.9%, enabling effective distinguishing between the three different types of breast cancer cell lines in a mixed solution. With the combination of immunomagnetic multiplex target specificity and separation, gap-enhancement Raman nanotags, and machine learning, our method provides an accurate and integrated platform to profile and classify different cancer cells, giving implications for identification of the origin of circulating tumor cells in the blood system.

Dialdehyde modification of laminarin for facile synthesis of ultrafine silver nanoparticles with excellent antibacterial and wound healing properties.

Laminarin is a promising marine biopolymer that is abundant, non-toxic, and biodegradable. However, laminarin has a weak reduction potential for metal ions, resulting in the synthesis of a lower content of large-sized silver nanoparticles (AgNPs). Here, we showed that after the introduction of aldehyde groups, the reduction potential of laminarin increased, decreasing the synthesis time and increasing the density of AgNPs. 1H NMR and FT-IR confirmed the addition of aldehyde groups on laminarin. The dialdehyde-modified laminarin (DLAM) showed in situ, simple, and rapid synthesis of ultrasmall-sized spherical AgNPs (<10 nm), as revealed by TEM images. The aldehyde and carboxyl groups of DLAM act as synchronized reducing and anchoring agents. The conversion of Ag ions into AgNPs-DLAM was confirmed by UV-Vis spectrophotometer, FTIR, XRD, and XPS analysis. The AgNPs-DLAM showed significantly enhanced antibacterial activities than silver ions against Escherichia coli and Staphylococcus aureus via causing morphological changes and pore formations in bacterial cells. The AgNPs-DLAM also inhibited bacterial biofilm formation. In contrast, the AgNPs-DLAM showed negligible toxicity toward human keratinocytes. Furthermore, AgNPs-DLAM increased the migration of human keratinocytes, indicating efficient wound healing properties. Thus, signifying the importance of AgNPs-DLAM in clinical applications.

Microwave-Assisted Synchronous Nanogold Synthesis Reinforced by Kenaf Seed and Decoding Their Biocompatibility and Anticancer Activity.

The combination of green-nanotechnology and biology may contribute to anticancer therapy. In this regard, using gold nanoparticles (GNPs) as therapeutic molecules can be a promising strategy. Herein, we proposed a novel biocompatible nanogold constructed by simply microwave-heating (MWI) Au3+ ions and kenaf seed (KS) extract within a minute. The phytoconstituents of KS extract have been utilized for safe synthesis of gold nanoparticles (KS@GNPs). The biogenic KS@GNPs were characterized by UV-vis Spectra, TEM, HR-TEM, XRD, FTIR, DLS, EDX, and SEAD techniques. The legitimacy and toxicity concern of KS@GNPs were tested against RAW 264.7 and NIH3T3 cell lines. The anticancer efficacy was verified using LN-229 cells. The pathways of KS@GNPs synthesis were optimized by varying the KS concentration (λmax 528 nm), gold salt amount (λmax 524 nm), and MWI times (λmax 522 nm). TEM displayed spherical shape and narrow size distribution (5-19.5 nm) of KS@GNPs, whereas DLS recorded Z-average size of 121.7 d·nm with a zeta potential of -33.7 mV. XRD and SAED ring patterns confirmed the high crystallinity and crystalline face centered cubic structure of gold. FTIR explored OH functional group involved in Au3+ ions reduction followed by GNPs stabilization. KS@GNPs exposure to RAW 264.7 and NIH3T3 cell lines did not induce toxicity while dose-dependent overt cell toxicity and reduced cell viability (26.6%) was observed in LN-229 cells. Moreover, the IC50 (18.79 µg/mL) treatment to cancer cell triggered cellular damages, excessive ROS generation, and apoptosis. Overall, this research exploits a sustainable method of KS@GNPs synthesis and their anticancer therapy.

Gold nanoparticles spontaneously grown on cellulose nanofibrils as a reusable nanozyme for colorimetric detection of cholesterol in human serum.

Recently, gold nanoparticles (AuNPs) are extensively used as peroxidase mimics. However, low catalytic activity, high synthesis cost, substrate-induced aggregation in reaction medium and difficulty in recovery and reuse still remain as major challenges. Here, a novel, simple, spontaneous, and reagent-less in-situ method for the production of AuNPs using dialdehyde cellulose nanofibrils (DACNF) is proposed. AuNPs synthesis time and size were greatly influenced by aldehyde content and the optimal aldehyde content for ultra-small AuNPs (≈10 nm) was 2.1 mM/g. AuNPs@DACNFs exhibited broad-spectrum peroxidase activity and steady-state kinetics revealed their better kinetic parameters (low Km and high Vmax) over horseradish peroxidase (HRP). AuNPs@DACNFs was further converted into paper strip, which served as a biosensor for H2O2 and cholesterol detection. The proposed method exhibited wide linear response in the range of 10-90 µM and 0.05-0.45 mM, and detection limit of 0.39 µM and 1.9 µM for H2O2 and cholesterol, respectively. Great shelf life and reusability were evident by FE-SEM and ICP-OES analysis. The smartphone application "Color Grab" was used to enable the portable onsite detection. The results of cholesterol detection in human serum samples were in agreement with clinically observed values, suggesting the great potential of the probe in disease diagnosis.

Effective fabrication of cellulose nanofibrils supported Pd nanoparticles as a novel nanozyme with peroxidase and oxidase-like activities for efficient dye degradation.

Nanozyme-based dye degradation methods are promising for the remediation of water pollution. Though Pd nanoparticles (PdNPs) are known to act as nanozymes, their dye degradation capability has not been investigated. Low nanozyme activities, easy aggregation, difficulties in recovery and reuse are the major challenges in achieving this. For the first time, cellulose nanofibrils-supported PdNPs (PdNPs/PCNF) as a novel nanozyme with good peroxidase and oxidase-mimicking activities and easy recyclability is explored for dye degradation. An efficient and rapid method of PdNPs/PCNF preparation was demonstrated by adjusting the pH and microwave irradiation. Enzyme kinetic studies revealed good kinetic parameters and specific activities of 415 and 277 U/g for peroxidase and oxidase, respectively. PdNPs/PCNF offered 99.64% degradation of methylene blue within 12 min (0.468 min-1) with 0.4 M H2O2 at pH 5.0. Mechanistic studies revealed the involvement of hydroxyl and superoxide radicals. Owing to the network-like structure of PCNF, films and foams were prepared, their dye degradation potentials were compared, and recyclability was tested. Successful degradation of mixed dye solutions and spiked real water samples was achieved and a continuous flow method was demonstrated using a foam-packed column.

Strategies for transdermal drug delivery against bone disorders: A preclinical and clinical update.

The transdermal drug delivery system is an exceptionally safe and well-tolerable therapeutic approach that has immense potential for delivering active components against bone-related pathologies. However, its use is limited in the current clinical practices due to the low skin permeability of most active drugs in the formulation. Thus, innovations in the methodologies of skin permeation enhancement techniques are suggested to overcome this limitation. Although various transdermal drug delivery systems are studied to date, there are insufficient studies comparing the therapeutic efficacy of transdermal delivery systems to oral delivery systems. Thus, creating a decision-making dilemma between oral or transdermal therapies. Therefore, a timely review is inevitable to develop a platform for future researchers to develop next-generation transdermal drug delivery strategies against skeletal diseases that must be convenient and cost-effective for the patients with improved therapeutic efficacy. Here, we will outline the most recent strategies that can overcome the choice limitation of the drug and enhance the transdermal adsorption of various types of drugs to treat bone disorders. For the first time, in this review paper, we will highlight the preclinical and clinical studies on the different transdermal delivery methods. Thus, providing insight into the current therapeutic approaches and suggesting new directions for the advancements in transdermal drug delivery systems against bone disorders.

In-situ fabrication of novel flower like MoS2/CoTiO3 nanorod heterostructures for the recyclable degradation of ciprofloxacin and bisphenol A under sunlight.

Effectual degradation of toxic water contaminants is a crucial step in water purification and designing an efficient semiconductor based hybrid structure photocatalyst is a good approach to achieve this. Benefiting from the combination of semiconductors, a series of novel visible-light active flower-like MoS2/CoTiO3 nanorod heterostructures with excellent morphological contact interface were prepared through a facile in-situ hydrothermal process. These heterostructures were well characterized and demonstrated high photocatalytic performance for ciprofloxacin (CIP) and bisphenol A (BPA) under sunlight irradiation. Compared to pristine CoTiO3 and MoS2, the optimal catalyst (5 wt% MoS2/CoTiO3) presented 39.97 and 22.32 times higher activity for CIP degradation and 26.85 and 15.66 times higher activity for BPA degradation, respectively. This improved activity can be accounted for the effective interfacial contact which promotes the efficient charge carriers separation and reduce its recombination. The catalyst exhibited decent stability and was potentially reused for five cycles without significant loss in activity. Furthermore, based on active species scavenging experiments the plausible photodegradation mechanism is discussed in detail.

Shape recoverable, Au nanoparticles loaded nanocellulose foams as a recyclable catalyst for the dynamic and batch discoloration of dyes.

An environmental benign in-situ formation and growth of gold nanoparticles (AuNPs) on TEMPO-oxidized cellulose nanofibrils (TOCNF) is reported here. With the active functional groups (aldehyde and carboxyl), TOCNF served as a synchronized reducing and supporting agent for the formation of AuNPs. The entire synthesis process was completed within 30 s under microwave irradiation and regarded as ultra-fast. As obtained AuNPs@TOCNF nanohybrid suspension was freeze-dried to form strong water-activated shape recovery 3D foam. Internal morphology and porosity of the foam were studied by SEM and BET. AuNPs@TOCNF foams exhibited excellent catalytic activity for the discoloration of cationic and anionic dyes in batch and dynamic column processes. The spent foams can be easily recovered and reused up to five cycles with more than 98 % efficiency. During the catalytic processes, no obvious deterioration of the foam structure was observed. Practical applicability of the nanocatalyst was evaluated by treating spiked sea water sample.

Rapid in-situ growth of gold nanoparticles on cationic cellulose nanofibrils: Recyclable nanozyme for the colorimetric glucose detection.

Novel microwave-assisted green in-situ synthesis of positively charged gold nanoparticles (AuNPs) supported by cationic cellulose nanofibrils (C.CNF) within 30 s and devoid of additional reducing agent is reported. Peroxidase activity of these positive AuNPs was studied and that appeared to be superior over its negative charged counterpart. Further the AuNPs@C.CNF is casted into a film which makes it reusable. Using TMB substrate, simple and sensitive colorimetric detection methods for H2O2 and glucose were established. Under optimal conditions, the linear ranges were found to be 0.5-30 µM and 1-60 µM, and the detection limits were 0.30 and 0.67 µM for H2O2 and glucose, respectively. The film was potentially reused for the detection of glucose up to five cycles without a decrease in the activity. Further, this technique was employed to quantify glucose in human serum samples, and the obtained results were comparable with those of the standard GOD-POD method.

Monoolein Cubic Phase Including Hydrophobized Modified Gelatin and Poly(ethyleneimine) and Its Effect on the Stability of Retinyl Palmitate.

Retinyl palmitate (RP) was added in monoolein (MO) cubic phase including decanoyl poly(ethyleneimine) (DePEI) and decanoyl gelatin (DeGel) in its water channel. RP, DePEI, and DeGel was incorporated In the cubic phase without structural disintegration, as confirmed by transmission electron microscopy. Differential scanning calorimetric and polarized optical microscopic analysis showed that adding the additives reduces phase transition temperature of cubic phase by 2 °C to 3 °C. The time-dependent chemical stability of RP added in the cubic phase was analyzed for 4 weeks at 5 °C, 20 °C, 30 °C, and 40 °C, using RP loaded in o/w emulsion as a control. The chemical stability of RP added in cubic phase containing DePEI and DeGel was somewhat higher as compared to the RP added in the cubic phase without DeGel/DePEI, possibly because DeGel/DePEI complex might shield RP from its environment by blocking the water channels inside the cubic phase. Moreover, the chemical stability of RP added in the cubic phase was comparatively higher than RP added in o/w emulsion.

Rapid synchronous synthesis of Ag nanoparticles and Ag nanoparticles/holocellulose nanofibrils: Hg(II) detection and dye discoloration.

A novel microwave-assisted green method that synchronously synthesizes silver nanoparticles (AgNPs) and AgNPs decorated holocellulose nanofibrils (AgNPs/HCNF) within a minute and without using a reducing agent is reported. As obtained nanomaterials were well characterized using various analytical techniques. AgNPs applied as a colorimetric probe for the selective recognition of Hg(II) (linear range 10-200 µg L-1, detection limit 1.16 µg L-1). The probe was able to quantify Hg(II) in spiked tap, bore, and lake water samples and paper strips were developed to facilitate the onsite detection. Furthermore, freeze-drying of the AgNPs/HCNF nanocomposite produced aerogel that served as an excellent catalyst for the reduction of Congo red and methylene blue. The aerogel was easily recovered and reused without a decrease in activity or deterioration of its structure for five cycles. These results indicate the great potential of the AgNPs/HCNF aerogel for waste water treatment and catalytic applications.

Doxorubicin-carboxymethyl xanthan gum capped gold nanoparticles: Microwave synthesis, characterization, and anti-cancer activity.

An ultrafast (e.g. 75 s) synthesis of carboxymethyl xanthan gum (CMXG) capped gold nanoparticles (AuNPs) (CMXG@AuNPs) was developed using microwave irradiation (MWI) method. The synthesis of AuNPs was optimized by varying CMXG amount, gold ion concentration, and MWI time. The CMXG@AuNPs exhibited a spherical shape, high crystallinity, and narrow size distribution (i.e. 8-10 nm). The electrostatic interaction-mediated the loading of doxorubicin (DOX) onto CMXG@AuNPs. The release of DOX, loaded on CMXG@AuNPs was extensive in an acidic condition but negligible at physiological pH value. The in vitro anticancer efficacy of DOX loaded on CMXG@AuNPs (i.e. DOX@CMXG@AuNPs) in the presence of an ionophore (i.e. nigericin) was about 4.6 folds higher than that of free DOX. Flow cytometry revealed that DOX@CMXG@AuNPs exhibited a higher cellular uptake under an acidic condition than free DOX. CMXG@AuNPs showed unique excellence in the pH-responsive DOX-releasing property and the cancer cell-killing capability.

Adsorption Characteristics of Ag Nanoparticles on Cellulose Nanofibrils with Different Chemical Compositions.

The adsorption characteristics of silver nanoparticles (AgNPs) on cellulose nanofibrils (CNFs) were investigated herein with different chemical compositions. Pure cellulose nanofibers (PCNFs), lignocellulose nanofibers (LCNFs) with different lignin contents (LCNF-20% and LCNF-31%), and holocellulose nanofibers (HCNFs) with hemicellulose were used in this study. Furthermore, CNFs and silver nitrate were mixed and reacted at different temperatures, and NaBH4 was used as the reducing agent. First, the effect of temperature on the adsorption of AgNPs on PCNF was studied. At an optimal temperature (45 °C), the effect of the chemical composition of CNF was studied. The overall properties were analyzed using UV-vis spectroscopy, transmission electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The AgNPs were found to be spherical under all conditions with average diameter of 5.3 nm (PCNF), 5.6 nm (HCNF), 6.3 nm (LCNF-20%) and 6.6 nm (LCNF-31%). The amount of AgNPs adsorbed on the CNF was observed to vary, based on the chemical composition of the CNF. The adsorption amount of AgNPs was observed to increase in the order of LCNF-20% > PCNF > LCNF-31% > HCNF. The results indicated that phenolic hydroxyl groups present in LCNF significantly affected the adsorption of AgNPs.

Oxidation- and Temperature-Responsive Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) Micelle as a Potential Anticancer Drug Carrier.

Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) (P(HEA-co-PVS)), as an oxidizable amphiphilic polymer, was prepared for the fabrication of an oxidation- and temperature-responsive micelle for the delivery of doxorubicin (DOX). The interfacial activity of H2O2-treated P(HEA-co-PVS) was significantly lower than that of the untreated variety, possibly because of the oxidization of PVS. P(HEA-co-PVS) exhibited a lower critical solution temperature (LCST) behavior and the LCST increased upon H2O2 treatment. The copolymer micelles, prepared by the dialysis method, were found to be round particles (less than 100 nm) on TEM micrograph. The release degree of Nile red loaded in the micelles was higher when the H2O2 concentration was higher, possibly because the micelles could be solubilized more readily at a higher H2O2 concentration. The release degree was more strongly dependent on the oxidizing agent concentration when the temperature was higher. DOX loaded in the micelles suppressed the in vitro growth of KB cells (a human cancer cell type originating from the cervix) much more effectively than DOX loaded in an unoxidizable control micelle and free DOX, possibly because the copolymer would undergo an increase in its LCST, lose its amphiphilic property, and the micelles would be disassembled. The DOX-loaded micelles were readily internalized into KB cells, as evidenced by flow cytometry (FACS) and confocal laser scanning microscopy (CLSM).