Preparation of glycyrrhizic acid-modified BSA-nanoparticles and evaluation of their hepatic cellular distribution.

OBJECTIVES: Orientation to specific cells is an important topic in active targeting strategy for nanoparticle-based drug delivery systems. While these administered nanoparticles will be sequestrated within the liver, their cellular distribution behaviors in the liver are not clear. The aim of this study was to fabricate glycyrrhizic acid (GL) modified BSA nanoparticles and evaluate their hepatic cellular distribution. METHODS: GL-modified BSA (GL-BSA) was tailored according to the periodate oxidation method, then GL-BSA nanoparticles loaded with paclitaxel (PTX@GL-BSA NPs) were prepared through self-assembly approach. In vitro cellular uptake was assessed by FITC-labeled BSA nanoparticles and immunofluorescent analysis was performed to track their relative distribution in the liver. KEY FINDINGS: The fabricated PTX@GL-BSA NPs were spherical structure with the particle size of 179 nm and a negative potential (-17.3 mV). Flow cytometry (FCM) studies exhibited that the accumulation of GL-BSA nanoparticles was 5.3-fold compared with BSA nanoparticles in HepG2 cells. The Nanoparticles were preferentially accumulated in the sinusoidal endothelial cells rather than the Kupffer cells. CONCLUSIONS: This study provides useful information to understand the distribution of hepatic targeting nanoparticles when using GL-modified BSA nanoparticles, which helps to further use for effective treatment of liver disease.

Synergistic Amplification of Ferroptosis with Liposomal Oxidation Catalyst and Gpx4 Inhibitor for Enhanced Cancer Therapy.

As a distinctly different way from apoptosis, ferroptosis can cause cell death through excessive accumulation of lipid peroxide (LPO) and show great potential for cancer therapy. However, efficient strategies for ferroptosis therapy are still facing great challenges, mainly due to insufficient endogenous H2 O2 or relatively high pH value for Fenton reaction-dependent ferroptosis, and the high redox level of tumor cells attenuates the oxidation therapy. Herein, an efficient lipid-based delivery system to load oxidation catalyst and glutathione peroxidase 4 (Gpx4) inhibitor is orchestrated, intending to amplify Fenton reaction-independent ferroptosis by bidirectional regulation of LPO accumulation. Ferric ammonium citrate (FAC), Gpx4 inhibitor sorafenib (SF), and unsaturated lipids are constructed into mPEG2K -DSPE-modified liposomes (Lip@SF&FAC). Influenced by the high level of intratumoral glutathione, FAC can be converted into Fe2+ , and subsequently the formed iron redox pair (Fe2+ /Fe3+ ) catalyzes unsaturated phospholipids of liposomes into LPO via a Fenton reaction-independent manner. Meanwhile, SF can downregulate LPO reduction by inhibiting Gpx4 activation. In vitro and in vivo antitumor experiments show that Lip@SF&FAC induces massive LPO accumulation in tumor cells and ultimately exhibits strong tumor-killing ability with negligible side effect. Consequently, this two-pronged approach provides a new ferroptosis strategy for predominant LPO accumulation and enhanced cancer therapy.

Application and Efficacy of Melatonin Elastic Liposomes in Photoaging Mice.

Transdermal drug delivery system is a preferable choice to overcome the low bioavailability of oral medication. Elastic liposomes have shown great effectiveness for percutaneous transport of melatonin (MLT). In this study, the elastic liposomes loaded with MLT were prepared using thin-film dispersion method and optimized through the central composite design (CCD) approach. The physicochemical properties and skin permeation against UV-induced skin photoaging efficacy of the developed MLT-ELs were assessed. The average size of the MLT-ELs was about 49 nm with a spherical shape and high encapsulation efficiency (73.91%) and drug loading (9.92%). The results of FTIR, DSC, and XRD revealed that the chemical structure of MLT was not changed after prepared elastic liposomes, and the drug was successfully encapsulated in the elastic liposome membrane material. In vitro skin permeation evaluation showed that the cumulative penetration of elastic liposomes was 1.5 times higher than that of conventional liposomes, highlighting that the elastic liposomes more easily penetrated into the body. The photoaging experiment results indicated that topical MLT-EL treatment ameliorated the skin elasticity, enhanced the skin hydration level, and preserved the integrity of dermal collagen and elastic fibers. It could be concluded that the elastic liposomes might serve as a promising platform for the transdermal delivery of melatonin.

"Cascaded Rocket" Nanosystems with Spatiotemporal Separation for Triple-Synergistic Therapy of Alzheimer's Disease.

Alzheimer's disease (AD) remains an incurable disease due to the intricate pathogenesis. The neuropathological hallmarks include extracellular amyloid-ß (Aß) plaques, tau phosphorylation and extensive oxidative stress in neurons, which facilitate the progression of AD. Based on the complex etiology, a spatiotemporally "cascaded rocket" delivery system (DPH/TPGAS NPs) with metal ion/enzyme responses is established in this study for triple-synergistic AD treatment. After targeting and permeating the blood-brain barrier (BBB), the histidine units in the DPH chelate excess metal ions at the extracellular microenvironment, restraining the formation of Aß aggregates, inducing the first-stage separation. Then, the remanent system targets neuronal cells and triggers the second separation with cathepsin B for reducing the level of phosphorylated tau and oxidative stress. Accordingly, the DPH/TPGAS NPs can achieve spatiotemporal drug release, which results in enhanced synergistic therapeutic effects both in the extracellular and intracellular region of the AD brain. After treating with DPH/TPGAS NPs, the memory deficits, levels of Aß and phosphorylated tau, inflammation and neuron damages are remarkably ameliorated in 3 × Tg-AD mice. Therefore, this "cascaded rocket" delivery system has great potential to serve as a powerful platform and provides a new horizon to the therapeutic strategy for AD and other brain diseases' treatments.

Osthole-Loaded Nanoemulsion Enhances Brain Target in the Treatment of Alzheimer's Disease via Intranasal Administration.

Osthole (OST) is a natural coumarin compound that exerts multiple pharmacologic effects. However, the poor water solubility and the low oral absorption of OST limit its clinical application for the treatment of neurologic diseases. A suitable preparation needs to be tailored to evade these unfavourable properties of OST. In this study, an OST nanoemulsion (OST-NE) was fabricated according to the pseudoternary phase diagram method, which was generally used to optimize the prescription in light of the solubility of OST in surfactants and cosurfactants. The final composition of OST-NE was 3.6% of ethyl oleate as oil phase, 11.4% of the surfactant (polyethylene glycol ester of 15-hydroxystearic acid: polyoxyethylene 35 castor oil = 1 : 1), 3% of polyethylene glycol 400 as cosurfactant, and 82% of the aqueous phase. The pharmacokinetic study of OST-NE showed that the brain-targeting coefficient of OST was larger by the nasal route than that by the intravenous route. Moreover, OST-NE inhibited cell death, decreased the apoptosis-related proteins (Bax and caspase-3), and enhanced the activity of antioxidant enzymes (superoxide dismutase and glutathione) in L-glutamate-induced SH-SY5Y cells. OST-NE improved the spatial memory ability, increased the acetylcholine content in the cerebral cortex, and decreased the activity of acetylcholinesterase in the hippocampus of Alzheimer's disease model mice. In conclusion, this study indicates that the bioavailability of OST was improved by using the OST-NE via the nasal route. A low dose of OST-NE maintained the neuroprotective effects of OST, such as inhibiting apoptosis and oxidative stress and regulating the cholinergic system. Therefore, OST-NE can be used as a possible alternative to improve its bioavailability in the prevention and treatment of Alzheimer's disease.

Small-molecule inhibitors of breast cancer-related targets: Potential therapeutic agents for breast cancer.

Despite dramatic advances in cancer research and therapy, breast cancer remains a tricky health problem and represents a top biomedical research priority. Nowadays, breast cancer is still the leading cause of malignancy-related deaths in women, and incidence and mortality rates of it are expected to increase significantly the next years. Currently more and more researchers are interested in the study of breast cancer by its arising in young women. The common treatment options of breast cancer are chemotherapy, immunotherapy, hormone therapy, surgery, and radiotherapy. Most of them require chemical agents, such as PARP inhibitors, CDK4/6 inhibitors, and HER2 inhibitors. Recent studies suggest that some targets or pathways, including BRD4, PLK1, PD-L1, HDAC, and PI3K/AKT/mTOR, are tightly related to the occurrence and development of breast cancer. This article reviews the interplay between these targets and breast cancer and summarizes the progress of current research on small molecule inhibitors of these anti-breast cancer targets. The review aims to provide structural and theoretical basis for designing novel anti-breast cancer agents.

Near-Infrared Light Irradiation Induced Mild Hyperthermia Enhances Glutathione Depletion and DNA Interstrand Cross-Link Formation for Efficient Chemotherapy.

DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links via mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt-I-IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced via NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.

Hollow Mesoporous Silica Nanoparticles Loaded with Eugenol for Regulating the Central Nervous System.

Fragrances are extensively applied in food, daily chemicals, tobacco and medicine industries. However, too strong volatility of fragrances results in a fast release rate, thereby reducing the usage time of aromatherapy products. Although loading fragrances into nanomaterials is capable of slowing their rates of release, the encapsulation efficiency of traditional nanomaterials is very low, and the nanomaterials themselves are not stable. Herein, hollow mesoporous silica nanoparticles (hMSNs) were designed for encapsulation of eugenol and the nano-fragrance was named EG@hMSNs. The structure of hMSNs was stable and the encapsulation rate of eugenol reached 46.5%. Besides, EG@hMSNs could significantly slow the release rate of eugenol. Subsequently, the EG@hMSNs were testified that they had positive roles in stress relief by open field tests. The molecular mechanisms of these positive effects on the central nervous system were then explored. Furthermore, the preparation method of hMSCs was simple, and the preparation cost was low. Therefore, EG@hMSNs are expected to be industrially produced and have a great application prospect.

Fluorescent nanomaterials combined with molecular imprinting polymer: synthesis, analytical applications, and challenges.

Fluorescent nanomaterials (FNMs) and molecular imprinted polymers (MIPs) have been widely used in analytical chemistry for determination. However, low selectivity of FNMs and low sensitivity of MIPs hinder their applications. Combining the merits of FNMs and MIPs, FNMs coated with MIPs (FNMs@MIPs) were proposed to solve those problems. Carbon dots, semiconductor quantum dots, noble metal nanoparticles, silica nanoparticles, and covalent-organic frameworks have been reported to be coated with MIPs. In order to overcome challenges for FNMs@MIPs, such as the lack of handy synthesis routes, incompatibility with aqueous solutions, heterogeneous size of particles, leakage of template molecules, the biocompatibility of FNMs@MIPs, and the inference between FNMs and MIPs, scientists proposed some solutions in recent years. We comprehensively review the newest advances of the FNMs@MIPs, and predict the direction of the future development. Graphical abstract.

Cationic Nano-Fragrance with Sustained Release Property for Neuroregulation.

Silk is a kind of textile with Chinese characteristics and widely used in clothing, decoration, military and medical fields. Recently, fragrances have been applied to silk to relieve anxiety and stress. However, the problems of too strong aroma and short scent lasting time seriously restrict the development of aromatic silk. Herein, Cationic nanoparticles encapsulating with linalool were prepared to prolong the scent lasting time. The fragrance-loaded nanoparticles are tightly attached to the silk by electrostatic interaction between cationic nanoparticles and anionic silk. Besides, the cationic nanoparticles could slow the release rate of linalool, thus extending the fragrance retention time. Subsequently, fragrant silk has been proven to have an effect of relieving stress. Therefore, this fragrance-loaded cationic nanoparticles-added silk has potential application value.

Nano-Fragrance with pH-Sensitive Release Property for Improvement of Central Nervous System.

Fragrance has the function of nerve regulation and is widely used in aromatic therapy. However, the rapid release of fragrance can cause discomfort in the body and have side effects. Besides, fragrance is still released when not in use, which can reduce the service life of fragrance products and limit their application. Herein, cationic nanoparticles loaded with linalool were prepared and then adhered on the silk. The fragrance-encapsulated nanoparticles have pH-sensitive release property. Linalool was promoted to release in acidic condition and was suppressed to release in alkaline condition. In addition, the nano-fragrance with controlled release properties had regulatory effects on the central nervous system. It had the effect of relieving stress according to the open field tests. Besides, it increased the expression levels of dopamine, acetylcholine and GABA according to results of liquid chromatographmass spectrometer. Therefore, these cationic nano-fragrance with pH-sensitive release property have the potential for aromatherapy.

Neutrophils, as "Trojan horses", participate in the delivery of therapeutical PLGA nanoparticles into a tumor based on the chemotactic effect.

Inspired by the fact that leukocytes have innate phagocytic functions and oriented migration capabilities in response to chemoattractants, we have unveiled that endogenous neutrophils as "Trojan horses", participate in the delivery of nanoparticles in an "in vivo self-armed assembly" manner. Neutrophils were the main population to preferentially sequester the intravenous administrated nanoparticles with an average size of 260 nm. The pre-implantation of CXCL1-laden hydrogels could trigger and induce a targeted signal to attract an influx of neutrophils carrying the therapeutic goods to the desired position. In mouse models of melanoma, the combinatorial regimen of using the PLGA nanoparticles with the CXCL1 hydrogels exhibited superior tumor inhibition capability. This work leveraged the natural phagocytosis of neutrophile and the chemotactic effect of chemokines for targeted delivery. We believe this strategy will improve the therapeutic efficiency of nanoparticle-based delivery systems, especially when the chemokines are implanted at sites of surgical tumor removal, during cancer treatment at the clinic.

Design and Development of Lidocaine Microemulsions for Transdermal Delivery.

Topical administration is a preferable choice for local anesthetic delivery. Microemulsions have shown great effectiveness for transdermal transport of lidocaine. However, fabrication of microemulsions containing highly concentrated lidocaine (10%) to provide an extended local anesthetic effect is still a challenge. This study investigated the feasibility of using microemulsions for transdermal delivery of a high dosage of lidocaine (10%). At first, eutectic mixtures by kneading lidocaine with thymol were tailored to form a lipophilic solution, then the mixtures were readily incorporated into the oil phase of microemulsions after addition of proper surfactants and cosurfactants. The physicochemical properties, the skin permeation, local anesthetic efficacy, and the irritation experiment of the developed microemulsions were evaluated. The optimum composition was as follows: 12% of ethyl oleate as oil phase, 28% of the mixed surfactant, and cosurfactant (polyoxyl 15 hydroxystearate and ethanol) and 60% of the aqueous phase. The average particle size was about 13 nm. The transmission electron microscope (TEM) studies revealed almost homogeneous spherical globules without aggregation. The Fourier-transform infrared spectroscopy (FTIR) results highlighted the drugs homogeneously dispersed in the microemulsions. In vitro skin permeation and in vivo anesthesia effect evaluation indicated that microemulsions can enhance and extend the anesthetic effect of lidocaine. The irritable results indicated that the microemulsions had the better biocompatibility and the negligible influence on the dermal. Therefore, incorporating the eutectic mixtures into microemulsions could be proposed as an attractive choice and a promising transdermal delivery strategy for the future topical anesthetic therapy.

Temporary suppression the sequestrated function of host macrophages for better nanoparticles tumor delivery.

Orchestration of nanoparticles to achieve targeting has become the mainstream for efficient delivery of antitumor drugs. However, the low delivery efficiency becomes the biggest barrier for clinical translation of cancer nanomedicines, as most of them are sequestrated in the liver where more macrophages located in are responsible for capture of systemic administrated nanoparticles. In this study, we found that the depletion of the liver macrophages could lead to a superior improvement in the nanoparticles delivery. Firstly, we developed clodronate-containing liposomes (clodrolip) to transiently suppress the phagocytic function of macrophages, the residual macrophages in liver only accounted for less than 1% when the mice were treated with clodrolip in advance. In addition, the pharmacokinetics results of treatment with paclitaxel-poly(lactic-co-glycolic acid) (PTX-PLGA) nanoparticles disclosed that the AUC of PTX in the macrophages depletion group increased 2.11-fold. These results meant that the removal of macrophages would decrease the nanoparticles accumulation in the liver and better the biodistribution and bioavailability of nanoparticles delivery systems. Moreover, treatment of mice with melanoma by the combination of clodrolip and PTX-PLGA nanoparticles resulted in an elevated anti-tumor efficacy, the tumor inhibition ratio was nearly reached to 80%. Furthermore, these combinatorial regimens have demonstrated negligible toxicity in incidence of adverse effects. In conclusion, the encouraging results from this study inspire the generation of a rational strategy to focus on microenvironmental priming for modulation of innate immunity and to improve delivery efficiency of nanoparticles.

Folic acid-functionalized drug delivery platform of resveratrol based on Pluronic 127/D-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles.

A folic acid (FA)-functionalized drug vehicle platform based on Pluronic 127 (P127)/D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles was orchestrated for an effective delivery of the model drug resveratrol in order to address the problem of poor water solubility and rapid metabolism of resveratrol and improve its targeted accumulation at tumor site. The FA-decorated mixed micelles were prepared using thin-film hydration method and optimized by central composite design approach. The micelles were also characterized in terms of size and morphology, drug entrapment efficiency and in vitro release profile. In addition, the cytotoxicity and cell uptake of the micelles were evaluated in folate receptor-overexpressing MCF-7 cell line. In vivo pharmacokinetic and biodistribution studies were also performed. The average size of the micelles was ~20 nm with a spherical shape and high encapsulation efficiency (99.67%). The results of fluorescence microscopy confirmed the targeting capability of FA-conjugated micelles in MCF-7 cells. FA-modified micelles exhibited superior pharmacokinetics in comparison with that of solution. Further, the low accumulation of resveratrol-loaded FA micelles formulation in the heart and kidney avoided toxicity of these vital organs. It could be concluded that folate-modified P127/TPGS mixed micelles might serve as a potential delivery platform for resveratrol.

Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery.

The objective of this study was to fabricate a composite in situ gelling formulation combining nanoparticulates and an ionic-triggered deacetylated gellan gum (DGG) matrix for challenging intranasal drug delivery. The prepared resveratrol nanosuspensions (Res-NSs) were distributed in DGG solutions. Parameters such as the in situ gelation capability, particle size, rheological properties, and texture profiles were used to describe the properties of the in situ gel. Pharmacokinetic and brain-targeting efficiency studies were performed after intranasal and intravenous administration, respectively. Biodistribution and localization using in vivo imaging systems and fluorescence microscopy are also described. The formulation containing 0.6% w/v DGG displayed a favorable gelling ability and the desired viscosity. The rheology results established that the DGG in situ gel possesses the characteristics of shear thinning, thixotropy and yield stress. The results of the textural profile revealed an increase in adhesiveness and viscosity for the in situ gel compared to the DGG solution. In vitro penetration studies followed a Higuchi mathematic model. Pharmacokinetics revealed a 2.88-times increase of bioavailability in the brain by intranasal Res-NSs in situ gel formulation. The drug targeting efficiency (458.2%) and direct transport percentages (78.18%) demonstrated direct delivery via the nose-brain pathway. The distribution and localization further illustrated the existence of direct nose-to-brain transport, bypassing the BBB. In sum, this hybrid in situ gel system is a promising approach for intranasal application in terms of the enhancement of nasal mucosal permeability and increased nasal cavity residence time by a nanotechnology delivery system and in situ gelling technology.

Facile large-scale preparation of mesoporous silica microspheres with the assistance of sucrose and their drug loading and releasing properties.

Mesoporous silica microspheres (MSMs) with a pore-size larger than 10nm and a large pore-volume have attracted considerable attention for their application in delivering poorly water-soluble drugs. Here we developed a simple method for large-scale synthesis of MSMs using sodium silicate as silica precursor. The novelty of this approach lies in the use of sucrose solution to achieve large size and volume of nanopores. The highest values of pore size and pore volume are 13.2 nm and 1.97 cm(3)/g, respectively. Importantly, the method is reliable and easily upscalable. The blank and drug-loaded MSMs were characterized by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Ibuprofen and resveratrol were successfully loaded into the nanopores of MSMs in amorphous and nanocrystalline form and showed high drug-loadings and enhanced dissolution rates. This kind of MSMs appears to be a promising candidate as a new oral drug delivery vehicle providing a rapid drug release.

Self-Assembled Cubic Liquid Crystalline Nanoparticles for Transdermal Delivery of Paeonol.

BACKGROUND: The aim of this study was to optimize the preparation method for self-assembled glyceryl monoolein-based cubosomes containing paeonol and to characterize the properties of this transdermal delivery system to improve the drug penetration ability in the skin. MATERIAL AND METHODS: In this study, the cubic liquid crystalline nanoparticles loaded with paeonol were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel by high-pressure homogenization. We evaluated the Zeta potential of these promising skin-targeting drug-delivery systems using the Malvern Zeta sizer examination, and various microscopies and differential scanning calorimetry were also used for property investigation. Stimulating studies were evaluated based on the skin irritation reaction score standard and the skin stimulus intensity evaluation standard for paeonol cubosomes when compared with commercial paeonol ointment. In vitro tests were performed on excised rat skins in an improved Franz diffusion apparatus. The amount of paeonol over time in the in vitro penetration and retention experiments both was determined quantitatively by HPLC. RESULTS: Stimulating studies were compared with the commercial ointment which indicated that the paeonol cubic liquid crystalline nanoparticles could reduce the irritation in the skin stimulating test. Thus, based on the attractive characteristics of the cubic crystal system of paeonol, we will further exploit the cosmetic features in the future studies. CONCLUSIONS: The transdermal delivery system of paeonol with low-irritation based on the self-assembled cubic liquid crystalline nanoparticles prepared in this study might be a promising system of good tropical preparation for skin application.

Simultaneous extraction, identification and quantification of phenolic compounds in Eclipta prostrata using microwave-assisted extraction combined with HPLC-DAD-ESI-MS/MS.

A simple and rapid method was developed using microwave-assisted extraction (MAE) combined with HPLC-DAD-ESI-MS/MS for the simultaneous extraction, identification, and quantification of phenolic compounds in Eclipta prostrata, a common herb and vegetable in China. The optimized parameters of MAE were: employing 50% ethanol as solvent, microwave power 400 W, temperature 70 °C, ratio of liquid/solid 30 mL/g and extraction time 2 min. Compared to conventional extraction methods, the optimized MAE can avoid the degradation of the phenolic compounds and simultaneously obtained the highest yields of all components faster with less consumption of solvent and energy. Six phenolic acids, six flavonoid glycosides and one coumarin were firstly identified. The phenolic compounds were quantified by HPLC-DAD with good linearity, precision, and accuracy. The extract obtained by MAE showed significant antioxidant activity. The proposed method provides a valuable and green analytical methodology for the investigation of phenolic components in natural plants.