Sustainable building materials-recycled aggregate and concrete: a systematic review of properties, modification techniques, and environmental impacts.

Resource utilization of construction and demolition (C&D) waste has great potential to significantly reduce the consumption of natural resources and improve the environment. Meanwhile, establishing a sound policy system and reducing production are the key ways to solve the problem of C&D waste. Numerous studies on C&D waste, recycled concrete aggregate (RA), and recycled aggregate concrete (RAC) have been reported in the literature, with few systematic summaries. From a global perspective, this paper assessed the current situation of C&D waste and the countermeasure of several major economies. Then, this paper systematically introduces the composition structure and characteristics of RA. Modification techniques from macro and micro perspectives of RA and its effect on RAC were also presented. Paper also reviews the environmental impacts of RA and RAC. The results showed that bonded mortar was the most significant defect of RA than natural aggregate (NA). Thus, RA weakened RAC's microstructure, workability, mechanical properties, and durability. The research on the modification of RA mainly focused on removing bonded mortar and enhancing bonded mortar containing physical or chemical methods. Enhancing bonded mortar was a more effective method than removing bonded mortar. Carbonation and microbially induced calcium carbonate precipitation were highly efficient and environmentally friendly for RA modification. Research progress in quantifying the environmental impacts associated with concrete from waste materials through the LCA methodology is presented. Suggestions and an outlook were given on the critical issues facing RA and RAC. We expect that this work can provide more technical support for C&D waste utilization.

Study on the relation between macro-mechanical properties and micro-structure of geopolymers with different activator modulus.

The fly ash-based geopolymer (FABG) containing slag has distinct advantages in field applications. In this work, given that the activator modulus is a significant parameter affecting the properties of FABG, the influence mechanism of activator modulus (SiO2/Na2O from 1.1 to 1.5) on the macro-mechanical properties and micro-structure composition of FABG containing slag is explored. According to the experimental results, the early product of FABG containing slag is mainly C-A-S-H gel, and N-(C)-A-S-H gel with high cross-linking degree is formed at a later stage. Both C-A-S-H and N-A-S-H gels are distinguished in reaction products by using 29Si NMR. The Si/Al ratio of N-A-S-H gel and C-A-S-H gel decreases with the increase of modulus, resulting in an increase of MCL in C-A-S-H. Appropriate activator modulus can effectively activate slag and fly ash to yield more gels and form a more uniform and dense micro-structure, resulting in a lower threshold pore size and macroporosity, and an associated increase of the material strength. Meanwhile, the gel amount has a positive effect on the strength development in the FABG.

Targeting ENPP1 for cancer immunotherapy: Killing two birds with one stone.

Cancer immunotherapy, particularly with immune checkpoint inhibitors, has revolutionized the paradigm of cancer treatment. Nevertheless, the efficacy of cancer immunotherapy remains limited in most clinical settings due to the lack of a preexisting antitumor T-cell response in tumors. Therefore, the clinical outcomes of cancer immunotherapy must be improved crucially. With increased awareness of the importance of the innate immune response in the recruitment of T cells, as well as the onset and maintenance of the T cell response, great interest has been shown in activating the cGAS-STING signaling pathway to awaken the innate immune response, thereby orchestrating both innate and adaptive immune responses to induce tumor clearance. However, tumor cells have evolved to overexpress ectonucleotide pyrophosphate phosphodiesterase 1 (ENPP1), which degrades the immunotransmitter 2',3'-cGAMP and promotes the production of immune-suppressing adenosine, resulting in inhibition of the anticancer immune response in the tumor microenvironment. Clinically, ENPP1 overexpression is closely associated with poor prognosis in patients with cancer. Conversely, depleting or inhibiting ENPP1 has been verified to elevate extracellular 2',3'-cGAMP levels and inhibit the generation of adenosine, thereby reinvigorating the anticancer immune response for tumor elimination. A variety of ENPP1 inhibitors have recently been developed and have demonstrated significant promise for cancer immunotherapy. In this review, we provide an overview of ENPP1, dissect its immunosuppressive mechanisms, and discuss the development of ENPP1 inhibitors with the potential to further improve the efficacy of cancer immunotherapy.

[Serum metabolomics study of Psoraleae Fructus in improving learning and memory ability of APP/PS1 mice].

This study aimed to investigate the mechanism of Psoraleae Fructus in improving the learning and memory ability of APP/PS1 mice by serum metabolomics, screen the differential metabolites of Psoraleae Fructus on APP/PS1 mice, and reveal its influence on the metabolic pathway of APP/PS1 mice. Thirty 3-month-old APP/PS1 mice were randomly divided into a model group and a Psoraleae Fructus extract group, and another 15 C57BL/6 mice of the same age were assigned to the blank group. The learning and memory ability of mice was evaluated by the Morris water maze and novel object recognition tests, and metabolomics was used to analyze the metabolites in mouse serum. The results of the Morris water maze test showed that Psoraleae Fructus shortened the escape latency of APP/PS1 mice(P<0.01), and increased the number of platform crossing and residence time in the target quadrant(P<0.01). The results of the novel object recognition test showed that Psoraleae Fructus could improve the novel object recognition index of APP/PS1 mice(P<0.01). Eighteen differential metabolites in serum were screened out by metabolomics, among which the levels of arachidonic acid, tryptophan, and glycerophospholipid decreased after drug administration, while the levels of glutamyltyrosine increased after drug administration. The metabolic pathways involved included arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, linoleic acid metabolism, α-linolenic acid metabolism, and glycerolipid metabolism. Therefore, Psoraleae Fructus can improve the learning and memory ability of APP/PS1 mice, and its mechanism may be related to the effects in promoting energy metabolism, reducing oxidative damage, protecting central nervous system, reducing neuroinflammation, and reducing Aß deposition. This study is expected to provide references for Psoraleae Fructus in the treatment of Alzheimer's disease(AD) and further explain the mechanism of Psoraleae Fructus in the treatment of AD.

[Mechanism of albiflorin in improvement of Alzheimer's disease based on network pharmacology and in vitro experiments].

This study aimed to explore the mechanism of albiflorin in the treatment of Alzheimer's disease(AD) based on network pharmacology, molecular docking, and in vitro experiments. Network pharmacology was used to predict the potential targets and pathways of albiflorin against AD, and molecular docking technology was used to verify the binding affinity of albiflorin to key target proteins. Finally, the AD cell model was induced by Aß_(25-35) in rat pheochromocytoma(PC12) cells and intervened by albiflorin to validate core targets and pathways. The results of network pharmacological analysis showed that albiflorin acted on key targets such as mitogen-activated protein kinase-1(MAPK1 or ERK2), albumin(ALB), epidermal growth factor receptor(EGFR), caspase-3(CASP3), and sodium-dependent serotonin transporter(SLC6A4), and signaling pathways such as MAPK, cAMP, and cGMP-PKG. The results of molecular docking showed that albiflorin had strong binding affinity to MAPK1(ERK2). In vitro experiments showed that compared with the blank group, the model group showed decreased cell viability, decreased expression level of B-cell lymphoma 2(Bcl-2), increased Bcl-2-associated X protein(Bax), and reduced phosphorylation level of extracellular signal-regulated kinase 1/2(ERK1/2) and the relative expression ratio of p-ERK1/2 to ERK1/2. Compared with the model group, the albiflorin group showed potentiated cell viability, up-regulated expression of Bcl-2, down-regulated Bax, and increased phosphorylation level of ERK1/2 and the relative expression ratio of p-ERK1/2 to ERK1/2. These results suggest that the mechanism of albiflorin against AD may be related to its activation of the MAPK/ERK signaling pathway and its inhibition of neuronal apoptosis.

Polylactic-co-glycolic acid-based nanoparticles modified with peptides and other linkers cross the blood-brain barrier for targeted drug delivery.

Because of the blood-brain barrier, only a limited fraction of drugs can penetrate the brain. As a result, there is a need to take larger doses of the drug, which may result in numerous undesirable side effects. Over the past few decades, a plethora of research has been conducted to address this issue. In recent years, the field of nanomedicine research has reported promising findings. Currently, numerous types of polylactic-co-glycolic acid-based drug-delivery systems are being studied, and great progress has been made in the modification of their surfaces with a variety of ligands. In this review, the authors highlight the preparation of polylactic-co-glycolic acid-based nanoparticles and single- and dual-targeted peptide modifications for site-specific drug delivery into the brain.

The blood­brain barrier prevents many drugs used to treat brain diseases from having clinical effects. To solve this issue, some promising findings have been reported in the field of nanomedicine research, which will be introduced in this article as possible effective methods for the treatment of brain diseases. This review will focus on the nature of the polylactic-co-glycolic acid polymers involved in the preparation of desired targeted nanocarriers, the synthesis methods for achieving the drug loaded system and the choice and preparation of the targeting agents.

Long non-coding RNAs in osteoporosis: from mechanisms of action to therapeutic potential.

Osteoporosis is a clinical disease characterized by decreased bone density due to a disrupted balance between bone formation and resorption, which increases fracture risk and negatively affects the quality of life of a patient. LncRNAs are RNA molecules over 200 nucleotides in length with non-coding potential. Many studies have demonstrated that numerous biological processes involved in bone metabolism are affected. However, the complex mechanisms of action of lncRNAs and their clinical applications in osteoporosis have not yet been fully elucidated. LncRNAs, as epigenetic regulators, are widely involved in the regulation of gene expression during osteogenic and osteoclast differentiation. LncRNAs affect bone homeostasis and osteoporosis development through different signaling pathways and regulatory networks. Additionally, researchers have found that lncRNAs have great potential for clinical application in the treatment of osteoporosis. In this review, we summarize the research results on lncRNAs for clinical prevention, rehabilitation treatment, drug development, and targeted therapy for osteoporosis. Moreover, we summarize the regulatory modes of various signaling pathways through which lncRNAs affect the development of osteoporosis. Overall, these studies suggest that lncRNAs can be used as novel targeted molecular drugs for the clinical treatment of osteoporosis to improve symptoms.

Ginsenoside Compound K Ameliorates Osteoarthritis by Inhibiting the Chondrocyte Endoplasmic Reticulum Stress-Mediated IRE1α-TXNIP-NLRP3 Axis and Pyroptosis.

Osteoarthritis (OA) is a common joint disease, and studies have reported that the endoplasmic reticulum stress (ERS) in chondrocytes caused by the cartilage tissue damage could mediate the activation of Nod-like receptor protein 3 (NLRP3) inflammasomes through inositol-requiring enzyme 1 alpha (IRE1α) and thioredoxin interacting protein (TXNIP). Ginsenoside compound K (CK) has an inhibitory effect on IRE1α activation. However, the role of IRE1α-TXNIP and its interaction with CK are still unclear. In this study, we examined the role and mechanism of action of CK in OA. We found that CK ameliorated OA and ERS in IL-1ß-treated chondrocytes and a monoiodoacetate-induced rat OA model. The effect of CK on inflammation, pyroptosis, and ERS was blocked by the ERS inducer tunicamycin. In conclusion, CK hindered OA progression by inhibiting the ERS-IRE1α-TXNIP-NLRP3 axis. Overall, our data indicate that CK could be useful in the treatment of OA and other chronic inflammatory diseases.

Targeting STING for cancer immunotherapy: From mechanisms to translation.

Cancer immunotherapy with immune checkpoint inhibitors has achieved unprecedented success in cancer treatment; However, only a subset of patients achieved clinical benefit from this treatment, underscoring the urgent need to identify new strategies to enhance the clinical efficacy of immune checkpoint inhibitors. Given the essential role of innate immunity in cancer immune surveillance, tremendous effort has been focused on the innate immune pathways that can be pharmacologically modulated to improve the clinical outcome of checkpoint inhibitors. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays essential roles in host defense against cancers. Activation of the cGAS-STING signaling pathway induces the expression of type I interferons and proinflammatory cytokines, culminating in promotion of a robust adaptive antitumor immunity. As part of this innate immune signaling pathway, STING is ubiquitously expressed in immune and nonimmune cells. STING activation has been demonstrated to propagate the cancer immunity cycle, remodel the tumor microenvironment, and ultimately eliminate tumor cells. The immunomodulatory roles of STING enable it to be an appealing target for cancer immunotherapy. As such, STING agonists that are capable of triggering antitumor immune responses have been developed in recent years, and several of them have advanced into clinical trials. In this review, we first give an overview on the STING signaling pathway, then dissect the roles of STING activation in different steps of the cancer immunity cycle and finally discuss the development of STING agonists as well as challenges with STING activation, with the potential to make cancer immunotherapy with STING agonists more effective.

Integrative modeling of the cell.

A whole-cell model represents certain aspects of the cell structure and/or function. Due to the high complexity of the cell, an integrative modeling approach is often taken to utilize all available information including experimental data, prior knowledge and prior models. In this review, we summarize an emerging workflow of whole-cell modeling into five steps: (i) gather information; (ii) represent the modeled system into modules; (iii) translate input information into scoring function; (iv) sample the whole-cell model; (v) validate and interpret the model. In particular, we propose the integrative modeling of the cell by combining available (whole-cell) models to maximize the accuracy, precision, and completeness. In addition, we list quantitative predictions of various aspects of cell biology from existing whole-cell models. Moreover, we discuss the remaining challenges and future directions, and highlight the opportunity to establish an integrative spatiotemporal multi-scale whole-cell model based on a community approach.

Bayesian metamodeling of complex biological systems across varying representations.

Comprehensive modeling of a whole cell requires an integration of vast amounts of information on various aspects of the cell and its parts. To divide and conquer this task, we introduce Bayesian metamodeling, a general approach to modeling complex systems by integrating a collection of heterogeneous input models. Each input model can in principle be based on any type of data and can describe a different aspect of the modeled system using any mathematical representation, scale, and level of granularity. These input models are 1) converted to a standardized statistical representation relying on probabilistic graphical models, 2) coupled by modeling their mutual relations with the physical world, and 3) finally harmonized with respect to each other. To illustrate Bayesian metamodeling, we provide a proof-of-principle metamodel of glucose-stimulated insulin secretion by human pancreatic ß-cells. The input models include a coarse-grained spatiotemporal simulation of insulin vesicle trafficking, docking, and exocytosis; a molecular network model of glucose-stimulated insulin secretion signaling; a network model of insulin metabolism; a structural model of glucagon-like peptide-1 receptor activation; a linear model of a pancreatic cell population; and ordinary differential equations for systemic postprandial insulin response. Metamodeling benefits from decentralized computing, while often producing a more accurate, precise, and complete model that contextualizes input models as well as resolves conflicting information. We anticipate Bayesian metamodeling will facilitate collaborative science by providing a framework for sharing expertise, resources, data, and models, as exemplified by the Pancreatic ß-Cell Consortium.

Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors.

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure-activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model.

Folic Acid and Poly(ethylene glycol) Decorated Paclitaxel Nanocrystals Exhibit Enhanced Stability and Breast Cancer-Targeting Capability.

In part because of their high drug loading, nanocrystals (NCs) have seen extensive use in drug delivery, particularly for insoluble or poorly soluble drugs. It remains a challenge, however, to prepare stable nanocrystals with tumor-targeting capability. Here, we designed a novel preparation of stable paclitaxel (PTX) nanocrystals with efficient active tumor-targeting properties. PTX NC was prepared using a bottom-up method and modified with both poly(ethylene glycol) (PEG) and folic acid (FA) derivatives using film hydration. The resulting PTX NC@lipid-PEG-FA had a rodlike shape, with hydrodynamic diameters and drug loading values of 201.90 ± 2.92 nm and 31.07 ± 3.41%, respectively. The size of the PTX NC@lipid-PEG-FA was unchanged after 168 h in the presence of plasma, whereas nonmodified paclitaxel nanocrystals (PTX NC) exceeded 600 nm within 12 h under the same conditions. Cellular uptake and cellular growth inhibition experiments in 4T1 breast cancer cells showed the superiority of PTX NC@lipid-PEG-FA over PTX NC or PEGylated paclitaxel nanocrystals without FA modification (PTX NC@lipid-PEG). A pharmacokinetic evaluation in rats revealed that PTX NC@lipid-PEG-FA significantly prolonged the circulation of PTX in the bloodstream, in comparison with PTX NC or Taxol. Tissue distribution and in vivo antitumor studies in 4T1 orthotopic breast cancer-bearing nude mice showed that PTX NC@lipid-PEG-FA significantly increased the intratumor accumulation of PTX and efficiently inhibited tumor growth, in comparison with PTX NC@lipid-PEG, PTX NC, or Taxol. In summary, PTX NC@lipid-PEG-FA showed good potential for breast cancer-targeted delivery for insoluble therapeutics.

DrugSpaceX: a large screenable and synthetically tractable database extending drug space.

One of the most prominent topics in drug discovery is efficient exploration of the vast drug-like chemical space to find synthesizable and novel chemical structures with desired biological properties. To address this challenge, we created the DrugSpaceX (https://drugspacex.simm.ac.cn/) database based on expert-defined transformations of approved drug molecules. The current version of DrugSpaceX contains >100 million transformed chemical products for virtual screening, with outstanding characteristics in terms of structural novelty, diversity and large three-dimensional chemical space coverage. To illustrate its practical application in drug discovery, we used a case study of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, to show DrugSpaceX performing a quick search of initial hit compounds. Additionally, for ligand identification and optimization purposes, DrugSpaceX also provides several subsets for download, including a 10% diversity subset, an extended drug-like subset, a drug-like subset, a lead-like subset, and a fragment-like subset. In addition to chemical properties and transformation instructions, DrugSpaceX can locate the position of transformation, which will enable medicinal chemists to easily integrate strategy planning and protection design.

Bioactivity Prediction Based on Matched Molecular Pair and Matched Molecular Series Methods.

BACKGROUND: Enhancing a compound's biological activity is the central task for lead optimization in small molecules drug discovery. However, it is laborious to perform many iterative rounds of compound synthesis and bioactivity tests. To address the issue, it is highly demanding to develop high quality in silico bioactivity prediction approaches, to prioritize such more active compound derivatives and reduce the trial-and-error process. METHODS: Two kinds of bioactivity prediction models based on a large-scale structure-activity relationship (SAR) database were constructed. The first one is based on the similarity of substituents and realized by matched molecular pair analysis, including SA, SA_BR, SR, and SR_BR. The second one is based on SAR transferability and realized by matched molecular series analysis, including Single MMS pair, Full MMS series, and Multi single MMS pairs. Moreover, we also defined the application domain of models by using the distance-based threshold. RESULTS: Among seven individual models, Multi single MMS pairs bioactivity prediction model showed the best performance (R2 = 0.828, MAE = 0.406, RMSE = 0.591), and the baseline model (SA) produced the most lower prediction accuracy (R2 = 0.798, MAE = 0.446, RMSE = 0.637). The predictive accuracy could further be improved by consensus modeling (R2 = 0.842, MAE = 0.397 and RMSE = 0.563). CONCLUSION: An accurate prediction model for bioactivity was built with a consensus method, which was superior to all individual models. Our model should be a valuable tool for lead optimization.

Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model.

Aldehyde oxidase (AOX) is a drug metabolizing molybdo-flavoenzyme that has gained increasing attention because of contribution to the biotransformation in phase I metabolism of xenobiotics. Unfortunately, the intra- and interspecies variations in AOX activity and lack of reliable and predictive animal models make evaluation of AOX-catalyzed metabolism prone to be misleading. In this study, we developed an improved computational model integrating both atom-level and molecule-level features to predict whether a drug-like molecule is a potential human AOX (hAOX) substrate and to identify the corresponding sites of metabolism. Additionally, we combined the proposed computational strategy and in vitro experiments for evaluating the metabolic property of a series of epigenetic-related drug candidates still in the early stage of development. In summary, this study provides an improved strategy to evaluate the liability of molecules toward hAOX and offers useful information for accelerating the drug design and optimization stage.

Diterpenoids from the Root Bark of Pinus massoniana and Evaluation of Their Phosphodiesterase Type 4D Inhibitory Activity.

Thirty-two diterpenoids were obtained from the root bark of Pinus massoniana, and, among them, five compounds (pinmassins A-E) were identified as undescribed analogues. Spectroscopic methods, X-ray single-crystal diffraction analysis, and ECD calculations were applied to establish the structure of the new isolates. Pinmassin D (4) and abieta-8,11,13,15-tetraen-18-oic acid (23) showed moderate phosphodiesterase type 4D (PDE4D) inhibitory effects with IC50 values of 2.8 ± 0.18 and 3.3 ± 0.50 µM, respectively, and their binding modes were investigated by a molecular docking study.

Increased microneedle-mediated transdermal delivery of tetramethylpyrazine to the brain, combined with borneol and iontophoresis, for MCAO prevention.

The aim of this research was to improve transdermal delivery and distribution of tetramethylpyrazine (TMP) in the brain, by adding borneol (BN) and iontophoresis (ITP), and using microneedles (MN), to prevent middle cerebral artery occlusion (MCAO). BN was encapsulated into sulfobutylated-ß-cyclodextrin (BN-SBE-ß-CD), and then dispersed together with TMP. Four delivery groups were tested: passive (with no ITP and MN), ITP, MN, and MN combined with ITP (MN-ITP). In vitro transdermal fluxes of the drugs in those groups and in that corresponding order were 79.12 ± 14.5, 395.43 ± 12.37, 319.16 ± 29.99, and 1018.07 ± 108.92 µg/cm2 (for TMP), and 39.34 ± 1.31, 202.81 ± 53.56, 715.47 ± 75.52, and 1088.60 ± 53.90 µg/cm2 (for BN), respectively, which indicated that the use of MN-ITP greatly enhanced transdermal TMP and BN delivery compared to the other groups. The AUC0-t for the combined use of TMP and BN drugs was measured using two in vivo studies, cutaneous microdialysis and pharmacodynamic, yielding increased folds of 3.69 and 1.98 in ITP, 6.05 and 2.73 in MN, and 12.43 and 7.47 in MN-ITP groups, respectively, as compared to those in the passive group. In addition, the combined use of TMP and BN increased TMP distribution in the heart and the brain, indicated by TMP Cmax of 1.76- and 1.59-fold higher (p < 0.05), and TMP AUC0-t of 1.50 times and 1.19-fold higher (p < 0.01), than with administration of TMP in absence of BN, respectively. The brain infarction area and IL-ß expression in the MCAO rat were significantly decreased in the MN-ITP group, compared with the control group (p < 0.05). In conclusion, combination of MN and ITP resulted in a synergistic enhancement of transdermal delivery and distribution of TMP in the brain, when in combination with BN, thereby significantly decreasing the infarct volumes and improving the neurological scores of MCAO.

Novel nanostructured lipid carriers-loaded dissolving microneedles for controlled local administration of aconitine.

Nanostructured lipid carriers (NLCs) can enhance the safe transdermal delivery system of drugs. Moreover, dissolving microneedles (MNs) can enhance the permeability and controlled drug release. In this study, NLCs were formulated as a suitable vehicle for aconitine (ACO) delivery to effectively inhibit the inflammation of fibroblast-like synoviocytes isolated from a rat model of adjuvant-induced arthritis (AA-FLS). To improve drug delivery, the ACO-loaded NLCs (ACO-NLCs) were embedded in polyvinylpyrrolidone-based dissolving MNs fabricated by an ultraviolet cross-linking method. The nanoparticles maintained good physical stability in the dissolving MNs. The insertion capabilities of the ACO-NLCs-MNs were determined by observing histological sections of the skin after insertion, and scanning electron microscopy was used to observe the changes in the MNs over time. In vivo microdialysis showed that the NLCs-MNs enhanced the transdermal delivery of ACO through disrupting the barrier function of the stratum corneum (SC) and releasing the drug continuously. The ACO-NLCs-MNs showed a significant inhibitory effect on the paw swelling and inflammation in AA model rats. Moreover, this dual approach involving NLCs-loaded dissolving MNs formed a drug reservoir and effectively improved the ACO-induced arrhythmia. These results indicate that NLCs-containing MNs could be promising systems for the effective transdermal delivery and controlled local administration of ACO.

Construction and in vitro and in vivo evaluation of folic acid-modified nanostructured lipid carriers loaded with paclitaxel and chlorin e6.

Breast cancer remains a major threat to women's health, and the incidence of breast cancer continues to increase each year. Paclitaxel (PTX) is commonly used to treat breast cancer, but shows limited solubility and is associated with major side effects, limiting its clinical applications. Photodynamic therapy (PDT) is a promising treatment for breast cancer but is limited by the poor solubility of photosensitizers and difficulties in targeting and enriching the tumor tissue with photosensitizers. Here, we prepared a new nanocarrier system using nanostructured lipid carriers (PTX@FA-NLC-PEG-Ce6) harboring PTX, chlorin e6 (Ce6), and folic acid-targeted head to overcome the limitations of PTX and Ce6 in hydrophobicity and increase the target efficiency of chemotherapy drugs and photosensitizers at the tumor. The results showed that the drug-loading system met the requirements for intravenous injection, had tumor targeting ability, and could be easily taken up by MDA-MB-231 cells. Moreover, Ce6 could be dissociated from the surface of the drug-loading system and evenly distributed in cells after a period of time when the nanostructured lipid carriers had entered lysosomes through endocytosis. Additionally, reactive oxygen species were then produced to induce PDT at a specific wavelength of illumination. In vitro pharmacodynamic experiments showed that combined PDT and chemotherapy had synergistic effects (combination index: 0.647). Furthermore, pharmacodynamic experiments in nude mice showed that the drug-loading system had ideal antitumor effects without obvious side effects. Thus, PTX@FA-NLC-PEG-Ce6 may have applications as a promising drug-loading system for PDT combined with chemotherapy in patients with breast cancer.