Spiderweb-Shaped Iron-Coordinated Polymeric Network as the Novel Coating on Microneedles for Transdermal Drug Delivery Against Infectious Wounds.

Coated microneedles (CMNs) are a minimally invasive platform for immediate-release transdermal drug delivery. However, the practical applications of CMNs have been significantly hindered by the challenges associated with complex formulations, single function, and limited drug loading capacity. This study has developed a spiderweb-shaped iron-coordinated polymeric nanowire network (Fe-IDA NWs). The resulting Fe-IDA NWs are endowed with a certain viscosity due to the synergy of multiple supramolecular interactions. This allows them to replace traditional polymeric thickeners as microneedle coatings. The Fe-IDA NWs-coated microneedles (Fe-IDA MNs) display rapid disintegration in the skin model, which also enables the swift diffusion of Fe-IDA NWs and their payloads into the deeper skin layers. Additionally, Fe-IDA MNs exhibit desirable enzymatic activity and potential antibacterial ability. Thus, Fe-IDA MNs can enhance the therapeutic efficacy against wound infection through synergistic effects, and avoid the overly complicated formulation and the release of nontherapeutic molecules of conventional CMNs. As a proof-of-concept, Fe-IDA MNs loaded with chlorin e6 showed a synergistic chemodynamic-photodynamic antibacterial effect in a methicillin-resistant Staphylococcus aureus-infected wound model in mice. Collectively, this work has significant implications for the future of CMNs-based transdermal drug delivery systems and expands the application fields of metal coordination polymer (MCP) materials.

Hyaluronidase-Responsive Bactericidal Cryogel for Promoting Healing of Infected Wounds: Inflammatory Attenuation, ROS Scavenging, and Immune Regulation.

Wounds infected with multidrug-resistant (MDR) bacteria are increasingly threatening public health and challenging clinical treatments because of intensive bacterial colonization, excessive inflammatory responses, and superabundant oxidative stress. To overcome this malignant burden and promote wound healing, a multifunctional cryogel (HA/TA2/KR2) composed of hyaluronic acid (HA), tannic acid (TA), and KR-12 peptides is designed. The cryogel exhibited excellent shape-memory properties, strong absorption performance, and hemostatic capacity. In vitro experiments demonstrated that KR-12 in the cryogel can be responsively released by stimulation with hyaluronidase produced by bacteria, reaching robust antibacterial activity against Escherichia coli (E. coli), MDR Pseudomonas aeruginosa (MDR-PA), and methicillin-resistant Staphylococcus aureus (MRSA) by disrupting bacterial cell membranes. Furthermore, the synergetic effect of KR-12 and TA can efficiently scavenge ROS and decrease expression of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α & interleukin (IL)-6), as well as modulate the macrophage phenotype toward the M2 type. In vivo animal tests indicated that the cryogel can effectively destroy bacteria in the wound and promote healing process via accelerating angiogenesis and re-epithelialization. Proteomic analysis revealed the underlying mechanism by which the cryogel mainly reshaped the infected wound microenvironment by inhibiting the Nuclear factor kappa B (NF-κB) signaling pathway and activating the Janus kinase-Signal transducer and activator of transcription (JAK-STAT6) signaling pathway. Therefore, the HA/TA2/KR2 cryogel is a promising dressing candidate for MDR bacteria-infected wound healing.

Curcumin suppresses RANKL-induced osteoclast precursor autophagy in osteoclastogenesis by inhibiting RANK signaling and downstream JNK-BCL2-Beclin1 pathway.

BACKGROUND: Curcumin ameliorates bone loss by inhibiting osteoclastogenesis. Curcumin inhibits RANKL-promoted autophagy in osteoclast precursors (OCPs), which mediates its anti-osteoclastogenic effect. But the role of RANKL signaling in curcumin-regulated OCP autophagy is unknown. This study aimed to explore the relationship between curcumin, RANKL signaling, and OCP autophagy during osteoclastogenesis. METHODS: We investigated the role of curcumin in RANKL-related molecular signaling in OCPs, and identified the significance of RANK-TRAF6 signaling in curcumin-treated osteoclastogenesis and OCP autophagy using flow sorting and lentiviral transduction. Tg-hRANKL mice were used to observe the in vivo effects of curcumin on RANKL-regulated bone loss, osteoclastogenesis, and OCP autophagy. The significance of JNK-BCL2-Beclin1 pathway in curcumin-regulated OCP autophagy with RANKL was explored via rescue assays and BCL2 phosphorylation detection. RESULTS: Curcumin inhibited RANKL-related molecular signaling in OCPs, and repressed osteoclast differentiation and autophagy in sorted RANK+ OCPs but did not affect those of RANK- OCPs. Curcumin-inhibited osteoclast differentiation and OCP autophagy were recovered by TRAF6 overexpression. But curcumin lost these effects under TRAF6 knockdown. Furthermore, curcumin prevented the decrease in bone mass and the increase in trabecular osteoclast formation and autophagy in RANK+ OCPs in Tg-hRANKL mice. Additionally, curcumin-inhibited OCP autophagy with RANKL was reversed by JNK activator anisomycin and TAT-Beclin1 overexpressing Beclin1. Curcumin inhibited BCL2 phosphorylation at Ser70 and enhanced protein interaction between BCL2 and Beclin1 in OCPs. CONCLUSIONS: Curcumin suppresses RANKL-promoted OCP autophagy by inhibiting signaling pathway downstream of RANKL, contributing to its anti-osteoclastogenic effect. Moreover, JNK-BCL2-Beclin1 pathway plays an important role in curcumin-regulated OCP autophagy.

GPER1 contributes to T3-induced osteogenesis by mediating glycolysis in osteoblast precursors.

Triiodothyronine (T3) is critical to osteogenesis, which is the key factor in bone growth. Our transcriptomic and metabolomic analysis results indicated that T3 leads to enhanced expression of G protein-coupled estrogen receptor 1 (GPER1) as well as increases in glycolysis metabolite levels. Accordingly, our study aimed to explore the role of GPER1-mediated glycolysis in T3-regulated osteogenesis. The MC3T3-E1 cell line was used as an osteoblast precursor model. After treatment with T3, a GPER1-specific antagonist (G15) and inhibitor of glycolysis (3PO) were used to explore the roles of GPER1 and glycolysis in T3-regulated osteogenesis, as measured by ALP activity, Alizarin red staining intensity and osteogenic molecule expression. Our results showed that T3 promoted osteogenesis-related activity, which was reversed by treatment with G15. In addition, T3 enhanced the glycolytic potential and production of lactic acid (LD) in MC3T3-E1 cells, and treatment with G15 restored the aforementioned effects of T3. Ultimately, the pharmacological inhibition of glycolysis with 3PO blocked the ability of T3 to enhance osteogenic activities. In conclusion, GPER1 mediates glycolysis in osteoblast precursors, which is critical for T3-promoted osteogenesis.

Spinal intradural extramedullary tumors: microscopic keyhole resection with the focus on intraoperative neurophysiological monitoring and long-term outcome.

OBJECTIVE: Spinal schwannomas (SS) and spinal meningiomas (SM) account for most intradural extramedullary (IDEM) tumors. These tumors are usually benign lesions, which generally respond favorably to surgical excision. Few studies up to now tried to determine the long-term outcome after minimally invasive surgery (MIS) with multimodal intraoperative neurophysiological monitoring (IONM) for IDEM tumors. The aim of this study was to present one of the largest case series with special regard to IONM findings and long-term outcome after MIS-keyhole surgery with a tubular retractor system. METHODS: Between January 2013 and August 2018, 87 patients with IDEM tumors who underwent tumor removal surgery via MIS-keyhole approach under multimodal IONM were retrospectively reviewed. The neurological status was assessed using a modified McCormick grading scale pre- and postoperatively. Multimodal IONM consisted of motor evoked potentials (MEP), somatosensory evoked potentials (SEP), and electromyography (EMG). Both short-term and long-term clinical evaluations as well as patients' medical files were retrospectively analyzed. RESULTS: Surgeries were performed for resection of SS in 49 patients and SM in 38 patients. Tumor locations were cervical in 16.1%, thoracic in 48.3%, thoracolumbar in 4.6%, lumbar 31%. Critical IONM changes were detected in 9 operations (10.3%) in which there were 2 SEPs, 5 MEPs, and 2 EMG events. Three IONM changes (2 MEPs, 1 EMG) were turned out to be transient change in nature since they were resolved in a short time when immediate corrective actions were initiated. Six patients with permanent IONM changes (2SEPs, 3MEPs, 1EMG event), all deficits had resolved during hospitalization or on short -term follow-up evaluation. Sensitivity, specificity, and positive and negative predicted values of IONM were 100, 96, 67, and 100%, respectively. Gross total resection rate was 100%, and a stable or improved McCormick grade exhibited in all patients. No tumor recurrence and no spinal instability were found in the long-term follow-up evaluation (mean 5.2 ± 2.9 years postoperatively). Overall, 94% of patients were either satisfied or very satisfied with their operation, and 93% patients reported excellent or good general clinical outcome according to Odom's criteria. CONCLUSION: MIS-keyhole surgery with multimodal IONM for IDEM tumors enables a high level of satisfaction and a satisfying long-term clinical and surgical outcome.

Multifunctional chitosan/gelatin@tannic acid cryogels decorated with in situ reduced silver nanoparticles for wound healing.

Background: Most traditional wound dressings only partially meet the needs of wound healing because of their single function. Patients usually suffer from the increasing cost of treatment and pain resulting from the frequent changing of wound dressings. Herein, we have developed a mutifunctional cryogel to promote bacterial infected wound healing based on a biocompatible polysaccharide. Methods: The multifunctional cryogel is made up of a compositive scaffold of chitosan (CS), gelatin (Gel) and tannic acid (TA) and in situ formed silver nanoparticles (Ag NPs). A liver bleeding rat model was used to evaluate the dynamic hemostasis performance of the various cryogels. In order to evaluate the antibacterial properties of the prepared cryogels, gram-positive bacterium Staphylococcus aureus (S. aureus) and gram-negative bacterium Escherichia coli (E. coli) were cultured with the cryogels for 12 h. Meanwhile, S. aureus was introduced to cause bacterial infection in vivo. After treatment for 2 days, the exudates from wound sites were dipped for bacterial colony culture. Subsequently, the anti-inflammatory effect of the various cryogels was evaluated by western blotting and enzyme-linked immunosorbent assay. Finally, full-thickness skin defect models on the back of SD rats were established to assess the wound healing performances of the cryogels. Results: Due to its porous structure, the multifunctional cryogel showed fast liver hemostasis. The introduced Ag NPs endowed the cryogel with an antibacterial efficiency of >99.9% against both S. aureus and E. coli. Benefited from the polyphenol groups of TA, the cryogel could inhibit nuclear factor-κB nuclear translocation and down-regulate inflammatory cytokines for an anti-inflammatory effect. Meanwhile, excessive reactive oxygen species could also be scavenged effectively. Despite the presence of Ag NPs, the cryogel did not show cytotoxicity and hemolysis. Moreover, in vivo experiments demonstrated that the biocompatible cryogel displayed effective bacterial disinfection and accelerated wound healing. Conclusions: The multifunctional cryogel, with fast hemostasis, antibacterial and anti-inflammation properties and the ability to promote cell proliferation could be widely applied as a wound dressing for bacterial infected wound healing.

In-situ synthesis silver nanoparticles in chitosan/Bletilla striata polysaccharide composited microneedles for infected and susceptible wound healing.

A novel antibacterial strategy is urgently required to develop for solving bacterial biofilm obstruction and bacterial drug resistance in the infected wound healing process. Herein, the Chitosan/Bletilla striata polysaccharide composited microneedles were prepared by chitosan, tannic acid, AgNO3 and Bletilla striata polysaccharide through step centrifugation. In our design system, the porous structure of microneedles gradually disappeared, and the mechanical properties were significantly improved after multiple fillings. Ag+ is reduced in-situ to silver nanoparticles by the abundant polyphenols of tannic acid, displaying antibacterial effects both in vitro and vivo, even for methicillin resistant Staphylococcus aureus. The addition of Bletilla striata polysaccharide increased the ability of piercing biofilm and promoted wound healing. The microneedles exhibited good biocompatibility and with function of piercing the bacterial biofilms, scavenging excessive free radicals, inhibiting inflammatory factors, and promoting wound healing. Therefore, the multifunctional composited microneedles show great potential to promote infected and susceptible wound healing.

Phosphorylation of BCL2 at the Ser70 site mediates RANKL-induced osteoclast precursor autophagy and osteoclastogenesis.

BACKGROUND: Phosphorylation modification of BCL2 is involved in receptor activator of nuclear factor-κB ligand (RANKL)-induced autophagy of osteoclast precursors (OCPs) and osteoclastogenesis. As an antiapoptotic molecule, the role of BCL2 phosphorylation in osteoclastogenesis is unknown. This study aimed to explore how BCL2 phosphorylation at specific sites regulates osteoclastogenesis. METHODS: We first examined the effects of RANKL on BCL2 phosphorylation at different sites (Ser70 and Ser87) in OCPs. In vivo, transgenic mice overexpressing RANKL (Tg-hRANKL mice) were used to observe the effects of RANKL on phosphorylated BCL2 at different sites in OCPs of trabecular bone. Subsequently, using site-directed mutagenesis, we observed the respective effect of BCL2 mutations at different phosphorylation sites in OCPs on osteoclastogenesis, apoptosis, autophagy and the affinity between BCL2 and Beclin1/BAX under RANKL intervention. RESULTS: RANKL promoted BCL2 phosphorylation at the Ser70 (S70) site, but not the Ser87 (S87) site, in OCPs. Moreover, Tg-hRANKL mice had stronger BCL2 phosphorylation capacity at S70, not S87, in the OCPs of trabecular bone than wild-type mice in the same nest. Furthermore, BCL2 mutation at S70, not S87, inhibited RANKL-induced osteoclast differentiation and bone resorption activity. In addition, BCL2 mutation at S70 promoted OCP apoptosis, while BCL2 mutation at S87 showed the opposite effect. Remarkably, the BCL2 mutation at S70, not S87, inhibited OCP autophagic activity. Furthermore, BCL2 mutation at S70 enhanced the coimmunoprecipitation of BCL2 and Beclin1, whereas BCL2 mutation at S87 enhanced the coimmunoprecipitation of BCL2 and BAX in OCPs. More importantly, OCP autophagy, osteoclast differentiation and resorption pits inhibited by BCL2 mutation at S70 could be reversed by Beclin1 upregulation with TAT-Beclin1. CONCLUSION: RANKL activates OCP autophagy through BCL2 phosphorylation at S70, thereby promoting osteoclastogenesis, which indicates that the inactivation of BCL2 at S70 in OCPs may be a therapeutic strategy for pathological bone loss.

Recent progress in tannic acid-driven antibacterial/antifouling surface coating strategies.

Medical devices and surgical implants are necessary for tissue engineering and regenerative medicines. However, the biofouling and microbial colonization on the implant surface continues to be a major concern, which is difficult to eradicate and typically necessitates either antibiotic therapy or implant removal. As a result, efficient and eco-friendly bioinspired coating strategies for tethering functional materials or molecules on different medical substrates are highly desirable, especially for endowing versatile surface functionalities. Tannic acid (TA), a well-known tea stain polyphenol, has a good affinity for various substrates and actively inhibits the adhesion and colonization of microbes. Thus, functionalization of polymers, nanomaterials, metal-phenolic networks (MPNs), and proteins using TA bestows the end-products with unique binding or anchoring abilities on various implantable surfaces. This review addresses the recent advancements in the essential biomedical perspective of TA-based bioinspired universal surface coating technologies by focusing on their intrinsic features and ability to produce engineered functional composites. Further, the possible contributions of TA-based composites in antifouling and antibacterial applications on various biomedical substrates are outlined.

"One-stitch" bioorthogonal prodrug activation based on cross-linked lipoic acid nanocapsules.

Bioorthogonal prodrug activation is fascinating but suffers from staggered administration of prodrug and trigger, which would not only reduce the therapeutic effect but bring great inconvenience for clinical application. Herein, we report a new cross-linked lipoic acid nanocapsules (cLANCs) based two-component bioorthogonal nanosystem for "one-stitch" prodrug activation. Due to the reversible stability of cLANCs, the loaded prodrug and trigger cannot release in advance while can react upon arrival in the tumor tissue. Moreover, the cLANCs would be degraded into dihydrolipoic acid in tumor cells to potentiate the anticancer effect of the drug synthesized in situ. The data showed that the new bioorthogonal system held a killing effect 1.63 times higher than that of parent drug 3 against human colorectal tumor cells (HT29) and a tumor inhibitory rate 34.2% higher than that of 3 against HT29 tumor xenograft model with negligible side effects. The biodistribution study showed that the "one-stitch" prodrug activation exhibited a selective accumulation of 3 in the tumor tissue compared with free 3 group (34.2 µg vs 3.56 µg of 3/g of tissue). This two-component bioorthogonal nanosystem based on cross-linked lipoic acid nanocapsules constitutes the first example of "one-stitch" bioorthogonal prodrug activation.

Chemical factors affecting uptake and translocation of six pesticides in soil by maize (Zea mays L.).

Uptake of residual pesticides in a soil by a certain crop plant may be governed by their physicochemical properties. Uptake and translocation of pesticides (imidacloprid, acetamiprid, tricyclazole, azoxystrobin, tebuconazole and difenoconazole) with the octanol/water partition coefficient (log Kow) ranging from 0.57 to 4.36 were investigated in soil with maize as a model plant. The results show that all tested pesticides in soil were uptaken by maize with accumulation amount of 27.73, 17.75, 18.96, 12.56, 10.66 and 2.13 µg for imidacloprid, acetamiprid, tricyclazole, azoxystrobin, tebuconazole and difenoconazole at 14 d, respectively. The accumulation amount was negatively correlated with adsorption coefficients and positively correlated with pesticide concentration in in situ pore water (CIPW). Root bioconcentration factor varied widely from 0.61 for imidacloprid to 974.64 for difenoconazole was positively correlated with log Kow and molecular weight but negatively with water solubility. Conversely, translocation factor varied from 0 for difenoconazole to 1.64 for imidacloprid was negatively correlated with log Kow but positively with water solubility. It determined that uptake, accumulation and translocation of the pesticides in soil by maize are governed by their physicochemical properties, especially log Kow. CIPW is an appropriate candidate to evaluate the accumulation of pesticides in maize from soil.

Deep Drug Penetration of Nanodrug Aggregates at Tumor Tissues by Fast Extracellular Drug Release.

Herein, a new nanodrug of azobenzene-functionalized interfacial cross-linked reverse micelles (AICRM) with 5-fluorouracil loading (5-FU@AICRM) is reported. Upon irradiation with 530 nm light in water, the surface azobenzenes of the nanoparticles change from polar cis-conformation to nonpolar trans-conformation, resulting in the aggregation of 5-FU@AICRM within minutes. Simultaneously, the conformation change unlocks hydrophilic 5-FU with a strong water immigration propensity, allowing them to spray out from the AICRM quickly. This fast release ensures a thorough release of the drug, before the aggregates are internalized by adjacent cells, making it possible to achieve deep tissue penetration. A study of in vivo anticancer activity in A549 tumor-bearing nude mice shows that the tumor inhibition rate (TIR) of 5-FU@AICRM is up to ≈86.2%, 31.6% higher than that of group without green light irradiation and 20.7% higher than that of carmofur (CF, a hydrophobic analog of 5-FU)-loaded AICRM (CF@AICRM), in which CF is released slowly under light irradiation because of its hydrophobicity. Fast drug release upon nanodrug aggregation provides a good solution for balancing the contradiction of "aggregation and penetration" in tumor treatment with nanodrugs.

Puerarin inhibits the migration of osteoclast precursors and osteoclastogenesis by inhibiting MCP-1 production.

Puerarin inhibits osteoclastogenesis and cells migration. This study aims to explore whether puerarin prevents osteoclastogenesis by inhibiting osteoclast precursors (OCPs) migration. The results showed that puerarin reduced MCP-1 production in OCPs, while inhibiting OCPs migration based on MCP-1. Puerarin reversed MCP-1-promoted osteoclastogenesis. CCR2 overexpression didn't increase osteoclastogenesis with puerarin. Therefore, puerarin prevents OCPs migration by reducing MCP-1, whereby inhibiting osteoclastogenesis.

Simple Method to Supply Organic Nanoparticles with Excitation-Wavelength-Dependent Photoluminescence.

Organic fluorescent nanoparticles (FNPs) have become increasingly prevalent in a variety of applications but the creation of organic FNPs using a simple procedure and that possess diverse morphology, multicolor luminescence, and high brightness has been challenging. Herein, a facile strategy to prepare this class of organic FNPs is established by way of preformed organic nanoparticles themselves. It was found that as long as the nanoparticles contained aromatic/heterocyclic rings in their base unit and regardless of morphologies (e.g., small-molecule micelles, polymeric micelles, reverse micelles, solid microspheres, and vesicles), simple UV irradiation can result in the particles exhibiting excitation-wavelength-dependent photoluminescence with considerable quantum yields (∼8.3-16.7% for tested particles). Upon initial investigation of the mechanism, the photoluminescence behavior was attributed to a polycyclic aromatic hydrocarbon (PAH) process. Furthermore, the application of the synthesized organic FNPs in cancer cell imaging is demonstrated as just one of the many potential applications. The straightforward method to supply preformed organic nanoparticles with photoluminescence would be attractive for scientists in both academia and industry.

Cross-linked small-molecule capsules with excitation wavelength-dependent photoluminescence and high loading capacity: design, synthesis and application in imaging-guided drug delivery.

The cross-linked small-molecule micelles (cSMs) have found applications in many fields but their low loading capacity and non-fluorescence property hindered their further development. Herein, water-soluble organic nanoparticles were applied as templates to "stretch" the hydrophobic core of cSMs and photo-cross-linking was employed to supply photoluminescence. The resulting cross-linked small-molecule capsules (cSCs) not only reserve the superior properties of cSMs of accurate monomer, easy functionalization and robust stability, but also achieve high drug loading capacity and excitation wavelength-dependent fluorescence, where the drug loading contents (DLCs) for various hydrophobic drugs were more than 30-fold higher than that of cSMs, and the maximum quantum yield could be as high as 12.0%. Featuring these superiorities, the cSCs hold promising potential in many fields and an example of doxorubicin-loaded cSCs (DOX@cSCs) for multichannel imaging-guided drug delivery is shown in this work.

Subcellular distribution governing accumulation and translocation of pesticides in wheat (Triticum aestivum L.).

Root uptake, translocation, and subcellular distribution of six pesticides (dinotefuran, thiamethoxam, imidacloprid, imazethapyr, propiconazole, and chlorpyrifos) with Kow ranging from -0.549 to 4.7 were investigated in wheat to study transportation and accumulation of pesticides. The root bioconcentration factor (RCF) of pesticides decreased with water solubility (R2 = 0.6121) and increased with hydrophobicity (when the pH-adjusted log Kow > 2, R2 = 0.925), respectively. The translocation of neutral pesticides from roots to shoots increased positively with water solubility (R2 > 0.6484) but decreased with hydrophobicity (R2 > 0.8039). The subcellular fraction concentration factor (SFCF) increased linearly with hydrophobicity of the tested pesticides (R2 > 0.958). The log RCF was positively correlated with log SFCF in root cell walls (R2 = 0.9894) and organelles (R2 = 0.9786). Transportation of the pesticides from roots to stems and stems to leaves was adversely affected by the log SFCF of cell walls and organelles of roots (R2 > 0.7997) and stems (R2 > 0.6666), respectively. Hydrophobicity-dependent SFCF is a factor governing accumulation of pesticides in roots after uptake and their subsequent upward translocation.

Curcumin-activated autophagy plays a negative role in its anti-osteoclastogenic effect.

BACKGROUND/PURPOSE: It remains unclear what role curcumin plays in the autophagy of osteoclast precursors (OCPs) during osteoclastogenesis, since some researchers found that curcumin has the ability to inhibit osteoclastogenesis. While others have considered it as an autophagy activator. This study aimed to determine the effect of curcumin-regulated autophagy on osteoclastogenesis. RESULTS: The results revealed that direct administration of curcumin enhanced the OCP autophagy response in bone marrow-derived macrophages (BMMs). Curcumin could also abate RANKL's stimulatory effect on OCP autophagy and osteoclastogenesis. Autophagic suppression related to pharmacological inhibitors or gene silencing could further enhance the inhibitory effect of curcumin on osteoclastogenesis. As expected, curcumin ameliorated ovariectomy (OVX)-induced bone loss and its effect could be promoted by an autophagy inhibitor (chloroquine). CONCLUSIONS: In conclusion, curcumin can directly enhance the autophagic activity of OCPs, which inhibits its anti-osteoclastogeneic effects. Autophagy inhibition-based drugs are expected to enhance curcumin's efficacy in treating osteoporosis.

Redox-responsive tetraphenylethylene-buried crosslinked vesicles for enhanced drug loading and efficient drug delivery monitoring.

Liposomes have been applied extensively as nanocarriers in the clinic (e.g., to deliver anticancer drugs) due to their biocompatibility and internal cavity structures. However, their low drug-loading capacity (DLC; <10%) and uncontrolled release reduce their efficacy in cancer treatment. To improve the DLC and monitor release of drugs in cells in real-time, stimuli-responsive vesicles must be developed. We present various amphiphilic tetraphenylethylene (TPE)-containing compounds designed to self-assemble into liposome-like vesicles that can load both hydrophilic and hydrophobic drugs. The highest DLC for doxorubicin (DOX) was ≤26% for vesicles (diameter = 105 nm) that could encapsulate hydrophilic DOX in the interior water pool and hydrophobic DOX viaπ-π stacking interactions between DOX and the TPE moiety. The stable vesicles could respond rapidly to overexpressed glutathione in the tumor microenvironment to release loaded DOX for cancer therapy. Vesicles modified by active targeting groups showed more efficacious tumor treatment compared with unmodified vesicles and free DOX in vitro and in vivo. Simultaneously we observed, spatiotemporally, the subcellular location of the delivery system and release process of DOX. Our work provides a novel nano-engineering technology to integrate the desired properties for anticancer theranostics: high DLC, stability, stimuli-responsiveness to the cancer environment, drug-delivery monitoring, active targeting, and suppression of tumor growth. These novel vesicles could be employed as multifunctional drug-delivery systems for cancer therapy.

Cascade-Reaction-Based Nanodrug for Combined Chemo/Starvation/Chemodynamic Therapy against Multidrug-Resistant Tumors.

We report a chemo/starvation/chemodynamic trimodal combination therapy to combat multidrug-resistant (MDR) tumors by developing a ferrocene-containing nanovesicle (FcNV), which encapsulates glucose oxidase (GOx) in the hydrophilic core and coordinates cisplatin (Pt) in the hydrophobic layer (GOx&Pt@FcNV). Contrasting with other reported multimodal combination therapies, the new nanodrug (GOx&Pt@FcNV) relies on cascade reactions to drastically increase the overall effectiveness against MDR tumors. Specifically, Pt blocks deoxyribonucleic acid replication and activates hydrogen peroxide (H2O2) generation for chemotherapy; GOx consumes glucose to produce H2O2 and gluconic acid for starvation therapy; and all H2O2 products are catalyzed by ferrous ions decomposed from ferrocene to generate the highly toxic hydroxyl radicals (•OH) for chemodynamic therapy. The in vitro studies reveal that GOx&Pt@FcNV exhibits a highly efficient killing effect against various MDR tumor cells. The in vivo studies of double-tumor-bearing nude mice demonstrate that the tumor inhibitory rates (TIRs) of GOx&Pt@FcNV against cisplatin-resistant A549/DDP are 8.1 times and 3.3 times higher than those of Pt and Pt@FcNV, respectively; they are also 8.6 times and 4.3 times higher than Pt and Pt@FcNV against adriamycin-resistant MCF-7/ADR, respectively. This nanodrug with endogenous stimuli-activated cascade reactions offers a reference for the design of effective trimodal combination therapies to combat MDR tumors.

A nanodrug to combat cisplatin-resistance by protecting cisplatin with p-sulfonatocalix[4]arene and regulating glutathione S-transferases with loaded 5-fluorouracil.

A nanodrug that can effectively combat cisplatin-resistant A549/CDDP cells was developed by protecting cisplatin from glutathione (GSH) detoxification trough a host-guest interaction between cisplatin and p-sulfonatocalix[4]arene. The enzymatic activity of glutathione S-transferases (GSTs) was also regulated by loaded 5-fluorouracil (5-FU).