Brefeldin A delivery nanomicelles in hepatocellular carcinoma therapy: Characterization, cytotoxic evaluation in vitro, and antitumor efficiency in vivo.

Hepatocellular carcinoma (HCC) is one of the major cancers with high mortality rate. Traditional drugs used in clinic are usually limited by the drug resistance and side effect and novel agents are still needed. Macrolide brefeldin A (BFA) is a well-known lead compound in cancer chemotherapy, however, with poor solubility and instability. In this study, to overcome these disadvantages, BFA was encapsulated in mixed nanomicelles based on TPGS and F127 copolymers (M-BFA). M-BFA was conferred high solubility, colloidal stability, and capability of sustained release of intact BFA. In vitro, M-BFA markedly inhibited the proliferation, induced G0/G1 phase arrest, and caspase-dependent apoptosis in human liver carcinoma HepG2 cells. Moreover, M-BFA also induced autophagic cell death via Akt/mTOR and ERK pathways. In HepG2 tumor-bearing xenograft mice, indocyanine green (ICG) as a fluorescent probe loaded in M-BFA distributed to the tumor tissue rapidly, prolonged the blood circulation, and improved the tumor accumulation capacity. More importantly, M-BFA (10 mg/kg) dramatically delayed the tumor progression and induced extensive necrosis of the tumor tissues. Taken together, the present work suggests that M-BFA has promising potential in HCC therapy.

Red cell membrane-coating Prussian blue for combined photothermal and NO gas therapy for nasopharyngeal carcinoma.

Nitric oxide (NO) gas molecules have demonstrated remarkable anti-tumor effects and minimal susceptibility to drug resistance, establishing as a promising modality for effective tumor treatment. However, how to realize its stable and efficient delivery in vivo is still a challenge. In this study, we have developed a heat-responsive biomimetic nano erythrocyte (M/B@R) by loading a NO donor (BNN6) onto mesoporous Prussian blue (M-PB) and subsequently enveloping them with red blood cell membranes. The preserved integrity of the red blood cell membrane (RBCm) structure could ensure its excellent biosafety, prolong its circulation time within the bloodstream and then enhance the accumulation of BNN6 at tumor sites. When M/B@R is stimulated by near-infrared light (NIR-II, 808 nm) irradiation, the nanoparticle could generate significant heat for photothermal therapy (PTT) by the characteristic NIR absorption of M-PB and then NO could also be efficiently released. The generated NO further facilitates the formation of ONOO-, a highly toxic species to tumors, while also alleviating tumor hypoxia. Remarkably, M/B@R, with NIR as the excitation source, induces combined lethality through hyperthermia, DNA damage, and tumor hypoxia relief. This novel combination strategy provides a new avenue for PTT/NO-induced cancer therapy.

Enhanced skin benefits of EGCG loaded in nonapeptide-1-conjugated mesoporous silica nanoparticles to reverse skin photoaging.

Epigallocatechin-3-gallate (EGCG), a catechin present in green tea, has been studied extensively for its potential as a cosmetic ingredient due to its various biological properties. However, the low stability and bioavailability of EGCG have hindered its effective utilization in cosmetic applications. This study, to improve the stability and bioavailability of EGCG for reversing skin photo-aging, nonapeptide-1-conjugated mesoporous silica nanoparticles (EGCG@NP-MSN) were fabricated to load EGCG. MSNs can regulate the EGCG release and provide ultraviolet light (UV) protection to possess excellent photostability. Nonapeptide-1 exhibits melanin transfer interference properties and reduces the melanin content in treated skin areas. In vitro and in vivo results confirmed that the EGCG-loaded MSNs retained antioxidant properties, effectively scavenged the melanin and significantly reduced the deoxyribonucleic acid (DNA) damage in skin cells exposed to UV irradiation. The melanin inhibition rate is 5.22 times and the tyrosinase inhibition rate is 1.57 times that of free EGCG. The utilization of this innovative platform offers the potential for enhanced stability, controlled release, and targeted action of EGCG, thereby providing significant advantages for skin application.This delivery system combines the advantages of antioxidant, anti-aging, and anti-UV radiation properties, paving the way for the cosmetics development with improved efficacy and better performance in promoting skin health and appearance.

Synergistic antibacterial and antifouling wound dressings: Integration of photothermal-activated no release and zwitterionic surface modification.

Addressing the pervasive issue of bacteria and biofilm infections is crucial in the development of advanced antifouling wound dressings. In this study, a novel wound healing treatment using sulfobetaine (SBMA) decorated electrospun fibrous membrane based on polycaprolactone (PCL)/nitric oxide (NO) donors was developed. The fabrication involved a dual strategy, first integrating NO donors into mesoporous polydopamine (MPDA) and complexed with PCL/PEI to electrospin nanofibers. The fibrous membrane exhibited a potent antibacterial response upon irradiation at 808 nm, owing to a combination of NO and photothermal effect that effectively targets bacteria and disrupts biofilms. Surface functionalization of the membrane with PEI allowed for the attachment of SBMA via Michael addition, fabricating a zwitterionic surface, which significantly hinders protein adsorption and reduces biofilm formation on the wound dressing. In vitro and in vivo assessments confirmed the rapid bactericidal capabilities and its efficacy in biofilm eradication. Combining photothermal activity, targeted NO release and antifouling surface, this multifaceted wound dressing addresses key challenges in bacterial infection management and biofilm eradication, promoting efficient wound healing.

High-performance self-cascade nanoreactors for combined ferroptosis, photothermal therapy, and starving therapy.

Despite the great potential of starving therapy caused by nanoreactor based on glucose oxidase (GOX) in tumor therapy, efficiency and uncontrolled reaction rates in vivo lead to inevitable toxicity to normal tissues, which seriously hindering their clinical conversion. Herein, a cascade nanoreactor (GOX/Mn/MPDA) was constructed by coating mesoporous polydopamine nanoparticles (MPDA) with MnO2 shell and then depositing GOX into honeycomb-shaped manganese oxide nanostructures to achieve a combination of ferroptosis, photothermal therapy and starving therapy. Upon uptake of nanodrugs to cancer cells, the MnO2 shell would deplete glutathione (GSH) and produce Mn2+, while a large amount of H2O2 generated from the catalytic oxidation of glucose by GOX would accelerate the Fenton-like reaction mediated by Mn2+, producing high toxic •OH. More importantly, the cascade reaction between GOX and MnO2 would be further strengthened by localized hyperthermia caused by irradiated by near-infrared laser (NIR), inducing significant anti-tumor effects in vitro and in vivo. Regarding the effectiveness of tumor treatment in vivo, the tumor inhibition rate achieved an impressive 64.33%. This study provided a new strategy for anti-tumor therapeutic by designing a photothermal-enhanced cascade catalytic nanoreactor.

Artesunate carriers induced ferroptosis to overcome biological barriers for anti-cancer.

Artesunate (ART) has potent anticancer activity but it suffers from poor stability and low bioavailability in vivo due to the special endoperoxide moiety in the molecules. In this work, we fabricated programmable enzyme/reactive oxygen species (ROS) responsive ART complex carriers with size and charge adaptive regulation in order to improve stability and overcome biochemical hurdles of solid tumor. The complex carries (ART/AA-PAMAM@HA) were created by electrostatic interaction between dendrimer-ART/arachidonic acid (AA) (ART/AA-PAMAM) and hyaluronic acid (HA), which can proactively penetrate deeply into tumors and selective drug release. Specifically, ART induced Fenton reaction and produced a mass of ROS and lipid peroxides (LPO), leading to the depressing of GSH level and glutathione peroxidase 4 (GPX4) activity. Meanwhile, exogenous AA further promoted the accumulation of LPO by cascade regulating ferroptosis pathway. In the anti-tumor efficacy in vivo, the tumor inhibition ratio was achieved to 46.92%. This work shows a new anti-tumor strategy triggering ferroptosis via regulating redox homeostasis.

Combined chemo and photo therapy of programmable prodrug carriers to overcome delivery barriers against nasopharyngeal carcinoma.

Indocyanine green (ICG) has been employed in medical diagnostics due to its superior photophysical characteristics. However, these advantages are offset by its quick body clearance and inferior photo-stability. In this work, programmable prodrug carriers for chemotherapy/PDT/PTT against nasopharyngeal carcinoma (NPC) were created in order to increase photo-stability and get around biochemical hurdles. The programmable prodrug carriers (PEG-PLA@DIT-PAMAM) that proactively penetrated deeply into NPC tumors and produced the deep phototherapy and selective drug release under laser irradiation was created by dendrimer-DOX/ICG/TPP (DIT-PAMAM) and PEGylated poly (α-lipoic acid) (PLA) copolymer. Long circulation times and minimal toxicity to mammalian cells are two benefits of PEG-coated carriers. The overexpressed GSH on the tumor cell or vascular endothelial cell of the NPC disintegrated the PEG-g-PLA chains and released the DIT-PAMAM nanoparticles after the carriers had reached the NPC tumor periphery. Small, positively charged DIT-PAMAM nanoparticles may penetrate tumors effectively and remain inside tumor for an extended period of time. In addition, the induced ROS cleaved the thioketal linkers for both DOX and nanoparticles and product hyperthermia (PTT) to kill cancer cells under laser irradiation, facilitating faster diffusion of nanoparticles and more effective tumor penetration with a programmable publication of DOX. The programmable prodrug carries showed high photo-stability high photo-stability, which enabled very effective PDT, PTT, and tumor-specific DOX release. With the goal of combining the effects of chemotherapy, PDT, and PTT against NPC, this research showed the great efficacy of programmable prodrug carriers.

Synthesis of allenamides by Pd-catalyzed coupling of 3-alkoxycarbonyloxy ynamides or 1-alkoxycarbonyloxy allenamides with arylboronic acids.

An efficient palladium-catalyzed method is reported for the synthesis of multi-substituted allenamides by Suzuki-Miyaura cross-coupling reaction between easily prepared 3-alkoxycarbonyloxy ynamides or 1-alkoxycarbonyloxy allenamides and arylboronic acids.

Chitosan derivatives functionalized dual ROS-responsive nanocarriers to enhance synergistic oxidation-chemotherapy.

The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with ß-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo.

Effects of combination docetaxel with NO treatment to enhance the anti-nasopharyngeal carcinoma efficiency in vitro and in vivo.

Nasopharyngeal carcinoma (NPC) is one of the major causes of death in Southern China. Due to the insidious location of NPC, the therapeutic effect of locoregionally advanced NPC is still unsatisfactory. In this work, to improve the treatment efficiency, combining DOC and JS-K to inhibit NPC cells (HNE-1) in vitro was investigated, as well as its possible mechanisms. Moreover, the in vivo effects of DOC and JS-K combination treatment were also evaluated in a xenograft model with HNE-1 cells. In vitro experiments including cell proliferation, migration ability, apoptosis, and expression levels of apoptosis-associated proteins revealed that the combination of DOC and JS-K was able to enhance antitumor effects. In vivo results further confirmed a significant treatment effect without obvious toxicity on mice. The present work provides a promising idea for the treatment of locally advanced NPC.

Alginate-based aerogels as wound dressings for efficient bacterial capture and enhanced antibacterial photodynamic therapy.

The development of novel wound dressings, such as aerogels, with rapid hemostasis and bactericidal capacities for pre-hospital care is necessary. To prevent the occurrence of bacterial resistance, antibacterial photodynamic therapy (aPDT) with broad-spectrum antibacterial ability and negligible bacterial resistance has been intensively studied. However, photosensitizers often suffer from poor water solubility, short singlet oxygen (1O2) half-life and restricted 1O2 diffusion distance. Herein, sodium alginate was covalently modified by photosensitizers and phenylboronic acid, and cross-linked by Ca(II) ions to generate SA@TPAPP@PBA aerogel after lyophilization as an antibacterial photodynamic wound dressing. Afterwards, its photodynamic and bacterial capture activities were intensively evaluated. Furthermore, its hemostasis and bactericidal efficiency against Staphylococcus aureus were assessed via in vitro and in vivo assays. First, chemical immobilization of photosensitizers led to an enhancement of its solubility. Moreover, it showed an excellent hemostasis capacity. Due to the formation of reversible covalent bonds between phenylboronic acid and diol groups on bacterial cell surface, the aerogel could capture S. aureus tightly and dramatically enhance aPDT. To sum up, the prepared aerogel illustrated excellent hemostasis capacity and antibacterial ability against S. aureus. Therefore, they have great potential to be utilized as wound dressing in clinical trials.

Dual-responsive TPGS crosslinked nanocarriers to overcome multidrug resistance.

Efficient delivery of chemotherapeutic agents into tumor cells and reversal of chemoresistance are crucially important to enhance cancer therapy. We fabricated pH/redox dual responsive nanocarriers based on cell penetrating peptides (TAT) functionalized TPGS (cTAT-TPGS) and polypeptide (PEG-b-poly(aspartic-lipoic acid), PPAL) to reduce the permanent drug release and overcome multidrug resistance. TAT was used to functionalize TPGS and shielded by pH-responsive fatty acids, and polypeptides with lipoic acid side chains (PPAL) were synthesized. Reversibly crosslinked hybrid micelles (RCMs) were fabricated based on cTAT-TPGS and PPAL. RCMs nanocarriers exhibited acid-responsive charge reversal and redox-responsive drug release. The in vitro results showed that the RCMs could be efficiently internalized by the MCF-7/ADR cells in an acidic microenvironment and inhibited the DOX efflux, causing a higher cytotoxicity than non-crosslinked nanocarriers. Furthermore, the dual-responsive structure effectively prolonged the circulation time of RCM nanocarriers and achieved a high level of accumulation in cancer cells in vivo, leading to much more effective inhibition of tumor growth. The DOX-loaded RCMs also showed excellent biosafety, especially for the myocardium tissue. This novel strategy provided an effective platform for drug target delivery and reversal of MDR.

Targeting Delivery Nanocarriers for (+)-Terrein to Enhance Its Anticancer Effects.

As a compound from marine fungi, (+)-terrein showed significant anticancer activity. In this study, (+)-terrein was extracted from the marine-derived fungus and showed significant cytotoxicity against cancer cells, especially in A549 cells. To enhance its anticancer effects, redox-responsive nanocarriers based on folic acid-chitosan decorating the mesoporous silica nanoparticles were designed to control (+)-terrein target delivery into cancer cells. (+)-Terrein was loaded in the holes, and folic acid-chitosan worked as a gatekeeper by disulfide linkage controlling (+)-terrein release in the tumor microenvironment. The (+)-terrein drug delivery systems exhibited cytotoxicity toward A549 cells through induction of apoptosis. The apoptosis effect was confirmed by the increase in the expression of cleaved caspase-3, caspase-9, and PARP. Taken together, this work evaluates for the first time the (+)-terrein delivery system and provides a promising nanomedicine platform for (+)-terrein.

A biofriendly silica gel for in situ protein entrapment: biopolymer-assisted formation and its kinetic mechanism.

In an attempt to develop a biofriendly sol-gel route for the rapid formation of biofunctional silica gels, a biopolymer with good biocompatibility was used to assist the gelation of glycol-modified tetraethoxysilane (GMT) in aqueous system without the addition of any organic solvents. It was found that the biopolymer used could act as an effective accelerator for the sol-gel transition of GMT and an increase of its amount could shorten greatly the gelation time. For such a gelation reaction, its apparent activation energy was determined to be 64.9 kJ/mol according to the Arrhenius equation. In particular, the kinetic mechanism for the formation of the silica gel was investigated by using dynamic theological data and a scaling fractal model. It was revealed that the biopolymer used could change the sol-gel transition mechanism from reaction-limited kinetics to diffusion-limited kinetics. Circular dichroism analyses confirmed the suitability of using the resultant silica gel for the in situ protein encapsulation.

Hierarchical bioresponsive nanocarriers for codelivery of curcumin and doxorubicin.

Hierarchical responsive nanocarriers have received much attention for targeted delivery of chemotherapeutics. In this study, we designed pH and redox dual-stage responsive nanocarriers in the different delivery stages for co-delivery phosphorylated curcumin (p-Cur) with doxorubicin (Dox). The MSNs nanocarriers were functionalized via specific cleavable PEGylation and hydrogel coating crosslinked by disulfide bonds: MSNs as core load Dox; p-Cur encapsulated in hydrogel coating. In blood circulation, PEGylation endow the nanocarriers with long time during blood circulation; while in tumor tissue, PEG shells could be cleaved due to the pH-sensitive bond and expose the cationic hydrogel coating to improve cell uptake; while inside tumor cells, hydrogel coating could be cleaved due to the GSH and release the drugs. The results showed that the dual-responsive shells endowed the nanocarriers with tumor extracellular pH-triggered cell uptake and specific cancer cell target release. The synergistic effects of the p-Cur and Dox enhanced cellular apoptosis in Hela cells.

Guanidine-modified cyclometalated iridium(III) complexes for mitochondria-targeted imaging and photodynamic therapy.

PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425 nm. Notably, Ir1 conferred almost no dark toxicity (IC50 > 100 µM) to HepG2 cells, but the value decreased by 387-fold to 0.36 µM following 10 min of light irradiation (425 nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425 nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.

Electroactive polyaniline/silica hybrid gels: Controllable sol-gel transition adjusted by chitosan derivatives.

In this study, the electroactive hybrid gels with controllable sol-gel process were fabricated based on the water soluble polyaniline complex and water soluble silica precursor. ß-cyclodextrin grafted on chitosan (CSCD) acted as a template, a new route for the synthesis of water soluble polyaniline complex (PA@CSCD) was designed by in-situ polymerization. Then, the hybrid silica gels without severe shrinkage were prepared by mixing PA@CSCD complex with water soluble precursor (tetrakis(2-hydroxyethyl)orthosilicates, THEOS). By dynamic rheological measurements, it was found that PA@CSCD complex could trigger and accelerate the sol-gel transition of the silica precursor. The gelation time could be largely shortened with the increase of PA@CSCD complex amount. By SEM observation, the PA@CSCD complex could be well compatible with the silica matrix. Moreover, the hybrid gels showed the good redox electroactivity, which could be successfully applied in a HRP-based biosensor.

Characterization of PBDD/F emissions from simulated polystyrene insulation foam via lab-scale programmed thermal treatment testing.

Accidental fires and open combustion are regarded as major potential contributors to the environmental release of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs). The characterization of PBDD/Fs emitted from thermal treatment of simulated polystyrene (PS) foam is reported in this study. PS, hexabromocyclododecane (HBCDD) and metals (or metallic compounds) composed the test samples, which imitated real extruded (XPS) and expanded (EPS) polystyrene thermal insulation foams. Test samples were subjected to thermal treatments under different experimental conditions. This study shows that the temperature, metal (metallic compound) content, and type of atmosphere are the key factors in the formation of congeners and PBDD/Fs during thermal processes. The total yield of polybrominated dibenzofurans (PBDFs) was greater than that of the polybrominated dibenzo-p-dioxins (PBDDs) during the test, and 1,2,3,7,8-PeBDF and 2,3,7,8-TBDF were the predominant congeners emitted during the thermal treatment experiments.

TAT-conjugated chitosan cationic micelle for nuclear-targeted drug and gene co-delivery.

We developed a high-efficiency nucleus-targeted co-delivery vector that delivers genes and drugs directly into the nucleus of cancer cells. The system is based on grafted poly-(N-3-carbobenzyloxy-lysine) (CPCL) with transactivator of transcription (TAT)- chitosan on the surface. It is designed to perform highly efficient nucleus- targeted gene and drug co-delivery. Confocal laser scanning microscopy (CLSM) revealed that more TAT-CPCL entered the nucleus than does CPCL alone. The TAT-modified vector serves as a gene and drug co-delivery mechanism to achieve high gene transfection efficiency, high apoptosis and low viability in HeLa cells. TAT-CPCL may become a vector for cancer gene treatment and a template for designing better co-deliver systems.

Efficient gene vector with size changeable and nucleus targeting in cancer therapy.

The nucleus is one of the most important cellular organelles, where gene encode and transcribe at that location. However, nucleus-targeting gene delivery are rare been reported. It is important to develop a high-efficiency nucleus-targeting gene vector that can deliver targeted gene into nucleus directly for destroy of cancer cells. Here, special nucleus-targeting and size changeable deliver system based on TAT-SS-PAMAM-D3 with TAT functional on the surface and disulfide linked between D2 and D3 is designed to perform highly efficient nucleus-targeting gene delivery for effective cancer cell killing in vitro. CLSM observations reveal that more TAT-SS-PAMAM-D3 are enter into the nucleus when compare to SS-PAMAM-D3. The TAT modified vector can also act as gene deliver to reach high gene transfection efficiencies, high apoptosis and low viability in HeLa cells. This TAT functionalized and disulfide linking in the carrier may become a prospective vector for cancer gene treatment and also offered a different strategy for designing a better gene delivery system.