A Two-Pronged Nanostrategy of Iron Metabolism Disruption to Synergize Tumor Therapy by Triggering the Paraptosis-Apoptosis Hybrid Pathway.

Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of "reprogramming" and "interfering" iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical "Trojan horse", mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis-apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.

Erythrocyte-Mimicking Nanovesicle Targeting Porphyromonas gingivalis for Periodontitis.

Porphyromonas gingivalis has been demonstrated to have the strongest association with periodontitis. Within the host, P. gingivalis relies on acquiring iron and heme through the aggregation and lysis of erythrocytes, which are important factors in the growth and virulence of P. gingivalis. Additionally, the excess obtained heme is deposited on the surface of P. gingivalis, protecting the cells from oxidative damage. Based on these biological properties of the interaction between P. gingivalis and erythrocytes, this study developed an erythrocyte membrane nanovesicle loaded with gallium porphyrins to mimic erythrocytes. The nanovesicle can target and adhere with P. gingivalis precisely, being lysed and utilized by P. gingivalis as erythrocytes. Ingested gallium porphyrin replaces iron porphyrin in P. gingivalis, causing intracellular metabolic disruption. Deposited porphyrin generates a large amount of reactive oxygen species (ROS) under blue light, causing oxidative damage, and its lethality is enhanced by bacterial metabolic disruption, synergistically killing P. gingivalis. Our results demonstrate that this strategy can target and inhibit P. gingivalis, reduce its invasion of epithelial cells, and alleviate the progression of periodontitis.

Melatonin-loaded mesoporous zinc- and gallium-doped hydroxyapatite nanoparticles to control infection and bone repair.

Effective treatment of infected bone defects resulting from multi-drug resistant bacteria (MDR) has emerged as a significant clinical challenge, highlighting the pressing demand for potent antibacterial bone graft substitutes. Mesoporous nanoparticles have been introduced as a promising class of biomaterials offering significant properties for treating bone infections. Herein, we synthesize antibacterial mesoporous hydroxyapatite substituted with zinc and gallium (Zn-Ga:mHA) nanoparticles using a facile sol-gel method. The resulting mesoporous nanoparticles are applied for the controlled release of melatonin (Mel). Zn-Ga:mHA nanoparticles with an average particle size of 36 ± 3 nm and pore size of 10.6 ± 0.4 nm reveal a Mel loading efficiency of 58 ± 1%. Results show that 50% of Mel is released within 20 h and its long-term release is recorded up to 50 h. The Zn-Ga:mHA nanoparticles exhibit highly effective antibacterial performance as reflected by a 19 ± 1% and 8 ± 2% viability reduction in Escherichia coli and Staphylococcus bacteria, respectively. Noticeably, Mel-loaded Zn-Ga:mHA nanoparticles are also cytocompatible and stimulate in vitro osteogenic differentiation of human mesenchymal stem cells (hMSCs) without any osteoinductive factor. In vivo studies in a rabbit skull also show significant regeneration of bone during 14 days. In summary, Mel-loaded Zn-Ga:mHA nanoparticles provide great potential as an antibacterial and osteogenic component in bone substitutes like hydrogels, scaffolds, and coatings.

Solution studies, synthesis and antibacterial activity of Ga(III) complexes with bis-kojate derivatives.

Given the recognized major problem of microbial drug resistance for human health, new metal-based drugs have been currently explored for their antimicrobial properties, including gallium-based compounds as potential metallophores that could perturb Fe's interactions with proteins. Herein we have designed and synthesized two bis-kojate ligands (named L4 and L6) and studied their Ga(III) complexes for their physico-chemical and biological properties. In particular a detailed study of their complexation properties in aqueous solution, showed equilibrium models with formation of quite stable dinuclear 2:3 metal:ligand complexes, though with different stability. Solid state complexes were also prepared and characterized and complementary DFT studies indicated that [Ga2(L4)3] complex, with higher stability, seems to adopt a three-ligand bridging conformation, while that for L6 adopt a one ligand bridging conformation. Preliminary investigation of the antibacterial activity of these gallium complexes showed antipseudomonal activity, which appeared higher for the complex with L4, a feature of potential interest for the scientific community.

Orally administrated liquid metal agents for inflammation-targeted alleviation of inflammatory bowel diseases.

Rapid drug clearance and off-target effects of therapeutic drugs can induce low bioavailability and systemic side effects and gravely restrict the therapeutic effects of inflammatory bowel diseases (IBDs). Here, we propose an amplifying targeting strategy based on orally administered gallium (Ga)-based liquid metal (LM) nano-agents to efficiently eliminate reactive oxygen and nitrogen species (RONS) and modulate the dysregulated microbiome for remission of IBDs. Taking advantage of the favorable adhesive activity and coordination ability of polyphenol structure, epigallocatechin gallate (EGCG) is applied to encapsulate LM to construct the formulations (LM-EGCG). After adhering to the inflamed tissue, EGCG not only eliminates RONS but also captures the dissociated Ga to form EGCG-Ga complexes for enhancive accumulation. The detained composites protect the intestinal barrier and modulate gut microbiota for restoring the disordered enteral microenvironment, thereby relieving IBDs. Unexpectedly, LM-EGCG markedly decreases the Escherichia_Shigella populations while augmenting the abundance of Akkermansia and Bifidobacterium, resulting in favorable therapeutic effects against the dextran sulfate sodium-induced colitis.

Effect of gallium nitrate on the antibacterial activity of vancomycin in methicillin-sensitive and resistant Staphylococcus aureus.

The extension of multidrug-resistant strains of Staphylococcus aureus (S. aureus) is one of the main health challenges in the world, which requires serious solutions to deal with it. Combination therapies using conventional antibiotics and new antibacterial compounds that target different bacterial pathways are effective methods against resistant bacterial infections. Gallium is an iron-like metal that competes with iron for uptake into bacteria and has the potential to disrupt iron-dependent vital processes in bacteria. In this study, we explored the antibacterial effects of gallium nitrate (Ga(NO3)3) and vancomycin alone and in combination with each other on methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) using microdilution assay and checkerboard test, respectively. Then, their effect on the formation and destruction of biofilms was investigated. Finally, the amount of ROS production in the presence of these two compounds in bacteria was evaluated. The results indicated that the vancomycin/ Ga(NO3)3 combination reduced the MIC of vancomycin in the MRSA strain and had an additive effect on it. Vancomycin plus Ga(NO3)3 reduced the formation of biofilms and increased the destruction of biofilms formed in both strains, especially in the MRSA strain. ROS production was also higher in the combination of vancomycin with Ga(NO3)3 compared to vancomycin alone, especially in MRSA. Therefore, our results showed that Ga(NO3)3 enhances the antibacterial activity of vancomycin and this combination therapy can be considered as a new strategy for the treatment of MRSA infections.

Immobilization of biosynthesized gallium nanoparticles in Polyvinylpyrrolidone/Sodium alginate films: Potent bactericidal protection against food spoilage bacteria.

The increasing threat of spoilage bacterial infections, driven by the resistance of bacteria to many antimicrobial treatments, is a significant worldwide public health problem, especially concerning food preservation. To tackle these difficulties, this research investigates the possibility of using packaging sheets that include antimicrobial agents and increasing the prolonged storage time by preventing the bioburden of foodborne pathogens. This approach uses metal nanoparticles' ability to prevent harmful bacteria that cause food spoiling. Gallium nanoparticles (GaNPs) were created using a water-based extract from Andrographis paniculata leaves as a bioreducing agent. The GaNPs were added to a film made of sodium alginate (SA) and polyvinylpyrrolidone (PVP). The study showed that incorporating GaNPs into polymer films resulted in films with a desirable contact angle and decreased water vapor permeability. Significantly, the developed films demonstrated increased efficiency against E.coli O157 compared to other species. Also, it exhibited increased vulnerability to bacterial strains at the biofilm stage, surpassing PVP-SA/GaNPs-0. Remarkably, the toxicity tests showed that the films exhibited no cytotoxicity. Overall, the films indicated their potential for avoiding bacterial bioburden, prolonging the shelf life of perishable products, and contributing to diverse antimicrobial applications in the food industry.

A win-win platform: Stabilized black phosphorous nanosheets loading gallium ions for enhancing the healing of bacterial-infected wounds through synergistic antibacterial approaches.

Bacterial infection is the most common complication in wound healing, highlighting an urgent need for the development of innovative antibacterial technologies and treatments to address the growing threats posed by bacterial infections. Black phosphorus nanosheets (BPNSs), as a promising two-dimensional nanomaterial, have been utilized in treating infected wounds. However, BP's limited stability restricts its application. In this study, we enhance BP's stability and its antibacterial properties by anchoring gallium ions (Ga3+) onto BP's surface, creating a novel antibacterial platform. This modification reduces BP's electron density and enhances its antibacterial capabilities through a synergistic effect. Under near-infrared (NIR) irradiation, the BP/Ga3+ combination exerts antibacterial effects via photothermal therapy (PTT) and photodynamic therapy (PDT), while also releasing Ga3+. The Ga3+ employ a 'Trojan horse strategy' to disrupt iron metabolism, significantly boosting the antibacterial efficacy of the complex. This innovative material offers a viable alternative to antibiotics and holds significant promise for treating infected wounds and aiding skin reconstruction.

Gallium-containing mesoporous nanoparticles influence in-vitro osteogenic and osteoclastic activity.

Mesoporous silica nanoparticles were synthesized using a microemulsion-assisted sol-gel method, and calcium, gallium or a combination of both, were used as dopants. The influence of these metallic ions on the physicochemical properties of the nanoparticles was investigated by scanning and transmission electron microscopy, as well as N2 adsorption-desorption methods. The presence of calcium had a significant impact on the morphology and textural features of the nanoparticles. The addition of calcium increased the average diameter of the nanoparticles from 80 nm to 150 nm, while decreasing their specific surface area from 972 m2/g to 344 m2/g. The nanoparticles of all compositions were spheroidal, with a disordered mesoporous structure. An ion release study in cell culture medium demonstrated that gallium was released from the nanoparticles in a sustained manner. In direct contact with concentrations of up to 100 µg/mL of the nanoparticles, gallium-containing nanoparticles did not exhibit cytotoxicity towards pre-osteoblast MC3T3-E1 cells. Moreover, in vitro cell culture tests revealed that the addition of gallium to the nanoparticles enhanced osteogenic activity. Simultaneously, the nanoparticles disrupted the osteoclast differentiation of RAW 264.7 macrophage cells. These findings suggest that gallium-containing nanoparticles possess favorable physicochemical properties and biological characteristics, making them promising candidates for applications in bone tissue regeneration, particularly for unphysiological or pathological conditions such as osteoporosis.

Ultrasound-responsive gallium protoporphyrin and oxygen loaded perfluoropentane nanodroplets for effective sonodynamic therapy of implant infections.

Implant infections are severe complications in clinical treatment, which often accompany the formation of bacterial biofilms with high antibiotic resistance. Sonodynamic therapy (SDT) is an antibiotic-free method that can generate reactive oxygen species (ROS) to kill bacteria under ultrasound (US) treatment. However, the extracellular polymeric substances (EPS) barrier of bacterial biofilms and the hypoxic microenvironment significantly limit the antibiofilm activity of SDT. In this study, lipid-shelled perfluoropentane (PFP) nanodroplets loaded with gallium protoporphyrin IX (GaPPIX) and oxygen (O2) (LPGO NDs) were developed for the treatment of implant infections. Under US stimulation, LPGO NDs undergo the cavitation effect and disrupt the biofilm structure like bombs due to liquid-gas phase transition. Meanwhile, the LPGO NDs release O2 and GaPPIX upon US stimulation. The released O2 can alleviate the hypoxic microenvironment in the biofilm and enhance the ROS formation by GaPPIX for enhanced bacterial killing. In vivo experimental results demonstrate that the LPGO NDs can efficiently treat implant infections of methicillin-resistant Staphylococcus aureus (MRSA) in a mouse model by disrupting the biofilm structure, alleviating hypoxia, and enhancing bacterial killing by SDT. Therefore, this work provides a new multifunctional sonosensitizer to overcome the limitations of SDT for treating implant infections.

MgCa-Based Alloys Modified with Zn- and Ga-Doped CaP Coatings Lead to Controlled Degradation and Enhanced Bone Formation in a Sheep Cranium Defect Model.

Mg-based biodegradable metallic implants are gaining increased attraction for applications in orthopedics and dentistry. However, their current applications are hampered by their high rate of corrosion, degradation, and rapid release of ions and gas bubbles into the physiological medium. The aim of the present study is to investigate the osteogenic and angiogenic potential of coated Mg-based implants in a sheep cranial defect model. Although their osteogenic potential was studied to some extent, their potential to regenerate vascularized bone formation was not studied in detail. We have studied the potential of magnesium-calcium (MgCa)-based alloys modified with zinc (Zn)- or gallium (Ga)-doped calcium phosphate (CaP) coatings as a strategy to control their degradation rate while enhancing bone regeneration capacity. MgCa and its implants with CaP coatings (MgCa/CaP) as undoped or as doped with Zn or Ga (MgCa/CaP + Zn and MgCa/CaP + Ga, respectively) were implanted in bone defects created in the sheep cranium. MgCa implants degraded faster than the others at 4 weeks postop and the weight loss was ca. 50%, while it was ca. 15% for MgCa/CaP and <10% in the presence of Zn and Ga with CaP coating. Scanning electron microscopy (SEM) analysis of the implant surfaces also revealed that the MgCa implants had the largest degree of structural breakdown of all the groups. Radiological evaluation revealed that surface modification with CaP to the MgCa implants induced better bone regeneration within the defects as well as the enhancement of bone-implant surface integration. Bone volume (%) within the defect was ca. 25% in the case of MgCa/CaP + Ga, while it was around 15% for undoped MgCa group upon micro-CT evaluation. This >1.5-fold increase in bone regeneration for MgCa/CaP + Ga implant was also observed in the histopathological examination of the H&E- and Masson's trichrome-stained sections. Immunohistochemical analysis of the bone regeneration (antiosteopontin) and neovascularization (anti-CD31) at the defect sites revealed >2-fold increase in the expression of the markers in both Ga- and Zn-doped, CaP-coated implants. Zn-doped implants further presented low inflammatory reaction, notable bone regeneration, and neovascularization among all the implant groups. These findings indicated that Ga- and Zn-doped CaP coating is an important strategy to control the degradation rate as well as to achieve enhanced bone regeneration capacity of the implants made of Mg-based alloys.

Dual-functional gallium/chitosan/silk/umbilical cord mesenchymal stem cell exosome sponge scaffold for diabetic wound by angiogenesis and antibacteria.

The treatment of diabetic wounds possessed significant challenges in clinical practice, which was accompanied with continuous infection, inflammation, and limited angiogenesis. Current wound dressings used for diabetic wound healing struggle to address these issues simultaneously. Therefore, Ga3+ was added to the chitosan/silk solution to confer potent antibacterial properties. Subsequently, umbilical cord mesenchymal stem cell exosomes (UCSC-Exo) were integrated into the gallium/chitosan/silk solution to enhance its angiogenesis-inducing activity. The mixture was lyophilized to prepare gallium/chitosan/silk/exosome sponge scaffolds (Ga/CSSF-Exo sponge scaffolds). The experiments of In vitro and in vivo demonstrated that Ga/CSSF-Exo sponge scaffolds exhibited sustained release of Ga3+ and bioactive exosomes, which effectively exerted continuous antibacterial effects and promoted angiogenesis. In diabetic rat wound models, Ga/CSSF-Exo sponge scaffolds facilitated angiogenesis, suppressed bacterial growth and inflammation, as well as promoted collagen deposition and re-epithelialization of wounds. Collectively, our findings suggested that Ga/CSSF-Exo held excellent potential for diabetic wound healing.

Decrease of ESKAPE virulence with a cationic heme-mimetic gallium porphyrin photosensitizer: The Trojan horse strategy that could help address antimicrobial resistance.

INTRODUCTION: Emerging antibiotic resistance among bacterial pathogens has forced an urgent need for alternative non-antibiotic strategies development that could combat drug resistant-associated infections. Suppression of virulence of ESKAPE pathogens' by targeting multiple virulence traits provides a promising approach. OBJECTIVES: Here we propose an iron-blocking antibacterial therapy based on a cationic heme-mimetic gallium porphyrin (GaCHP), which antibacterial efficacy could be further enhanced by photodynamic inactivation. METHODS: We used gallium heme mimetic porphyrin (GaCHP) excited with light to significantly reduce microbial viability and suppress both the expression and biological activity of several virulence traits of both Gram-positive and Gram-negative ESKAPE representatives, i.e., S. aureus and P. aeruginosa. Moreover, further improvement of the proposed strategy by combining it with routinely used antimicrobials to resensitize the microbes to antibiotics and provide enhanced bactericidal efficacy was investigated. RESULTS: The proposed strategy led to substantial inactivation of critical priority pathogens and has been evidenced to suppress the expression and biological activity of multiple virulence factors in S. aureus and P. aeruginosa. Finally, the combination of GaCHP phototreatment and antibiotics resulted in promising strategy to overcome antibiotic resistance of the studied microbes and to enhance disinfection of drug resistant pathogens. CONCLUSION: Lastly, considering high safety aspects of the proposed treatment toward host cells, i.e., lack of mutagenicity, no dark toxicity and mild phototoxicity, we describe an efficient alternative that simultaneously suppresses the functionality of multiple virulence factors in ESKAPE pathogens.

Wake biofilm up to enhance suicidal uptake of gallium for chronic lung infection treatment.

The hypometabolic and nutrient-limiting condition of dormant bacteria inside biofilms reduces their susceptibility to antibacterial agents, making the treatment of biofilm-dominating chronic infections difficult. Herein, we demonstrate an intratracheal aerosolized maltohexaose-modified catalase-gallium integrated nanosystem that can 'wake up' dormant Pseudomonas aeruginosa biofilm to increase the metabolism and nutritional iron demand by reconciling the oxygen gradient. The activated bacteria then enhance suicidal gallium uptake since gallium acts as a 'Trojan horse' to mimic iron. The internalized gallium ions disrupt biofilms by interfering with the physiological processes of iron ion acquisition and utilization, biofilm formation, and quorum sensing. Furthermore, aerosol microsprayer administration and bacteria-specific maltohexaose modification enable accumulation at biofilm-infected lung and targeted release of gallium into bacteria to improve the therapeutic effect. This work provides a potential strategy for treating infection by reversing the dormant biofilm's resistance condition.

Construction of 5-Fluorouracil and Gallium Corrole Conjugates for Enhanced Photodynamic Therapy.

Molecular hybridization is a well-established strategy for developing new drugs. In the pursuit of promising photosensitizers (PSs) with enhanced photodynamic therapy (PDT) efficiency, a series of novel 5-fluorouracil (5FU) gallium corrole conjugates (1-Ga-4-Ga) were designed and synthesized by hybridizing a chemotherapeutic drug and PSs. Their photodynamic antitumor activity was also evaluated. The most active complex (2-Ga) possesses a low IC50 value of 0.185 µM and a phototoxic index of 541 against HepG2 cells. Additionally, the 5FU-gallium corrole conjugate (2-Ga) exhibited a synergistic increase in cytotoxicity under irradiation. Excitedly, treatment of HepG2 tumor-bearing mice with 2-Ga under irradiation could completely ablate tumors without harming normal tissues. 2-Ga-mediated PDT could disrupt mitochondrial function, cause cell cycle arrest in the sub-G1 phase, and activate the cell apoptosis pathway by upregulating the cleaved PARP expression and the Bax/Bcl-2 ratios. This work provides a useful strategy for the design of new corrole-based chemo-photodynamic therapy drugs.

Injectable composite hydrogels embedded with gallium-based liquid metal particles for solid breast cancer treatment via chemo-photothermal combination.

Photothermal therapy (PTT) holds great promise as a cancer treatment modality by generating localized heat at the tumor site. Among various photothermal agents, gallium-based liquid metal (LM) has been widely used as a new photothermal-inducible metallic compound due to its structural transformability. To overcome limitations of random aggregation and dissipation of administrated LM particles into a human body, we developed LM-containing injectable composite hydrogel platforms capable of achieving spatiotemporal PTT and chemotherapy. Eutectic gallium-indium LM particles were first stabilized with 1,2-Distearoyl-sn­glycero-3-phosphoethanolamine (DSPE) lipids. They were then incorporated into an interpenetrating hydrogel network composed of thiolated gelatin conjugated with 6-mercaptopurine (MP) chemodrug and poly(ethylene glycol)-diacrylate. The resulted composite hydrogel exhibited sufficient capability to induce MDA-MB-231 breast cancer cell death through a multi-step mechanism: (1) hyperthermic cancer cell death due to temperature elevation by near-infrared laser irradiation via LM particles, (2) leakage of glutathione (GSH) and cleavage of disulfide bonds due to destruction of cancer cells. As a consequence, additional chemotherapy was facilitated by GSH, leading to accelerated release of MP within the tumor microenvironment. The effectiveness of our composite hydrogel system was evaluated both in vitro and in vivo, demonstrating significant tumor suppression and killing. These results demonstrate the potential of this injectable composite hydrogel for spatiotemporal cancer treatment. In conclusion, integration of PTT and chemotherapy within our hydrogel platform offers enhanced therapeutic efficacy, suggesting promising prospects for future clinical applications. STATEMENT OF SIGNIFICANCE: Our research pioneers a breakthrough in cancer treatments by developing an injectable hydrogel platform incorporating liquid metal (LM) particle-mediated photothermal therapy and 6-mercaptopurine (MP)-based chemotherapy. The combination of gallium-based LM and MP achieves synergistic anticancer effects, and our injectable composite hydrogel acts as a localized reservoir for specific delivery of both therapeutic agents. This platform induces a multi-step anticancer mechanism, combining NIR-mediated hyperthermic tumor death and drug release triggered by released glutathione from damaged cancer populations. The synergistic efficacy validated in vitro and in vivo studies highlights significant tumor suppression. This injectable composite hydrogel with synergistic therapeutic efficacy holds immense promise for biomaterial-mediated spatiotemporal treatment of solid tumors, offering a potent targeted therapy for triple negative breast cancers.

Gallium and silver-doped titanium surfaces provide enhanced osteogenesis, reduce bone resorption and prevent bacterial infection in co-culture.

Bacterial infection remains a significant problem associated with orthopaedic surgeries leading to surgical site infection (SSI). This unmet medical need can become an even greater complication when surgery is due to malignant bone tumor. In the present study, we evaluated in vitro titanium (Ti) implants subjected to gallium (Ga) and silver (Ag)-doped thermochemical treatment as strategy to prevent SSI and improve osteointegration in bone defects caused by diseases such as osteoporosis, bone tumor, or bone metastasis. Firstly, as Ga has been reported to be an osteoinductive and anti-resorptive agent, its performance in the mixture was proved by studying human mesenchymal stem cells (hMSC) and pre-osteoclasts (RAW264.7) behaviour. Then, the antibacterial potential provided by Ag was assessed by resembling "The Race for the Surface" between hMSC and Pseudomonas aeruginosa in two co-culture methods. Moreover, the presence of quorum sensing molecules in the co-culture was evaluated. The results highlighted the suitability of the mixture to induce osteodifferentiation and reduce osteoclastogenesis in vitro. Furthermore, the GaAg surface promoted strong survival rate and retained osteoinduction potential of hMSCs even after bacterial inoculation. Therefore, GaAg-modified titanium may be an ideal candidate to repair bone defects caused by excessive bone resorption, in addition to preventing SSI. STATEMENT OF SIGNIFICANCE: This article provides important insights into titanium for fractures caused by osteoporosis or bone metastases with high incidence in surgical site infection (SSI) because in this situation bacterial infection can become a major disaster. In order to solve this unmet medical need, we propose a titanium implant modified with gallium and silver to improve osteointegration, reduce bone resorption and avoid bacterial infection. For that aim, we study osteoblast and osteoclast behavior with the main novelty focused on the antibacterial evaluation. In this work, we recreate "the race for the surface" in long-term experiments and study bacterial virulence factors (quorum sensing). Therefore, we believe that our article could be of great interest, providing a great impact on future orthopedic applications.

Hybrid Sono-Photodynamic Combination Therapy Mediated by Water-Soluble Gallium Phthalocyanine Enhances the Cytotoxic Effect against Breast Cancer Cell Lines.

Breast cancer is a life-threatening disease that is gaining increasing importance due to its rising incidence, highlighting the need for novel treatment methods with the least disadvantages. Recently, scientists have focused on developing therapeutic treatment modalities for effective cancer treatment. In contrast to conventional cancer treatment methods such as immunotherapy, surgery, chemotherapy, or radiotherapy, photodynamic therapy (PDT) is gaining prominence. Besides, sonodynamic treatment (SDT) is a noninvasive therapeutic approach that uses ultrasound to induce high tissue penetration. In both methods, sensitizers are activated to generate cytotoxic reactive oxygen species such as •OH and 1O2. In particular, the combined use of hybrid and complementary treatment methods has become an important modality in cancer treatment in recent years. Sono-photodynamic therapy (SPDT), which is an important method applied in combination with PDT and SDT, has started to be preferred in terms of reducing potential side effects compared to monotherapy. One of the most important types of sensitizers used in PDT and SDT is known as phthalocyanines (Pcs). Motivated by these facts, this research presents the sono-photochemical, in vitro cytotoxicity, and theoretical evaluation of water-soluble gallium phthalocyanine (GaPc). The results indicate that the quantum yield of the generation of singlet oxygen increased in sono-photochemical studies (ΦΔ = 0.94), compared to photochemical studies (ΦΔ = 0.72). In vitro analyses revealed that GaPc did not exhibit significant cytotoxic effects at the specified varying concentration doses (1-20 µM). Furthermore, GaPc-mediated SPDT triggered cell death by inducing reactive oxygen species formation in the breast cancer cell line (MCF-7). The interaction mechanism of the GaPc with EGFR and VEGFR2 target proteins, which are critical regulators of metastasis, proliferation, and angiogenesis, was investigated by molecular docking simulation. GaPc has effective binding affinities against target proteins, and this affinity was found to be the highest against VEGFR2. Molecular docking results showed a good correlation with the obtained biological results. Eventually, this molecular building of the efficient water-soluble phthalocyanine-based sensitizer is a potential therapeutic for PDT, SDT, and SPDT applications.

Fabrication of 3D-printed scaffolds loaded with gallium acetylacetonate for potential application in osteoclastic bone resorption.

We recently reported the potential of a new gallium compound, gallium acetylacetonate (GaAcAc) in combating osteoclastic bone resorption through inhibition of osteoclast differentiation and function. Herein, we focused on 3D-printed polylactic acid scaffolds that were loaded with GaAcAc and investigated the impact of scaffold pretreatment with polydopamine (PDA) or sodium hydroxide (NaOH). We observed a remarkable increase in scaffold hydrophilicity with PDA or NaOH pretreatment while biocompatibility and in vitro degradation were not affected. NaOH-pretreated scaffolds showed the highest amount of GaAcAc loading when compared to other scaffolds (p < 0.05). NaOH-pretreated scaffolds with GaAcAc loading showed effective reduction of osteoclast counts and size. The trend was supported by suppression of key osteoclast differentiation markers such as NFAT2, c-Fos, TRAF6, & TRAP. All GaAcAc-loaded scaffolds, regardless of surface pretreatment, were effective in inhibiting osteoclast function as evidenced by reduction in the number of resorptive pits in bovine cortical bone slices (p < 0.01). The suppression of osteoclast function according to the type of scaffold followed the ranking: GaAcAc loading without surface pretreatment > GaAcAc loading with NaOH pretreatment > GaAcAc loading with PDA pretreatment. Additional studies will be needed to fully elucidate the impact of surface pretreatment on the efficacy and safety of GaAcAc-loaded 3D-printed scaffolds.

Breaking Iron Homeostasis: Iron Capturing Nanocomposites for Combating Bacterial Biofilm.

Given the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin-uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga-CT@P nanocomposites constructed with gallium, copper-doped tetrakis (4-carboxyphenyl) porphyrin (TCPP) metal-organic framework, and polyamine-amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium-incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a "give and take" approach for Ga3+/Fe3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real-time fluorescent iron-sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga-CT@P nanocomposites induced long-term iron starvation, which affected iron-sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application.