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Thrombotic cardiovascular diseases are a prevalent factor contributing to both physical impairment and mortality. Thrombolysis and ischemic mitigation have emerged as leading contemporary therapeutic approaches for addressing the consequences of ischemic injury and reperfusion damage. Herein, an innovative cellular-cloaked spermatozoon-driven microcellular submarine (SPCS), comprised of multimodal motifs, was designed to integrate nano-assembly thrombolytics with an immunomodulatory ability derived from innate magnetic hyperthermia. Rheotaxis-based navigation was utilized to home to and cross the clot barrier, and finally accumulate in ischemic vascular organs, where the thrombolytic motif was "switched-on" by the action of thrombus magnetic red blood cell-driven magnetic hyperthermia. In a murine model, the SPCS system combining innate magnetic hyperthermia demonstrated the capacity to augment delivery efficacy, produce nanotherapeutic outcomes, exhibit potent thrombolytic activity, and ameliorate ischemic tissue damage. These findings underscore the multifaceted potential of our designed approach, offering both thrombolytic and ischemia-mitigating effects. Given its extended therapeutic effects and thrombus-targeting capability, this biocompatible SPCS system holds promise as an innovative therapeutic agent for enhancing efficacy and preventing risks after managing thrombosis.
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Isquemia , Espermatozoides , Trombose , Animais , Masculino , Camundongos , Isquemia/terapia , Espermatozoides/efeitos dos fármacos , Trombose/tratamento farmacológico , Terapia Trombolítica/métodos , Hipertermia Induzida/métodos , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Fibrinolíticos/química , Humanos , Camundongos Endogâmicos C57BLRESUMO
Impaired wound healing is a significant complication of diabetes. Platelet-derived extracellular vesicles (pEVs), rich in growth factors and cytokines, show promise as a powerful biotherapy to modulate cellular proliferation, angiogenesis, immunomodulation, and inflammation. For practical home-based wound therapy, however, pEVs should be incorporated into wound bandages with careful attention to delivery strategies. In this work, a gelatin-alginate hydrogel (GelAlg) loaded with reduced graphene oxide (rGO) was fabricated, and its potential as a diabetic wound dressing was investigated. The GelAlg@rGO-pEV gel exhibited excellent mechanical stability and biocompatibility in vitro, with promising macrophage polarization and reactive oxygen species (ROS)-scavenging capability. In vitro cell migration experiments were complemented by in vivo investigations using a streptozotocin-induced diabetic rat wound model. When exposed to near-infrared light at 2 W cm- 2, the GelAlg@rGO-pEV hydrogel effectively decreased the expression of inflammatory biomarkers, regulated immune response, promoted angiogenesis, and enhanced diabetic wound healing. Interestingly, the GelAlg@rGO-pEV hydrogel also increased the expression of heat shock proteins involved in cellular protective pathways. These findings suggest that the engineered GelAlg@rGO-pEV hydrogel has the potential to serve as a wound dressing that can modulate immune responses, inflammation, angiogenesis, and follicle regeneration in diabetic wounds, potentially leading to accelerated healing of chronic wounds.
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Plaquetas , Complicações do Diabetes , Vesículas Extracelulares , Cicatrização , Plaquetas/química , Vesículas Extracelulares/química , Oxirredução , Complicações do Diabetes/tratamento farmacológico , Humanos , Animais , Camundongos , Ratos , Linhagem Celular , Ratos Wistar , Sobrevivência Celular , Espécies Reativas de Oxigênio/metabolismo , Hidrogéis/químicaRESUMO
Thrombotic vascular disorders, specifically thromboembolisms, have a significant detrimental effect on public health. Despite the numerous thrombolytic and antithrombotic drugs available, their efficacy in penetrating thrombus formations is limited, and they carry a high risk of promoting bleeding. Consequently, the current medication dosage protocols are inadequate for preventing thrombus formation, and higher doses are necessary to achieve sufficient prevention. By integrating phototherapy with antithrombotic therapy, this study addresses difficulties related to thrombus-targeted drug delivery. We developed self-assembling nanoparticles (NPs) through the optimization of a co-assembly engineering process. These NPs, called DIP-FU-PPy NPs, consist of polypyrrole (PPy), dipyridamole (DIP), and P-selectin-targeted fucoidan (FU) and are designed to be delivered directly to thrombi. DIP-FU-PPy NPs are proposed to offer various potentials, encompassing drug-loading capability, targeted accumulation in thrombus sites, near-infrared (NIR) photothermal-enhanced thrombus management with therapeutic efficacy, and prevention of rethrombosis. As predicted, DIP-FU-PPy NPs prevented thrombus recurrence and emitted visible fluorescence signals during thrombus clot penetration with no adverse effects. Our co-delivery nano-platform is a simple and versatile solution for NIR-phototherapeutic multimodal thrombus control.
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Nanopartículas , Trombose , Dipiridamol/farmacologia , Nanopartículas/uso terapêutico , Selectina-P , Fototerapia/métodos , Polímeros , Pirróis , Trombose/tratamento farmacológico , AnimaisRESUMO
The introduction and designing of functional thermoresponsive hydrogels have been recommended as recent potential therapeutic approaches for biomedical applications. The development of bioactive materials such as thermosensitive gelatin-incorporated nano-organic materials with a porous structure and photothermally triggerable and cell adhesion properties may potentially achieve this goal. This novel class of photothermal hydrogels can provide an advantage of hyperthermia together with a reversibly transformable hydrogel for tissue engineering. Polypyrrole (Ppy) is a bioorganic conducting polymeric substance and has long been used in biomedical applications owing to its brilliant stability, electrically conductive features, and excellent absorbance around the near-infrared (NIR) region. In this study, a cationic photothermal triggerable/guidable gelatin hydrogel containing a polyethylenimine (PEI)â»Ppy nanocomplex with a porous microstructure was established, and its physicochemical characteristics were studied through dynamic light scattering, scanning electronic microscopy, transmission electron microscopy, an FTIR; and cellular interaction behaviors towards fibroblasts incubated with a test sample were examined via MTT assay and fluorescence microscopy. Photothermal performance was evaluated. Furthermore, the in vivo study was performed on male Wistar rat full thickness excisions model for checking the safety and efficacy of the designed gelatinâ»PEIâ»Ppy nanohydrogel system in wound healing and for other biomedical uses in future. This photothermally sensitive hydrogel system has an NIR-triggerable property that provides local hyperthermic temperature by PEIâ»Ppy nanoparticles for tissue engineering applications. Features of the designed hydrogel may fill other niches, such as being an antibacterial agent, generation of free radicals to further improve wound healing, and remodeling of the promising photothermal therapy for future tissue engineering applications.
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Gelatina/farmacologia , Hidrogéis/química , Pirróis/química , Engenharia Tecidual/métodos , Cicatrização/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Gelatina/química , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Nanopartículas/química , Polietilenoimina/química , Porosidade , Ratos , Ratos Wistar , TemperaturaRESUMO
In this study, thermo-sensitive poly(N-isopropyl acrylamide) (PNP) was polymerized with pH-sensitive poly(acrylic acid) (PAA) to prepare a PAA-b-PNP block copolymer. Above its cloud point, the block copolymer self-assembled into nanoparticles (NPs), encapsulating the anticancer drug camptothecin (CPT) in situ. Chitosan (CS) and fucoidan (Fu) further modified these NPs, forming Fu-CPT-NPs to enhance biocompatibility, drug encapsulation efficiency (EE), and loading content (LC), crucially facilitating P-selectin targeting of lung cancer cells through a drug delivery system. The EE and LC reached 82 % and 3.5 %, respectively. According to transmission electron microscope observation, these Fu-CPT-NPs had uniform spherical shapes with an average diameter of ca. 250 nm. They could maintain their stability in a pH range of 5.0-6.8. In vitro experimental results revealed that the Fu-CPT-NPs exhibited good biocompatibility and had anticancer activity after encapsulating CPT. It could deliver CPT to cancer cells by targeting P-selectin, effectively increasing cell uptake and inducing cell apoptosis. Animal study results showed that the Fu-CPT-NPs inhibited lung tumor growth by increasing tumor cell apoptosis without causing significant tissue damage related to generating reactive oxygen species in lung cancer cells. This system can effectively improve drug-delivery efficiency and treatment effects and has great potential for treating lung cancer.
Assuntos
Camptotecina , Quitosana , Neoplasias Pulmonares , Nanopartículas , Polissacarídeos , Quitosana/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Humanos , Camptotecina/farmacologia , Camptotecina/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Nanopartículas/química , Animais , Camundongos , Apoptose/efeitos dos fármacos , Portadores de Fármacos/química , Células A549 , Linhagem Celular Tumoral , Resinas Acrílicas/química , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Selectina-P/metabolismo , Polímeros/químicaRESUMO
Bone regeneration is a critical and intricate process vital for healing fractures, defects, and injuries. Although conventional bone grafts are commonly used, they may fall short of optimal outcomes, thereby driving the need for alternative therapies. This research endeavors to explore synergistically designed Hyalo Glass Gel (HGG), and its explicitly for bone tissue engineering and regenerative medicine. The HGG composite comprises a modifiable calcium-based bioactive phosphosilicates-incorporated/crosslinked gelatin-hyaluronic scaffold showcasing promising functional characteristics. The study underscores the distinct attributes of each constituent (gelatin (Gel), hyaluronic acid (HA), and 45S5 calcium sodium phosphosilicates (BG)), and their cooperative influences on the scaffold's performance. Careful manipulation of crosslinking methods facilitates customization of HGG's mechanical attributes, degradation kinetics, and structural features, aligning them with the requisites of bone tissue engineering applications. Moreover, the integration of BG augments the scaffold's bioactivity, thereby expediting tissue regenerative processes. This comprehensive evaluation encompasses HGG's physicochemical aspects, mechanical traits rooted in viscoelasticity, as well as its biodegradability, in-vitro bioactivity, and interactions with stem cells. The result obtained underscores the viscoelastic nature of HGG, substantiating its capacity to foster mesenchymal stem cell viability, proliferation, and differentiation. Significantly, HGG manifests biocompatibility and adjustable attributes, exhibits pronounced drug (vancomycin) retention abilities, rendering it apt for wound healing, drug delivery, and bone regeneration. Its distinctive composition, tailored attributes, and mimicry of bone tissue's extracellular matrix (ECM) due to its bioactive nature, collectively situate its potential as a versatile biomaterial for subsequent research and development endeavors with compelling prospects in bone tissue engineering and regenerative medicine.
Assuntos
Gelatina , Hidrogéis , Hidrogéis/farmacologia , Hidrogéis/química , Gelatina/farmacologia , Gelatina/química , Cálcio , Materiais Biocompatíveis/química , Engenharia Tecidual/métodos , Regeneração Óssea , Alicerces TeciduaisRESUMO
Creating a versatile and remotely self-assembling biocomposite for delivering therapeutics to alleviate inflammatory diseases poses significant challenges. This study introduces a novel biocomposite, created through cold-atmosphere plasma treatment, that combines fucoidan (Fu) and neutrophil lysate (Nu) to mediate the self-assembly of diferuloylmethane (DIF) and iron oxide (IO) nanoclusters, termed DIF-Nu/Fu-IO NC. This biocomposite forms a phototherapeutic and magnetically-driven in situ gel with open-porous architecture loaded with DIF, offering non-invasive theranostic capabilities for treating inflammatory diseases. It demonstrates efficacy in both an intraarticular zymosan-induced rheumatoid arthritis animal model and an intranasal LPS-induced inflammatory lung model. Upon administration, near-infrared (NIR) irradiation and magnet application significantly improved the condition of the animals with rheumatoid arthritis and lung inflammation. This breakthrough heralds a new paradigm in bioinspired, versatile, theranostic, self-assembling biocomposites for addressing clinical inflammatory diseases.
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Segmental bone defects can arise from trauma, infection, metabolic bone disorders, or tumor removal. Hydrogels have gained attention in the field of bone regeneration due to their unique hydrophilic properties and the ability to customize their physical and chemical characteristics to serve as scaffolds and carriers for growth factors. However, the limited mechanical strength of hydrogels and the rapid release of active substances have hindered their clinical utility and therapeutic effectiveness. With ongoing advancements in material science, the development of injectable and biofunctionalized hydrogels holds great promise for addressing the challenges associated with segmental bone defects. In this study, we incorporated lyophilized platelet-rich fibrin (LPRF), which contains a multitude of growth factors, into a genipin-crosslinked gelatin/hyaluronic acid (GLT/HA-0.5 % GP) hydrogel to create an injectable and biofunctionalized composite material. Our findings demonstrate that this biofunctionalized hydrogel possesses optimal attributes for bone tissue engineering. Furthermore, results obtained from rabbit model with segmental tibial bone defects, indicate that the treatment with this biofunctionalized hydrogel resulted in increased new bone formation, as confirmed by imaging and histological analysis. From a translational perspective, this biofunctionalized hydrogel provides innovative and bioinspired capabilities that have the potential to enhance bone repair and regeneration in future clinical applications.
Assuntos
Regeneração Óssea , Liofilização , Gelatina , Ácido Hialurônico , Hidrogéis , Iridoides , Fibrina Rica em Plaquetas , Animais , Iridoides/química , Iridoides/farmacologia , Gelatina/química , Coelhos , Hidrogéis/química , Hidrogéis/farmacologia , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Regeneração Óssea/efeitos dos fármacos , Fibrina Rica em Plaquetas/química , Engenharia Tecidual/métodos , Reagentes de Ligações Cruzadas/química , Alicerces Teciduais/química , Tíbia/efeitos dos fármacos , Tíbia/cirurgiaRESUMO
A combination of chemotherapy and chemodynamic therapy (CDT) is being developed to improve the theranostic efficacy and biological safety of current therapies. However, most CDT agents are restricted due to complex issues such as multiple components, low colloidal stability, carrier-associated toxicity, insufficient reactive oxygen species generation, and poor targeting efficacy. To overcome these problems, a novel nanoplatform composed of fucoidan (Fu) and iron oxide (IO) nanoparticles (NPs) was developed to achieve chemotherapy combined with CDT synergistic treatment with a facile self-assembling manner, and the NPs were made up of Fu and IO, in which the Fu was not only used as a potential chemotherapeutic but was also designed to stabilize the IO and target P-selectin-overexpressing lung cancer cells, thereby producing oxidative stress and thus synergizing the CDT efficacy. The Fu-IO NPs exhibited a suitable diameter below 300 nm, which favored their cellular uptake by cancer cells. Microscopic and MRI data confirmed the lung cancer cellular uptake of the NPs due to active Fu targeting. Moreover, Fu-IO NPs induced efficient apoptosis of lung cancer cells, and thus offer significant anti-cancer functions by potential chemotherapeutic-CDT.
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Neoplasias Pulmonares , Nanopartículas , Neoplasias , Humanos , Medicina de Precisão , Selectina-P , Linhagem Celular Tumoral , Nanomedicina Teranóstica , Neoplasias/tratamento farmacológico , Estresse Oxidativo , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas Magnéticas de Óxido de Ferro , Nanopartículas/uso terapêuticoRESUMO
Due to the mortality associated with thrombosis and its high recurrence rate, there is a need to investigate antithrombotic approaches. Noninvasive site-specific thrombolysis is a current approach being used; however, its usage is characterized by the following limitations: low targeting efficiency, poor ability to penetrate clots, rapid half-life, lack of vascular restoration mechanisms, and risk of thrombus recurrence that is comparable to that of traditional pharmacological thrombolysis agents. Therefore, it is vital to develop an alternative technique that can overcome the aforementioned limitations. To this end, a cotton-ball-shaped platelet (PLT)-mimetic self-assembly framework engineered with a phototherapeutic poly(3,4-ethylenedioxythiophene) (PEDOT) platform has been developed. This platform is capable of delivering a synthetic peptide derived from hirudin P6 (P6) to thrombus lesions, forming P6@PEDOT@PLT nanomotors for noninvasive site-specific thrombolysis, effective anticoagulation, and vascular restoration. Regulated by P-selectin mediation, the P6@PEDOT@PLT nanomotors target the thrombus site and subsequently rupture under near-infrared (NIR) irradiation, achieving desirable sequential drug delivery. Furthermore, the movement ability of the P6@PEDOT@PLT nanomotors under NIR irradiation enables effective penetration deep into thrombus lesions, enhancing bioavailability. Biodistribution analyses have shown that the administered P6@PEDOT@PLT nanomotors exhibit extended circulation time and metabolic capabilities. In addition, the photothermal therapy/photoelectric therapy combination can significantly augment the effectiveness (ca. 72%) of thrombolysis. Consequently, the precisely delivered drug and the resultant phototherapeutic-driven heat-shock protein, immunomodulatory, anti-inflammatory, and inhibitory plasminogen activator inhibitor-1 (PAI-1) activities can restore vessels and effectively prevent rethrombosis. The described biomimetic P6@PEDOT@PLT nanomotors represent a promising option for improving the efficacy of antithrombotic therapy in thrombus-related illnesses.
Assuntos
Trombose , Ativador de Plasminogênio Tecidual , Humanos , Ativador de Plasminogênio Tecidual/farmacologia , Biomimética , Distribuição Tecidual , Trombose/tratamento farmacológico , Terapia Trombolítica/métodosRESUMO
Long-standing administration of disease-modifying antirheumatic drugs confirms their clinical value for managing rheumatoid arthritis (RA). Nevertheless, there are emergent worries over unwanted adverse risks of systemic drug administration. Hence, a novel strategy that can be used in a drug-free manner while diminishing side effects is immediately needed, but challenges persist in the therapy for RA. To this end, herein we conjugated tyramine (TYR) with alginate (ALG) to form ALG-TYR and then treated it for 5 min with oxygen plasma (ALG-TYR + P/5 min). It was shown that the ALG-TYR + P/5 min hydrogel exhibited favorable viscoelastic, morphological, mechanical, biocompatible, and cellular heat-shock protein amplification behaviors. A thorough physical and structural analysis was conducted on the ALG-TYR + P/5 min hydrogel, revealing favorable physical characteristics and uniform porous structural features within the hydrogel. Moreover, ALG-TYR + P/5 min not only effectively inhibited inflammation of RA but also potentially regulated lesion immunity. Once ALG-TYR + P/5 min was intra-articularly administered to joints of rats with zymosan-induced arthritis, we observed that ALG-TYR + P/5 min could ameliorate syndromes of RA joint. This bioinspired and self-restorable ALG-TYR + P/5 min hydrogel can thus serve as a promising system to provide prospective outcomes to potentiate RA therapy.
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A new approach to treating vascular blockages has been developed to overcome the limitations of current thrombolytic therapies. This approach involves biosafety and multimodal plasma-derived theranostic platelet vesicle incorporating iron oxide constructed nano-propellers platformed technology that possesses fluorescent and magnetic features and manifold thrombus targeting modes. The platform is capable of being guided and visualized remotely to specifically target thrombi, and it can be activated using near-infrared phototherapy along with an actuated magnet for magnetotherapy. In a murine model of thrombus lesion, this proposed multimodal approach showed an approximately 80 % reduction in thrombus residues. Moreover, the new strategy not only improves thrombolysis but also boosts the rate of lysis, making it a promising candidate for time-sensitive thrombolytic therapy.
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Traditional thrombolytic therapeutics for vascular blockage are affected by their limited penetration into thrombi, associated off-target side effects, and low bioavailability, leading to insufficient thrombolytic efficacy. It is hypothesized that these limitations can be overcome by the precisely controlled and targeted delivery of thrombolytic therapeutics. A theranostic platform is developed that is biocompatible, fluorescent, magnetic, and well-characterized, with multiple targeting modes. This multimodal theranostic system can be remotely visualized and magnetically guided toward thrombi, noninvasively irradiated by near-infrared (NIR) phototherapies, and remotely activated by actuated magnets for additional mechanical therapy. Magnetic guidance can also improve the penetration of nanomedicines into thrombi. In a mouse model of thrombosis, the thrombosis residues are reduced by ≈80% and with no risk of side effects or of secondary embolization. This strategy not only enables the progression of thrombolysis but also accelerates the lysis rate, thereby facilitating its prospective use in time-critical thrombolytic treatment.
Assuntos
Terapia Trombolítica , Trombose , Camundongos , Animais , Medicina de Precisão , Fibrinolíticos/química , Fibrinolíticos/uso terapêutico , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológico , Fenômenos MagnéticosRESUMO
The innate cartilage extracellular matrix is avascular and plays a vital role in innate chondrocytes. Recapping the crucial components of the extracellular matrix in engineered organs via polymeric gels and bioinspired approaches is promising for improving the regenerative aptitude of encapsulated cartilage/chondrocytes. Conventional gel formation techniques for polymeric materials rely on employing oxidative crosslinking, which is constrained in this avascular environment. Further, poor mechanical properties limit the practical applications of polymeric gels and reduce their therapeutic efficacy. Herein, the purpose of this study was to develop a bioadhesive gel possessing dual crosslinking for engineering cartilage. Tyramine (TYR) was first chemically conjugated to the alginate (ALG) backbone to form an ALG-TYR precursor, followed by the addition of calcium peroxide (CaO2); calcium ions of CaO2 physically crosslink with ALG, and oxygen atoms of CaO2 chemically crosslink TYR with tyrosinase, thus enabling dual/enhanced crosslinking and possessing injectability. The ALG-TYR/tyrosinase/CaO2 gel system was chemically, mechanically, cellularly, and microscopically characterized. The gel system developed herein was biocompatible and showed augmented mechanical strength. The results showed, for the first time, that CaO2 supplementation preserved cell viability and enhanced the crosslinking ability, bioadhesion, mechanical strength, chondrogenesis, and stability for cartilage regeneration.
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Alginatos , Monofenol Mono-Oxigenase , Alginatos/química , Cartilagem , Condrócitos , Condrogênese , Hidrogéis/química , Peróxidos , Engenharia Tecidual/métodos , Alicerces Teciduais/química , TiraminaRESUMO
Curcumin can reduce the production of brain inflammatory mediators and symptoms of brain diseases. However, a large amount of free curcumin needs to be administered to achieve an effective level in the brain because of its poor water-solubility. Fucoidan and chitosan were reported to respectively target P-selectin and acidic microenvironment expressed by pathologically inflammatory cells/tissues. Herein, the self-assembly of chitosan and fucoidan which could encapsulate curcumin was developed to form the multi-stimuli-responsive nanocarriers, and their pathological pH- and P-selectin-responsive aspects were characterized. Through intranasal delivery to the brain, these curcumin-containing chitosan/fucoidan nanocarriers with dual pH-/P-selectin-targeting properties to the brain lesions improved drug delivery, distribution, and accumulation in the inflammatory brain lesions as evidenced by an augmented inhibitory effect against brain inflammation. This promising multifunctional nanocarrier with a novel drug-delivery route should allow potential clinical biomedical uses by neurosurgeon in the future.
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Quitosana/química , Curcumina/administração & dosagem , Curcumina/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Encefalite/tratamento farmacológico , Nanopartículas/química , Polissacarídeos/química , Administração Intranasal , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Fluorescência , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura , Selectina-P/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual/efeitos dos fármacos , Difração de Raios XRESUMO
Several studies have applied tricalcium phosphate (TCP) or autografts in bone tissue engineering to enhance the clinical regeneration of bone. Unfortunately, there are several drawbacks related to the use of autografts, including a risk of infection, blood loss, limited quantities, and donor-site morbidities. Platelet-rich fibrin (PRF) is a natural extracellular matrix (ECM) biomaterial that possesses bioactive factors, which can generally be used in regenerative medicine. The goal of the present investigation was to develop osteoconductive TCP incorporated with bioactive PRF for bio-synergistic bone regeneration and examine the potential biological mechanisms and applications. Our in vitro results showed that PRF plus TCP had excellent biosafety and was favorable for initiating osteoblast cell attachment, slow release of bioactive factors, cell proliferation, cell migration, and ECM formation that potentially impacted bone repair. In a rabbit femoral segmental bone defect model, regeneration of bone was considerably augmented in defects locally implanted by PRF plus TCP according to radiographic and histologic examinations. Notably, the outcomes of this investigation suggest that the combination of PRF and TCP possesses novel synergistic and bio-inspired functions that facilitate bone regeneration.
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Fibrina Rica em Plaquetas , Animais , Materiais Biocompatíveis , Regeneração Óssea , Fosfatos de Cálcio/farmacologia , CoelhosRESUMO
Nanomaterial mediated cancer/tumor photo driven hyperthermia has obtained great awareness. Nevertheless, it is a challenge for improving the hyperthermic efficacy lacking resistance to stimulated thermal stress. We thus developed a bioinspired nano-platform utilizing inclusion complexation between photosensitive polypyrrole (Ppy) nanoparticles (NP) and fucoidan (FU). This FU-Ppy NP proved to be an excellent P-selectin-mediated, lung cancer-cell/tumor targeting delivery and specific accumulation, could augment cancer/tumor oxidative stress levels through producing cellular reactive oxygen species. Potent ROS/photothermal combinational therapeutic effects were exhibited by the bioinspired FU-Ppy NP through a selective P-selectin cancer/tumor targeting aptitude for the lung cancer cells/tumor compared with other nano-formulations. The usage of FU-Ppy NP also involves the potential mechanism of suppressing the biological expression of tumor vascular endothelial growth factor (VEGF). This FU biological macromolecule-amplified photothermally therapeutic nano-platform has promising potential for future medical translation in eradicating numerous tumors.
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Neoplasias Pulmonares/terapia , Nanopartículas/química , Terapia Fototérmica/métodos , Polímeros/química , Polissacarídeos/química , Pirróis/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Luz , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Nanopartículas/efeitos da radiação , Nanopartículas/uso terapêutico , Selectina-P/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND AND PURPOSE: Strontium ranelate (SrR) is an oral pharmaceutical agent for osteoporosis. In recent years, numerous unwanted side effects of oral SrR have been revealed. Therefore, its clinical administration and applications are limited. Hereby, this study aims to develop, formulate, and characterize an effective SrR carrier system for spinal bone regeneration. METHODS: Herein, glycol chitosan with hyaluronic acid (HA)-based nanoformulation was used to encapsulate SrR nanoparticles (SrRNPs) through electrostatic interaction. Afterward, the poly(ethylene glycol) diacrylate (PEGDA)-based hydrogels were used to encapsulate pre-synthesized SrRNPs (SrRNPs-H). The scanning electron microscope (SEM), TEM, rheometer, Fourier-transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS) were used to characterize prepared formulations. The rabbit osteoblast and a rat spinal decortication models were used to evaluate and assess the developed formulation biocompatibility and therapeutic efficacy. RESULTS: In vitro and in vivo studies for cytotoxicity and bone regeneration were conducted. The cell viability test showed that SrRNPs exerted no cytotoxic effects in osteoblast in vitro. Furthermore, in vivo analysis for new bone regeneration mechanism was carried out on rat decortication models. Radiographical and histological analysis suggested a higher level of bone regeneration in the SrRNPs-H-implanted groups than in the other experimental groups. CONCLUSION: Local administration of the newly developed formulated SrR could be a promising alternative therapy to enhance bone regeneration in bone-defect sites in future clinical applications.
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Regeneração Óssea/efeitos dos fármacos , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Polietilenoglicóis/química , Coluna Vertebral/fisiologia , Tiofenos/administração & dosagem , Tiofenos/farmacologia , Animais , Comunicação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacologia , Hidrogéis/química , Masculino , Nanopartículas/ultraestrutura , Tamanho da Partícula , Coelhos , Ratos Wistar , Coluna Vertebral/efeitos dos fármacosRESUMO
Thrombolysis is a standard treatment for rapidly restoring blood flow. However, the application of urokinase-type plasminogen activator (Uk) in clinical therapy is limited due to its nonspecific distribution and inadequate therapeutic accumulation. Precise thrombus imaging and site-specific drug delivery can enhance the diagnostic and therapeutic efficacy for thrombosis. Accordingly, we developed a P-selectin-specific, photothermal theranostic nanocomposite for thrombus-targeted codelivery of Uk and indocyanine green (ICG, a contrast agent for near-infrared (NIR) fluorescence imaging). We evaluated its capabilities for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. Mesoporous silica-coated gold nanorods (Si-AuNRs) were functionalized with an arginine-rich peptide to create an organic template for the adsorption of ICG and fucoidan (Fu), an algae-derived anticoagulant. Uk was loaded into the SiO2 pores of the Si-AuNRs through the formation of a Fu-Uk-ICG complex on the peptide-functionalized template. The Fu-Uk/ICG@SiAu NRs nanocomposite increased the photostability of ICG and improved its targeting/accumulation at blood clot sites with a strong NIR fluorescence intensity for precise thrombus imaging. Furthermore, ICG incorporated into the nanocomposite enhanced the photothermal effect of Si-AuNRs. Fu, as a P-selectin-targeting ligand, enabled the nanocomposite to target a thrombus site where platelets were activated. The nanocomposite enabled a faster release of Uk for rapid clearing of blood clots and a slower release of Fu for longer lasting prevention of thrombosis regeneration. The nanocomposite with multiple functions, including thrombus-targeting drug delivery, photothermal thrombolysis, and NIR fluorescence imaging, is thus an advanced theranostic platform for thrombolytic therapy with reduced hemorrhaging risk and enhanced imaging/thrombolysis efficiency. STATEMENT OF SIGNIFICANCE: Herein, for the first time, a P-selectin specific, photothermal theranostic nanocomposite for thrombus-targeted co-delivery of urokinase and NIR fluorescence contrast agent indocyanine green (ICG) was developed. We evaluated the potential of this theranostic nanocomposite for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. The nanocomposite showed multiple functions including thrombus targeting and imaging, and photothermal thrombolysis. Besides, it allowed faster release of the thrombolytic urokinase for rapidly clearing blood clots and slower release of a brown algae-derived anticoagulant fucoidan (also acting as a P-selectin ligand) for prevention of thrombosis regeneration. The nanocomposite is thus a new and advanced theranostic platform for targeted thrombolytic therapy.
Assuntos
Nanocompostos , Nanopartículas , Trombose , Anticoagulantes/farmacologia , Linhagem Celular Tumoral , Meios de Contraste , Fibrinolíticos/farmacologia , Humanos , Verde de Indocianina , Fototerapia , Medicina de Precisão , Dióxido de Silício , Nanomedicina Teranóstica , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológicoRESUMO
Near-infrared (NIR)-light-modulated photothermal thrombolysis has been investigated to overcome the hemorrhage danger posed by clinical clot-busting substances. A long-standing issue in thrombosis fibrinolytics is the lack of lesion-specific therapy, which should not be ignored. Herein, a novel thrombolysis therapy using photothermal disintegration of a fibrin clot was explored through dual-targeting glycol chitosan/heparin-decorated polypyrrole nanoparticles (GCS-PPY-H NPs) to enhance thrombus delivery and thrombolytic therapeutic efficacy. GCS-PPY-H NPs can target acidic/P-selectin high-expression inflammatory endothelial cells/thrombus sites for initiating lesion-site-specific thrombolysis by hyperthermia using NIR irradiation. A significant fibrin clot-clearance rate was achieved with thrombolysis using dual-targeting/modality photothermal clot disintegration in vivo. The molecular level mechanisms of the developed nanoformulations and interface properties were determined using multiple surface specific analytical techniques, such as particle size distribution, zeta potential, electron microscopy, Fourier-transform infrared spectroscopy (FTIR), wavelength absorbance, photothermal, immunofluorescence, and histology. Owing to the augmented thrombus delivery of GCS-PPY-H NPs and swift treatment time, dual-targeting photothermal clot disintegration as a systematic treatment using GCS-PPY-H NPs can be effectively applied in thrombolysis. This novel approach possesses a promising future for thrombolytic treatment.