RESUMEN
The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nanogels, which effectively reduced the cytotoxicity of protamine. The protamine/PAA-b-PNIPAAm nanogels were responsive to the stimuli including temperature, pH, and enzyme due to disaggregation of PAA-b-PNIPAAm, change in random coil/α-helix conformation of protamine, and enzymatic hydrolysis of the protein. Changing the pH from 7.4 to a lowered pHe (6.5-5.0) resulted in an increase in mean particle size and smartly converted surface charge from negative to positive. The cationic nanogels easily passed through the cell membrane and enhanced intracellular localization and accumulation of doxorubicin-loaded nanogels in multidrug resistant MCF-7/ADR breast cancer cells. Cold shock treatment triggered rapid intracellular release of doxorubicin against P-glycoprotein (Pgp)-mediated drug efflux, showing significantly improved anticancer efficacy as compared with free DOX. Furthermore, the nanogels were able to carry a rose bengal photosensitizer and caused significant damage to the multidrug resistant cancer cells under irradiation. The cationic nanogels with stimuli-responsive properties show promise as drug carrier for chemotherapy and photodynamic therapy against cancers.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Portadores de Fármacos/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Fármacos Fotosensibilizantes/administración & dosificación , Resinas Acrílicas/química , Neoplasias de la Mama/patología , Permeabilidad de la Membrana Celular , Doxorrubicina/administración & dosificación , Geles/química , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Nanopartículas/química , Fotoquimioterapia/métodos , Protaminas/química , Temperatura , Microambiente Tumoral/efectos de los fármacosRESUMEN
Bioactive composites that enable the formation of calcium phosphates have received increased attention over the last decade, in the development of osteoconductive biomaterials for orthopaedic applications. In this work, tripolyphosphate (TPP)-cross-linked chitosan/gelatin composites (TPP-CG) were prepared for the growth of shape- and size-controlled calcium phosphates on/in the composites. The mineralization pattern of the composites, after soaking in the Ca(OH)(2) aqueous solution, clearly demonstrated oriented, needle-like nanocrystallites of calcium phosphates in the matrix with especially high Ca/P molar ratio (3.98) as detected by energy dispersive X-ray spectroscopy (EDX) analysis. Subsequent to mineralization in a simulated body fluid (SBF), the mineralized composites showed micro-scaled spherical aggregates deposited on the surface and granule-like nanocrystallites grew in the matrix. The Ca/P molar ratio (1.72) and X-ray diffraction pattern of the nanocrystallites grown in the composites were similar to those of hydroxyapatite (HAp). Osteoblastic differentiation of ROS cells cultured on the mineralized composites allowed an enhanced expression of the chosen osteogenic marker (alkaline phosphatase, ALPase). These results indicated that the composites mineralized with micro- and nano-scaled calcium phosphates with various structural features make them attractive for bone tissue engineering applications.
Asunto(s)
Apatitas/química , Sustitutos de Huesos/química , Polifosfatos/química , Materiales Biocompatibles/química , Líquidos Corporales/química , Fosfatos de Calcio/química , Línea Celular , Quitosano/química , Gelatina/química , Humanos , Células Madre Mesenquimatosas/química , Células Madre Mesenquimatosas/citología , Espectrometría por Rayos X , Ingeniería de Tejidos , Difracción de Rayos XRESUMEN
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.
Asunto(s)
Neoplasias Pulmonares/terapia , Nanopartículas/química , Terapia Fototérmica/métodos , Polímeros/química , Polisacáridos/química , Pirroles/química , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular Tumoral , Humanos , Luz , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Nanopartículas/efectos de la radiación , Nanopartículas/uso terapéutico , Selectina-P/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Active and intelligent packaging films with multiple functions including antioxidant, antibacterial and colorimetric pH indicator properties were developed by incorporating Clitoria ternatea (CT) extract into gellan gum (G) film. G enhanced the stability of CT anthocyanins and allowed the anthocyanins to release from G film in a pH-responsive behavior. Heat-treated soy protein isolate (HSPI) was able to interact with G and CT anthocyanins through the formation of electrostatic forces and covalent bonds. G film blended with HSPI greatly reduced the swelling capacity of G/HSPI composite film and controlled the anthocyanins release at pH greater than 6.0. The physical and mechanical properties of G films such as hydrophobicity, water vapor permeability, swelling capacity and tensile strength were also significantly modified by addition of HSPI to G films. The smart films changed their color with the increase of total volatile basic nitrogen (TVBN) values during progressive spoilage of shrimp, revealing their potential application for monitoring seafood freshness.
Asunto(s)
Antocianinas/química , Clitoria/química , Embalaje de Alimentos/métodos , Calidad de los Alimentos , Extractos Vegetales/química , Polisacáridos Bacterianos/química , Materiales Inteligentes/química , Color , Colorimetría/métodos , Concentración de Iones de Hidrógeno , Indicadores y Reactivos , Permeabilidad , Alimentos Marinos , Proteínas de Soja/química , Electricidad Estática , Vapor , Resistencia a la TracciónRESUMEN
The use of conductive materials to promote the activity of electrically responsive cells is an effective means of accelerating wound healing. This article focuses on recent advancements in conductive materials, with emphasis on overviewing their incorporation with non-conducting polymers to fabricate electroactive wound dressings. The characteristics of these electroactive dressings are deliberated, and the mechanisms on how they accelerate the wound healing process are discussed. Potential directions for the future development of electroactive wound dressings and their potential in monitoring the course of wound healing in vivo concomitantly are also proposed.
Asunto(s)
Vendajes , Cicatrización de Heridas , Conductividad Eléctrica , PolímerosRESUMEN
Nanofiber-based materials have recently gained increasing attention in food packaging, drug delivery, and biomedical applications. In this study, a multi-nanoï¬bers composite film was developed based on bacterial cellulose nanofiber (BCNF)/chitin nanofiber (CNF) hybridization. The nanofibers were responsible for the formation of well-dispersed curcumin (Cur) micro/nanoparticles in the nanocomposite films. The release of Cur from the films were affected by CNF and the sizes of Cur particles formed in situ. The Cur particles reduced tensile strength and increased water vapor permeability of BCNF film. However, CNF improved the mechanical strength and barrier property of the Cur/BCNF/CNF composite film. Moreover, the multi-nanoï¬bers composite film showed excellent dynamic antioxidant capacity and antibacterial activity, as well as was capable to monitor pH change and trace amount of boric acid. Results of this study suggested that the Cur/BCNF/CNF composite film can be used as a smart and active food packaging material.
Asunto(s)
Celulosa/química , Quitina/química , Nanofibras/química , Animales , Antibacterianos/farmacología , Antioxidantes/farmacología , Curcumina/farmacología , Decapodiformes/metabolismo , Portadores de Fármacos , Liberación de Fármacos , Escherichia coli/efectos de los fármacos , Embalaje de Alimentos , Microesferas , Nanocompuestos/química , Nanopartículas/química , Staphylococcus aureus/efectos de los fármacos , Resistencia a la TracciónRESUMEN
Chitosan is suggested as no or low toxicity and biocompatible biomaterial. Digestion of chitosan to reduce molecular weight and formulate nanoparticle was generally used to improve efficiency for DNA or protein delivery. However, the toxicity of low-molecular-weight chitosan (LMWCS) towards freshwater fishes has not been well evaluated. Here, we reported the toxic mechanism of LMWCS using zebrafish (Danio rerio) liver (ZFL) cell line, zebrafish larvae, and adult fish. LMWCS rapidly induced cytotoxicity of ZFL cells and death of zebrafish. Cell membrane damaged by LMWCS reduced cell viability. Damaged membrane of epithelial cell in zebrafish larvae induced breakage of the yolk. Adult fish exhibited hypoxia before death due to multiple damages induced by LMWCS. Although the toxicity of LMWCS was revealed in zebrafish model, the toxicity was only present in pH < 7 and easy be neutralized by other negative ions. Collectively, these data improved a new understanding of LMWCS properties.
Asunto(s)
Materiales Biocompatibles/toxicidad , Quitosano/toxicidad , Larva/efectos de los fármacos , Hígado/efectos de los fármacos , Pez Cebra/metabolismo , Animales , Línea Celular , Membrana Celular/efectos de los fármacos , Quitosano/análogos & derivados , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Peso Molecular , Pruebas de ToxicidadRESUMEN
Hydroxypropyl chitosan (HPCS) has recently attracted increasing attention in biomedical applications because it has enhanced water solubility, excellent biocompatibility, and better antioxidant and antibacterial activities compared with chitosan. However, HPCS doesn't meet the mechanical strength requirement in bone tissue engineering and is not suitable for cell adhesion and growth because of its hydrophilic nature and low crystallinity. In this study, nano-scaled hydroxyapatite (n-HA) and HPCS were synthesized, respectively, and then n-HA/HPCS nanocomposite scaffolds were developed by incorporating n-HA into HPCS matrix accompanied with crosslinking of HPCS by a naturally occurring compound, genipin (GP), which in turn greatly altered the hydrophilicity and mechanical properties. The nanocomposite scaffolds showed an open structure with interconnected pores and a rough morphology with n-HA inserted in the GP-crosslinked HPCS matrix. The porosity, swelling capacity, compressive strength, fluorescence emission and degradation rate can be regulated by varying GP concentrations and n-HA contents. An osteoconductive and osteogenic marine algae polysaccharide, fucoidan, was further adsorbed to the composite scaffolds via electrostatic interactions. Incorporation of n-HA and adsorption of FD into the composite scaffolds increased ALP activity in 7F2 osteoblast cells and promoted their mineralization. The FD-adsorbed n-HA/HPCS composite scaffolds can be a potential biomaterial for BTE applications.
Asunto(s)
Huesos/citología , Quitosano/química , Durapatita/química , Iridoides/química , Polisacáridos/química , Ingeniería de Tejidos , Andamios del Tejido/química , Adsorción , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Regeneración Ósea/efectos de los fármacos , Huesos/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular , Fuerza Compresiva , Descubrimiento de Drogas , Humanos , Nanocompuestos/química , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Porosidad , Propiedades de SuperficieRESUMEN
Vaccination is an effective medical intervention for preventing disease. However, without an adjuvant, most subunit vaccines are poorly immunogenic. This work develops a bioinspired nanocomposite hyaluronic acid hydrogel system that incorporates N-trimethyl chitosan nanoparticles (TMC/NPs) that carry a model subunit vaccine ovalbumin (OVA) that can elicit a potent and prolonged antigen-specific humoral response. Experimental results indicate that the nanocomposite hydrogel system (NPs-Gel) can retain a large proportion of its TMC/NPs that are bonded by covalent/electrostatic interactions and extend the release of the encapsulated OVA, enabling their localization at the site of hydrogel injection. The positively charged TMC/NPs can be effectively internalized by dendritic cells, significantly augmenting their maturation, suggesting that TMC can function as an adjuvant-based OVA delivery system. Upon subcutaneous implantation in mice, the NPs-Gel acts as an in situ depot that recruits and concentrates immune cells. The TMC/NPs that do not have any specific interactions with the hydrogel network are released rapidly and internalized by the neighboring immune cells, providing a priming dose, while those retained inside the NPs-Gel are ingested by the recruited and concentrated immune cells over time, acting as a booster dose, eliciting high titers of OVA-specific antibody responses. These experimental results suggest particulate vaccines that are integrated in such a bioinspired hydrogel system may be used as single-injection prime-boost vaccines, enabling effective and persistent humoral immune responses.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Quitosano/administración & dosificación , Inmunidad Humoral/efectos de los fármacos , Nanogeles/administración & dosificación , Ovalbúmina/administración & dosificación , Vacunas de Subunidad/administración & dosificación , Células 3T3 , Adyuvantes Inmunológicos/farmacología , Animales , Quitosano/farmacología , Sistemas de Liberación de Medicamentos , Inyecciones , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/farmacología , Vacunas de Subunidad/farmacologíaRESUMEN
Fibrinolytic treatments for venous or arterial thrombotic syndromes using systemic administration of thrombolytics, such as streptokinase, can induce life-threatening bleeding complications. In this study, we offer the first proof of concept for a targeted photothermal fibrin clot prevention and reduction technology using macrophages loaded with polypyrrole-polyethylenimine nanocomplexes (Ppy-PEI NCs) and subjected to near-infrared radiation (NIR). We first show that the developed Ppy-PEI NCs could be taken up by defensive macrophages in vitro through endocytosis. The Ppy-PEI NCs generated local hyperthermia upon NIR treatment, which appeared to produce reactive oxygen species in Ppy-PEI NC-loaded macrophages. Preliminary evidence of efficacy as an antithrombotic tool is provided, in vitro, using fibrinogen-converted fibrin clots, and in vivo, in a rat femoral vascular thrombosis model generated by exposure to ferric chloride substance. The in vivo biocompatibility, photothermal behavior, biodistribution, and histological observation of cellular interactions with the Ppy-PEI NCs in the rat model provide rationale in support of further preclinical studies. This Ppy-PEI NC/NIR-based method, which uses a unique macrophage-guided targeting approach to prevent and lyse fibrin clots, may potentially overcome some of the disadvantages of current thrombolytic treatments. STATEMENT OF SIGNIFICANCE: Fibrinolytic treatments for venous or arterial thrombotic syndromes using systemic administration of thrombolytics, such as streptokinase, can induce life-threatening bleeding complications. In this study, we offer the first proof of concept for a targeted photothermal fibrin clot reduction technology using macrophages loaded with polypyrrole-polyethylenimine nanocomplexes (Ppy-PEI NCs) and subjected to near-infrared radiation (NIR). We first show that the developed Ppy-PEI NCs can be taken up by defensive macrophages in vitro through endocytosis. The Ppy-PEI NCs generated local hyperthermia upon NIR treatment, which appeared to produce reactive oxygen species in Ppy-PEI NC-loaded macrophages. Preliminary evidence of efficacy as an antithrombotic tool is provided, in vitro, using fibrinogen-converted fibrin clots, and in vivo, in a rat femoral vascular thrombosis model generated by exposure to ferric chloride substance. The in vivo biocompatibility, photothermal behavior, biodistribution, and histological observation of cellular interactions with the Ppy-PEI NCs in the rat model provide rationale in support of further preclinical studies. This Ppy-PEI NC/NIR-based method, which uses a unique macrophage-guided targeting approach to disintegrate fibrin clots, may potentially overcome some of the disadvantages of current thrombolytic treatments.
Asunto(s)
Materiales Biomiméticos/química , Fibrina/metabolismo , Hipertermia Inducida , Macrófagos/citología , Nanopartículas/química , Polietileneimina/farmacología , Polímeros/farmacología , Pirroles/farmacología , Trombosis/prevención & control , Animales , Endocitosis , Humanos , Rayos Infrarrojos , Ratones , Ratones Endogámicos ICR , Nanopartículas/ultraestructura , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Temperatura , Distribución TisularRESUMEN
In the study, chitosan (CS) was conjugated with trimethyl groups for the synthesis of N-trimethyl chitosan (TMC) polymers with different degrees of quaternization. Nanoparticles (NPs) self-assembled by the synthesized TMC and poly(gamma-glutamic acid) (gamma-PGA, TMC/gamma-PGA NPs) were prepared for oral delivery of insulin. The loading efficiency and loading content of insulin in TMC/gamma-PGA NPs were 73.8 +/- 2.9% and 23.5 +/- 2.1%, respectively. TMC/gamma-PGA NPs had superior stability in a broader pH range to CS/gamma-PGA NPs; the in vitro release profiles of insulin from both test NPs were significantly affected by their stability at distinct pH environments. At pH 7.0, CS/gamma-PGA NPs became disintegrated, resulting in a rapid release of insulin, which failed to provide an adequate retention of loaded insulin, while the cumulative amount of insulin released from TMC/gamma-PGA NPs was significantly reduced. At pH 7.4, TMC/gamma-PGA NPs were significantly swelled and a sustained release profile of insulin was observed. Confocal microscopy confirmed that TMC40/gamma-PGA NPs opened the tight junctions of Caco-2 cells to allow the transport of insulin along the paracellular pathway. Transepithelial-electrical-resistance measurements and transport studies implied that CS/gamma-PGA NPs can be effective as an insulin carrier only in a limited area of the intestinal lumen where the pH values are close to the p K a of CS. In contrast, TMC40/gamma-PGA NPs may be a suitable carrier for transmucosal delivery of insulin within the entire intestinal tract.
Asunto(s)
Quitosano/química , Portadores de Fármacos/química , Insulina/química , Insulina/farmacología , Nanopartículas/química , Ácido Poliglutámico/análogos & derivados , Polímeros/química , Administración Oral , Animales , Células CACO-2 , Portadores de Fármacos/síntesis química , Impedancia Eléctrica , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Insulina/administración & dosificación , Metilación , Modelos Moleculares , Conformación Molecular , Ácido Poliglutámico/química , Polímeros/síntesis química , SolubilidadRESUMEN
Bacterial cellulose (BC) is a biopolymer composed of nanofibers which has excellent film-forming ability. However, BC do not have antibacterial or antioxidant activity, thus limiting the applicability of BC for food and biomedical applications. In this study, flavonoid silymarin (SMN) and zein were assembled into spherical SMN-Zein nanoparticles that could be effectively adsorbed onto BC nanofibers. SMN-Zein nanoparticles greatly changed the wettability and swelling property of BC films due to the formation of nanoparticles/nanofibers nanocomposites. SMN-Zein nanoparticles enhanced the release of sparingly soluble silymarin from the nanocomposite films. The active films showed more effective antioxidant and antibacterial activities as compared with pure BC films and thus were able to protect salmon muscle from deterioration and lipid oxidation. These findings suggest that the nanoparticle/nanofiber composites may offer a suitable platform for modification of BC films with improved drug release properties and biological activities.
Asunto(s)
Antibacterianos/química , Antioxidantes/química , Celulosa/análogos & derivados , Conservación de Alimentos/métodos , Nanocompuestos/química , Silimarina/química , Zeína/química , Antibacterianos/farmacología , Antioxidantes/farmacología , Liberación de Fármacos , Productos Pesqueros , Gluconacetobacter xylinus/química , Nanofibras/química , Nanopartículas/química , Polisacáridos Bacterianos/química , Pseudomonas/efectos de los fármacos , Silimarina/farmacología , Staphylococcus/efectos de los fármacos , Humectabilidad , Zeína/farmacologíaRESUMEN
Bone tissue engineering holds great promise and clinical efficacy for the regeneration of bone defects. In this study, an amphoteric N,O-carboxymethyl chitosan (NOCC) and fucoidan (FD) were covalently cross-linked via an amidation reaction to synthesize NOCC/FD composite hydrogels. The hydrogels were lyophilized and then three-dimensional scaffolds with interconnected macropores were obtained. To enhance the mechanical properties and osteogenic activity, the NOCC/FD scaffolds were biomineralized for the growth of hydroxyapatite crystals. A comparative assessment of the structures, morphologies, and physical properties of the original and mineralized scaffolds were performed by SEM, EDS, X-ray diffraction and FT-IR analysis. FD regulated the growth of hydroxyapatite nanocrystallites (n-HAp) and thus the NOCC/FD scaffolds showed better mineralization efficiency than NOCC scaffolds. The compressive strength of the scaffolds was greatly enhanced after mineralization with n-HAp. The n-HAp/NOCC/FD scaffolds enhanced the proliferation, ALP activity, and mineralization of osteoblast cells more strongly than the original and mineralized NOCC scaffolds. Hence, the n-HAp-mineralized NOCC/FD scaffolds may prove to be an excellent and versatile scaffold for bone tissue engineering.
Asunto(s)
Materiales Biocompatibles/farmacología , Huesos/citología , Quitosano/química , Minerales/metabolismo , Nanocompuestos/química , Polisacáridos/química , Andamios del Tejido/química , Adsorción , Fosfatasa Alcalina/metabolismo , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/metabolismo , Proliferación Celular/efectos de los fármacos , Fuerza Compresiva , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Ingeniería de TejidosRESUMEN
A natural compound, aglycone geniposidic acid (aGSA), originated from the fruits of Gardenia jasminoides ELLIS was used for the fixation of collagenous tissues. The presumed crosslinking reaction mechanism of collagenous tissues with aGSA was inferred by reacting aGSA with a bifunctional amine, 1,6-hexanediamine, using a series of (1)H NMR, FT-IR, and UV/Vis spectra analyses. aGSA reacted with 1,6-hexanediamine by a nucleophilic attack on the olefinic carbon atom at C-2 of deoxyloganin aglycone, followed by opening the dihydropyran ring to form heterocyclic amine compounds. It is inferred that aGSA may form intramolecular and intermolecular crosslinks with a heterocyclic structure within collagen fibers in tissues. The degrees of tissue fixation by aGSA at different pH values were investigated by examining the fixation indices and denaturation temperatures of test samples. It was found that the fixation indices and denaturation temperatures of test samples fixed at neutral or basic pH (pH 7.4 or pH 8.5) were significantly greater than at acidic pH (pH 4.0). The results obtained in this study may be used to elucidate the crosslinking mechanism and optimize the fixation process for developing bioprostheses fixed by aGSA.
Asunto(s)
Bioprótesis , Colágeno/química , Reactivos de Enlaces Cruzados/química , Gardenia/química , Glucósidos/química , Iridoides/química , Adhesivos Tisulares/química , Glucósidos/síntesis química , Concentración de Iones de Hidrógeno , Glucósidos Iridoides , Iridoides/síntesis químicaRESUMEN
Cancer cells exhibit specific physiological differences compared to normal cells. Most surface membranes of cancer cells are characterized by high expression of given protein receptors, such as albumin, transferrin, and growth factors that are also present in the plasma of patients themselves, but are lacking on the surface of normal cells. These distinct features between cancer and normal cells can serve as a niche for developing specific treatment strategies. Near-infrared (NIR)-light-triggered therapy platforms are an interesting novel avenue for use in clinical nanomedicine. As a photothermal agent, conducting polymer nanoparticles, such as polypyrrole (PPy), of great NIR light photothermal effects and good biocompatibility, show promising applications in cancer treatments through the hyperthermia mechanism. Autologous plasma proteins coated PPy nanoparticles for hyperthermia therapy as a novel core technology platform to treat cancers through secreted protein acid and rich in cysteine targeting are developed here. This approach can provide unique features of specific targeting toward cancer cell surface markers and immune transparency to avoid recognition and attack by defense cells and achieve prolonged circulation half-life. This technology platform unveils new clinical options for treatment of cancer patients, supporting the emergence of innovative clinical products.
Asunto(s)
Proteínas Sanguíneas , Materiales Biocompatibles Revestidos , Sistemas de Liberación de Medicamentos/métodos , Hipertermia Inducida/métodos , Nanoestructuras , Neoplasias Experimentales/terapia , Animales , Proteínas Sanguíneas/química , Proteínas Sanguíneas/farmacología , Línea Celular Tumoral , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanoestructuras/química , Nanoestructuras/uso terapéutico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The development of a novel, three-dimensional, macroporous artificial extracellular matrix (AECM) based on chondroitin sulfate (ChS)-chitosan (Chito) combination is reported. The composite AECM composed of ChS-Chito conjugated network was prepared by a homogenizing interpolyelectrolyte complex/covalent conjugation technique through co-crosslinked with N,N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide (EDC) and N-hydroxysuccinimide (NHS). In contrast to EDC/NHS, two different reagents, calcium ion and glutaraldehyde, were used to react with ChS or Chito for the preparation of ChS-Chito composites containing crosslinked ChS or Chito network in the matrix. The stability and in vitro enzymatic degradability of the glutaraldehyde-, EDC/NHS-, and Ca2+ -crosslinked ChS-Chito composite AECMs were all investigated in this study. The results showed that crosslinking improved the stability of prepared ChS-Chito AECMs in physiological buffer solution (PBS) and provided superior protective effect against the enzymatic hydrolysis of ChS, compared with their non-crosslinked counterpart. Because ChS was a heparin-like glycosaminoglycan (GAG), the ChS-Chito composite AECMs appeared to promote binding efficiency for basic fibroblast growth factor (bFGF). The bFGF releasing from the ChS-Chito composite AECMs retained its biological activity as examined by the in vitro proliferation of human fibroblast, depending on the crosslinking mode for the preparation of these composite AECMs. Histological assay showed that the EDC/NHS-crosslinked ChS-Chito composite AECM, after incorporated with bFGF, was biodegradable and could result in a significantly enhanced vascularization effect and tissue penetration. These results suggest that the ChS-Chito composite AECMs fabricated in this study may be a promising approach for tissue-engineering application.
Asunto(s)
Materiales Biocompatibles/aislamiento & purificación , Quitosano/aislamiento & purificación , Sulfatos de Condroitina/aislamiento & purificación , Matriz Extracelular , Factor 2 de Crecimiento de Fibroblastos/administración & dosificación , Animales , Materiales Biocompatibles/química , Biodegradación Ambiental , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quitosano/química , Sulfatos de Condroitina/química , Reactivos de Enlaces Cruzados , Estabilidad de Medicamentos , Matriz Extracelular/química , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Ensayo de Materiales , Microscopía Electrónica de Rastreo , Ratas , Ratas Wistar , Ingeniería de Tejidos , Difracción de Rayos XRESUMEN
A novel injectable-chitosan-based delivery system with low cytotoxicity was fabricated in the study. The chitosan microspheres with small particle size, low crystallinity and good sphericity were prepared by a spray-drying method followed by treating with a crosslinker. In the study, a naturally occurring crosslinking reagent (genipin), which has been used in herbal medicine and in the production of food dyes, was used to crosslink the chitosan microspheres. The glutaraldehyde-crosslinked counterparts were used as a control. Histological study of the genipin-crosslinked chitosan microspheres injected intramuscularly into the skeletal muscle of a rat model showed a less inflammatory reaction than its glutaraldehyde-crosslinked counterparts. The results of the scanning electron microscopic examination indicated that the glutaraldehyde-crosslinked chitosan microspheres retrieved at 12-week postoperatively were already degraded into a loose and porous structure. However, the degradation of the genipin-crosslinked chitosan microspheres was not significant after 20 weeks of implantation. The results of the study demonstrated that the genipin-crosslinked chitosan microspheres have a superior biocompatibility and a slower degradation rate than the glutaraldehyde-crosslinked chitosan microspheres. Accordingly, the genipin-crosslinked chitosan microspheres may be a suitable polymeric carrier for long-acting injectable drug delivery.
Asunto(s)
Materiales Biocompatibles , Biodegradación Ambiental , Quitina/administración & dosificación , Implantes de Medicamentos , Animales , Secuencia de Carbohidratos , Quitina/análogos & derivados , Quitosano , Microscopía Electrónica de Rastreo , Datos de Secuencia Molecular , Ratas , Ratas Wistar , Difracción de Rayos XRESUMEN
A novel chitin-based microsphere was developed for anti-cancer drug-delivery purpose in the present study. These biodegradable microspheres were prepared by directly blending chitin with different contents of poly(D,L-lactide-co-glycolide 50:50) (PLGA 50/50) in dimethylacetamide-lithium chloride solution, and following it by coagulating in water via wet phase inversion. Scanning electron microscopy (SEM) micrography of the blend microsphere showed that there are numerous PLGA particulates homogeneously dispersed in chitin matrix, suggesting the occurrence of obvious phase separation from the blended chitin and PLGA 50/50 phase due to their thermodynamic incompatibility. Degradation of the chitin/PLGA 50/50 blend microsphere depends on the surface erosion of chitin phase and bulk hydrolysis of PLGA phase, according to the examinations of SEM and differential scanning calorimetry studies. Weight loss of the chitin/PLGA 50/50 blend microsphere increases with the increase of chitin content in the microsphere. A two-phase drug-release model is observed from the release of chlorambucil from chitin/PLGA 50/50 blend microspheres. The initial stage of drug-release rate increases with the increased chitin content due to the hydration and surface erosion of hydrophilic chitin phase; however, the following stage of slow release is sustained for several days, mainly contributed by the bulk hydrolysis of hydrophobic PLGA phase. In conclusion, such a chitin/PLGA 50/50 blend microsphere is novel and interesting, and may be used as a special drug-delivery system.
Asunto(s)
Materiales Biocompatibles , Quitina , Ácido Láctico , Ácido Poliglicólico , Polímeros , Biodegradación Ambiental , Clorambucilo/administración & dosificación , Sistemas de Liberación de Medicamentos , Técnicas In Vitro , Ensayo de Materiales , Microscopía Electrónica de Rastreo , Microesferas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , AguaRESUMEN
Novel chitin/PLGAs and chitin/PLA based microspheres were developed for the delivery of protein. These biodegradable microspheres were prepared by polymers blending and wet phase-inversion methods. The parameters such as selected non-solvents, temperature of water and ratio of polylactide to polyglycolide were adjusted to improve thermodynamic compatibility of individual polymer (chitin and PLGAs or chitin/PLA), which affects the hydration and degradation properties of the blend microspheres. Triphasic pattern of drug release model is observed from the release of protein from the chitin/PLGAs and chitin/PLA microspheres: the initially fast release (the first phase), the following slow release (the second phase) and the second burst release (the third phase). Formulations of the blends, which are based on the balance among the hydration rate of the chitin phase and degradation of chitin/PLA and PLGA phase, can lead to a controllable release of bovine serum albumin (BSA). In conclusion, such a chitin/PLGA 50/50 microsphere is novel and interesting, and may be used as a protein delivery system.
Asunto(s)
Quitina/química , Materiales Biocompatibles Revestidos/química , Preparaciones de Acción Retardada/química , Ácido Láctico/química , Microesferas , Vehículos Farmacéuticos/química , Ácido Poliglicólico/química , Polímeros/química , Albúmina Sérica Bovina/administración & dosificación , Albúmina Sérica Bovina/química , Implantes Absorbibles , Adsorción , Materiales Biocompatibles Revestidos/síntesis química , Materiales Biocompatibles Revestidos/aislamiento & purificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/aislamiento & purificación , Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodos , Ensayo de Materiales , Conformación Molecular , Movimiento (Física) , Vehículos Farmacéuticos/síntesis química , Vehículos Farmacéuticos/aislamiento & purificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Proteínas/administración & dosificación , Proteínas/química , Propiedades de SuperficieRESUMEN
Catalase is an antioxidant enzyme abundant in natural resources. However, the enzyme is usually inactivated by gastric acid and digestive enzymes after oral ingestion. In this study, carboxymethyl chitosan (CM-chitosan) and hyaluronic acid (HA) conjugate hydrogel microspheres have been prepared by an emulsion cross-linking technique to retain the activity of catalase in simulated gastrointestinal (GI) fluids. Cross-linking reduced the swelling capability and increased the resistance toward hyaluronidase digestion of prepared HA-CM-chitosan hydrogel microspheres. Catalase entrapped in the hydrogel microspheres exhibited superior stability over a wide pH range (pH 2.0 and 6.0-8.0) as compared to the native enzyme. The entrapped catalase was also protected against degradation by digestive enzymes. Following the treatments, the catalase-loaded microspheres, in contrast to native catalase, could effectively decrease the intracellular H2O2 level and protect HT-29 colonic epithelial cells against H2O2-induced oxidative damage to preserve cell viability. These results suggested that the HA-CM-chitosan hydrogel microspheres can be used for entrapment, protection and intestinal delivery of catalase for H2O2 scavenging.