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1.
Pharmaceutics ; 14(5)2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35631646

RESUMO

The rapidly growing interest in the application of nanoscience in the future design of radiopharmaceuticals and the development of nanosized radiopharmaceuticals in the late 2000's, resulted in the creation of a Coordinated Research Project (CRP) by the International Atomic Energy Agency (IAEA) in 2014. This CRP entitled 'Nanosized delivery systems for radiopharmaceuticals' involved a team of expert scientist from various member states. This team of scientists worked on a number of cutting-edge areas of nanoscience with a focus on developing well-defined, highly effective and site-specific delivery systems of radiopharmaceuticals. Specifically, focus areas of various teams of scientists comprised of the development of nanoparticles (NPs) based on metals, polymers, and gels, and their conjugation/encapsulation or decoration with various tumor avid ligands such as peptides, folates, and small molecule phytochemicals. The research and development efforts also comprised of developing optimum radiolabeling methods of various nano vectors using diagnostic and therapeutic radionuclides including Tc-99m, Ga-68, Lu-177 and Au-198. Concerted efforts of teams of scientists within this CRP has resulted in the development of various protocols and guidelines on delivery systems of nanoradiopharmaceuticals, training of numerous graduate students/post-doctoral fellows and publications in peer reviewed journals while establishing numerous productive scientific networks in various participating member states. Some of the innovative nanoconstructs were chosen for further preclinical applications-all aimed at ultimate clinical translation for treating human cancer patients. This review article summarizes outcomes of this major international scientific endeavor.

2.
Int J Biol Macromol ; 211: 639-652, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35569680

RESUMO

Polymeric hydrogels are increasingly considered as scaffolds for tissue engineering due to their extraordinary resemblance with the extracellular matrix (ECM) of many tissues. As cell adhesion is a key factor in regulating important cell functions, hydrogel scaffolds are often functionalized or loaded with a variety of bioactive molecules that can promote adhesion. Interesting biomimetic approaches exploit the properties of mussel-inspired recombinant adhesive proteins. In this work, we prepared hydrogel scaffolds with a 50%w mixture of k-carrageenan (kC) and polyvinyl alcohol (PVA), by a two-step physical gelation process, and we coated them with Perna viridis foot protein-5ß (Pvfp5ß). The mechanical and morphological properties of hydrogels were investigated both after conditioning with typical cell culture media and also after coating with the Pvfp5ß. The protein resulted strongly adsorbed onto the surface of the hydrogel and also able to penetrate in its interiors to a certain depth, mainly interacting with the kC component of the scaffold as resulted from the confocal analysis. Mouse embryonic fibroblasts NIH-3T3 were seeded on top of the hydrogels and cultured up to two weeks. The role of Pvfp5ß in promoting cell adhesion, spreading and colonization of the scaffold was demonstrated.


Assuntos
Fibroblastos , Álcool de Polivinil , Animais , Carragenina/metabolismo , Adesão Celular/fisiologia , Fibroblastos/metabolismo , Hidrogéis/metabolismo , Hidrogéis/farmacologia , Camundongos , Álcool de Polivinil/metabolismo , Proteínas Recombinantes/metabolismo , Engenharia Tecidual/métodos , Tecidos Suporte
3.
Biology (Basel) ; 11(3)2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35336790

RESUMO

The aim of the present work is the characterization of biscuit doughs enriched with pomegranate peel powder (PPP) at 3 (PPP3) and 5 (PPP5) wt% in the prospect of developing a fortified aliment as a support of the therapy of chronic inflammatory diseases of the intestinal tract. The total phenolic content of the powder was preliminarily evaluated. Then, the main compounds present in the PPP were identified by HPLC-ESI-TOF-MS analysis, being mainly hydrolysable tannins. The PPP was then treated at 180 °C for 20 min to mimic the baking treatment, and its water-soluble fraction (PPPwsf) was then added in the Caco-2 cell culture as a model of the intestinal epithelial barrier to verify its dose-dependent toxicity, ability in counteracting the oxidative stress, and anti-inflammatory action. Rheological experiments were performed to predict the macroscopic behavior of the PPP-added doughs during lamination and biscuit baking. SEM investigations gave their contribution to the microscopic comprehension of the dough structure. Finally, a consumer panel composed by thirty volunteers was enrolled to express its opinion on the sensory agreeableness of the biscuits prepared with two different concentrations of PPP compared with the reference dough. The discussion is focused on the biological effects of the main components found in the PPP.

4.
Mater Sci Eng C Mater Biol Appl ; 131: 112545, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34857257

RESUMO

Cartilage or bone regeneration approaches based on the direct injection of mesenchymal stem cells (MSCs) at the lesion site encounter several challenges, related to uncontrolled cell spreading and differentiation, reduced cell viability and poor engrafting. This work presents a simple and versatile strategy based on the synergic combination of in-situ forming hydrogels and spheroids of adipose stem cells (SASCs) with great potential for minimally invasive regenerative interventions aimed to threat bone and cartilage defects. Aqueous dispersions of partially degalactosylated xyloglucan (dXG) are mixed with SASCs derived from liposuction and either a chondroinductive or an osteoinductive medium. The dispersions rapidly set into hydrogels when temperature is brought to 37 °C. The physico-chemical and mechanical properties of the hydrogels are controlled by polymer concentration. The hydrogels, during 21 day incubation at 37 °C, undergo significant structural rearrangements that support cell proliferation and spreading. In formulations containing 1%w dXG cell viability increases up to 300% for SASCs-derived osteoblasts and up to 1000% for SASCs-derived chondrocytes if compared with control 2D cultures. The successful differentiation into the target cells is supported by the expression of lineage-specific genes. Cell-cell and cell-matrix interactions are also investigated. All formulations resulted injectable, and the incorporated cells are fully viable after injection.


Assuntos
Hidrogéis , Xilanos , Regeneração Óssea , Cartilagem , Diferenciação Celular , Glucanos , Células-Tronco
5.
Regen Biomater ; 8(5): rbab040, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34386265

RESUMO

Hydrogel wound dressings can play critical roles in wound healing protecting the wound from trauma or contamination and providing an ideal environment to support the growth of endogenous cells and promote wound closure. This work presents a self-assembling hydrogel dressing that can assist the wound repair process mimicking the hierarchical structure of skin extracellular matrix. To this aim, the co-assembly behaviour of a carboxylated variant of xyloglucan (CXG) with a peptide amphiphile (PA-H3) has been investigated to generate hierarchical constructs with tuneable molecular composition, structure, and properties. Transmission electron microscopy and circular dichroism at a low concentration shows that CXG and PA-H3 co-assemble into nanofibres by hydrophobic and electrostatic interactions and further aggregate into nanofibre bundles and networks. At a higher concentration, CXG and PA-H3 yield hydrogels that have been characterized for their morphology by scanning electron microscopy and for the mechanical properties by small-amplitude oscillatory shear rheological measurements and compression tests at different CXG/PA-H3 ratios. A preliminary biological evaluation has been carried out both in vitro with HaCat cells and in vivo in a mouse model.

6.
Polymers (Basel) ; 12(12)2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33266261

RESUMO

Ionizing radiation has become the most effective way to modify natural and synthetic polymers through crosslinking, degradation, and graft polymerization. This review will include an in-depth analysis of radiation chemistry mechanisms and the kinetics of the radiation-induced C-centered free radical, anion, and cation polymerization, and grafting. It also presents sections on radiation modifications of synthetic and natural polymers. For decades, low linear energy transfer (LLET) ionizing radiation, such as gamma rays, X-rays, and up to 10 MeV electron beams, has been the primary tool to produce many products through polymerization reactions. Photons and electrons interaction with polymers display various mechanisms. While the interactions of gamma ray and X-ray photons are mainly through the photoelectric effect, Compton scattering, and pair-production, the interactions of the high-energy electrons take place through coulombic interactions. Despite the type of radiation used on materials, photons or high energy electrons, in both cases ions and electrons are produced. The interactions between electrons and monomers takes place within less than a nanosecond. Depending on the dose rate (dose is defined as the absorbed radiation energy per unit mass), the kinetic chain length of the propagation can be controlled, hence allowing for some control over the degree of polymerization. When polymers are submitted to high-energy radiation in the bulk, contrasting behaviors are observed with a dominant effect of cross-linking or chain scission, depending on the chemical nature and physical characteristics of the material. Polymers in solution are subject to indirect effects resulting from the radiolysis of the medium. Likewise, for radiation-induced polymerization, depending on the dose rate, the free radicals generated on polymer chains can undergo various reactions, such as inter/intramolecular combination or inter/intramolecular disproportionation, b-scission. These reactions lead to structural or functional polymer modifications. In the presence of oxygen, playing on irradiation dose-rates, one can favor crosslinking reactions or promotes degradations through oxidations. The competition between the crosslinking reactions of C-centered free radicals and their reactions with oxygen is described through fundamental mechanism formalisms. The fundamentals of polymerization reactions are herein presented to meet industrial needs for various polymer materials produced or degraded by irradiation. Notably, the medical and industrial applications of polymers are endless and thus it is vital to investigate the effects of sterilization dose and dose rate on various polymers and copolymers with different molecular structures and morphologies. The presence or absence of various functional groups, degree of crystallinity, irradiation temperature, etc. all greatly affect the radiation chemistry of the irradiated polymers. Over the past decade, grafting new chemical functionalities on solid polymers by radiation-induced polymerization (also called RIG for Radiation-Induced Grafting) has been widely exploited to develop innovative materials in coherence with actual societal expectations. These novel materials respond not only to health emergencies but also to carbon-free energy needs (e.g., hydrogen fuel cells, piezoelectricity, etc.) and environmental concerns with the development of numerous specific adsorbents of chemical hazards and pollutants. The modification of polymers through RIG is durable as it covalently bonds the functional monomers. As radiation penetration depths can be varied, this technique can be used to modify polymer surface or bulk. The many parameters influencing RIG that control the yield of the grafting process are discussed in this review. These include monomer reactivity, irradiation dose, solvent, presence of inhibitor of homopolymerization, grafting temperature, etc. Today, the general knowledge of RIG can be applied to any solid polymer and may predict, to some extent, the grafting location. A special focus is on how ionizing radiation sources (ion and electron beams, UVs) may be chosen or mixed to combine both solid polymer nanostructuration and RIG. LLET ionizing radiation has also been extensively used to synthesize hydrogel and nanogel for drug delivery systems and other advanced applications. In particular, nanogels can either be produced by radiation-induced polymerization and simultaneous crosslinking of hydrophilic monomers in "nanocompartments", i.e., within the aqueous phase of inverse micelles, or by intramolecular crosslinking of suitable water-soluble polymers. The radiolytically produced oxidizing species from water, •OH radicals, can easily abstract H-atoms from the backbone of the dissolved polymers (or can add to the unsaturated bonds) leading to the formation of C-centered radicals. These C-centered free radicals can undergo two main competitive reactions; intramolecular and intermolecular crosslinking. When produced by electron beam irradiation, higher temperatures, dose rates within the pulse, and pulse repetition rates favour intramolecular crosslinking over intermolecular crosslinking, thus enabling a better control of particle size and size distribution. For other water-soluble biopolymers such as polysaccharides, proteins, DNA and RNA, the abstraction of H atoms or the addition to the unsaturation by •OH can lead to the direct scission of the backbone, double, or single strand breaks of these polymers.

7.
Int J Biol Macromol ; 164: 2818-2830, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853619

RESUMO

Hydrogels for complex and chronic wound dressings must be conformable, absorb and retain wound exudates and maintain hydration. They can incorporate and release bioactive molecules that can accelerate the healing process. Wound dressings have to be in contact with the wound and epidermis, even for long periods, without causing adverse effects. Hydrogel dressing formulations based on biopolymers derived from terrestrial or marine flora can be relatively inexpensive and well tolerated. In the present article hydrogel films composed by agarose (1.0 wt%), κ-carrageenan at three different concentrations (0.5, 1.0 and 1.5 wt%) and glycerol (3.0 wt%) were prepared without recourse to crosslinking agents, and characterized for their mechanical properties, morphology, swelling and erosion behavior. The films resulted highly elastic and able to absorb and retain large amounts of fluids without losing their integrity. One of the films was loaded with the aqueous extract from Cryphaea heteromalla (Hedw.) D. Mohr for its antioxidant properties. Absence of cytotoxicity and ability to reduce the oxidative stress were demonstrated on NIH-3T3 fibroblast cell cultures. These results encourage further biological evaluations to assess their impact on the healing process.


Assuntos
Antioxidantes/farmacologia , Bryopsida/química , Carragenina/química , Fibroblastos/citologia , Extratos Vegetais/farmacologia , Sefarose/química , Animais , Antioxidantes/química , Bandagens , Fenômenos Biomecânicos , Sobrevivência Celular , Elasticidade , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Metilgalactosídeos , Camundongos , Células NIH 3T3 , Extratos Vegetais/química
8.
Int J Biol Macromol ; 149: 309-319, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31987942

RESUMO

Injectable, in-situ forming kefiran gels have been developed for potential applications as implantable drug delivery devices or scaffolds for tissue regeneration. Concentrated solutions (4, 5 and 6%w) of kefiran, extracted from kefir grains, have been assessed in term of viscosity and injectability through G26 syringe needles, and for their ability to undergo gelation upon mixing with different alcohols. Propylene glycol (PG) has been selected as gelling agent because it ensures homogenous gelation in relatively short times (from few minutes up to 6 h). The investigation of the rheological behavior of kefiran/PG gels varying polymer concentration and temperature (25 °C and 37 °C) has provided interesting hints to support a possible gelation mechanism that accounts also for the observed influence of the alcohol type. Finally, the study of kefiran/PG gels has been complemented with the investigation on selected formulations of the swelling/degradation behavior upon immersion in isotonic buffer solution for up to 40 days at 37 °C; of the ability of the gels to retain and/or release two model molecules; and within vitro cell viability and cytotoxicity tests, to support the absence of toxic effects on cells induced by direct contact with the gels or by leached components from these gels.


Assuntos
Sistemas de Liberação de Medicamentos , Hidrogéis/química , Polissacarídeos/química , Álcoois/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Hidrogéis/farmacologia , Propilenoglicol/química , Reologia
9.
Biomolecules ; 11(1)2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33396401

RESUMO

Bio-hybrid hydrogels consist of a water-swollen hydrophilic polymer network encapsulating or conjugating single biomolecules, or larger and more complex biological constructs like whole cells. By modulating at least one dimension of the hydrogel system at the micro- or nanoscale, the activity of the biological component can be extremely upgraded with clear advantages for the development of therapeutic or diagnostic micro- and nano-devices. Gamma or e-beam irradiation of polymers allow a good control of the chemistry at the micro-/nanoscale with minimal recourse to toxic reactants and solvents. Another potential advantage is to obtain simultaneous sterilization when the absorbed doses are within the sterilization dose range. This short review will highlight opportunities and challenges of the radiation technologies to produce bio-hybrid nanogels as delivery devices of therapeutic biomolecules to the target cells, tissues, and organs, and to create hydrogel patterns at the nano-length and micro-length scales on surfaces.


Assuntos
Hidrogéis/química , Nanopartículas/química , Engenharia Tecidual , Hidrogéis/efeitos da radiação , Nanopartículas/efeitos da radiação , Polímeros/química , Polímeros/efeitos da radiação , Radiação Ionizante
10.
J Phys Chem A ; 123(24): 5043-5050, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31140810

RESUMO

A new method for the numerical simulation of the radiation chemistry of aqueous polymer solutions is introduced. The method makes use of a deterministic approach combining the conventional homogeneous radiation chemistry of water with the chemistry of polymer radicals and other macromolecular species. The method is applied on single-pulse irradiations of aqueous polymer solutions. The speciation of macromolecular species accounts for the variations in the number of alkyl radicals per chain, molecular weight, and number of internal loops (as a consequence of an intramolecular radical-radical combination). In the simulations, the initial polymer molecular weight, polymer concentration, and dose per pulse (function of pulse length and dose rate during the pulse) were systematically varied. In total, 54 different conditions were simulated. The results are well in line with the available experimental data for similar systems. At a low polymer concentration and a high dose per pulse, the kinetics of radical decay is quite complex for the competition between intra- and intermolecular radical-radical reactions, whereas at a low dose per pulse the kinetics is purely second-order. The simulations demonstrate the limitations of the polymer in scavenging all the radicals generated by water radiolysis when irradiated at a low polymer concentration and a high dose per pulse. They also show that the radical decay of lower-molecular-weight chains is faster and to a larger extent dominated by intermolecular radical-radical reactions, thus explaining the mechanism behind the experimentally observed narrowing of molecular weight distributions.

11.
Int J Biol Macromol ; 121: 784-795, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30342149

RESUMO

Crosslinked xyloglucan-poly(vinyl alcohol) based hydrogel films are interesting materials for wound healing applications. This work focuses on the hydrolytic degradation and consequent morphological modification of a XG-PVA film and on its interaction with cells, blood, bacteria. Biocompatibility of the film was assessed in vitro by investigating different aspects, such as cell viability, oxidative stress level, mitochondrial dysfunction and specific stress biomarkers. Partial adhesiveness was demonstrated by performing different attaching assays and phalloidin staining. Hemocompatibility of XG-PVA film after interaction with blood was evaluated by using a multi-parametric approach, including human Red Blood Cells (RBC) count, hemolytic response and platelets activation. Thrombin and fibrinogen concentrations were examined as marker of the coagulation cascade. After direct contact with human blood and peripheral blood mononuclear cells (PBMC), no evidence of cell defense response was observed. Antimicrobial activity of XG-PVA film was tested against Escherichia coli (E.coli). XG-PVA film promotes bacterial retentivity and provides mechanical protection against bacterial infiltration. After loading the film with ampicillin, an inhibitory E. coli growth zone was observed. All together these results indicate that the XG-PVA system is a promising material to be tested in vivo for wound healing applications.


Assuntos
Glucanos/química , Glucanos/farmacologia , Metilgalactosídeos/química , Cicatrização/efeitos dos fármacos , Xilanos/química , Xilanos/farmacologia , Células A549 , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Hemostasia/efeitos dos fármacos , Humanos , Hidrólise , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos
12.
Data Brief ; 21: 1950-1953, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30510982

RESUMO

In wound dressing applications, exudate absorption and retention are important properties. The data presented here assess the ability of the crosslinked xyloglucan-poly(vinyl alcohol) hydrogel films (XG-PVA), described in "Xyloglucan-based hydrogel films for wound dressing: Structure-property relationships" (Ajovalasit et al., 2018) [1] and "Biocompatibility, hemocompatibility and antimicrobial properties of xyloglucan-based hydrogel film for wound healing application" (Picone et al., 2019), to absorb and retain proteins. These properties were investigated by Comassie blue staining and electrophoresis of Fetal Serum Proteins.

13.
J Control Release ; 270: 23-36, 2018 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-29196041

RESUMO

Recent evidences suggest that insulin delivery to the brain can be an important pharmacological therapy for some neurodegenerative pathologies, including Alzheimer disease (AD). Due to the presence of the Blood Brain Barrier, a suitable carrier and an appropriate route of administration are required to increase the efficacy and safety of the treatment. Here, poly(N-vinyl pyrrolidone)-based nanogels (NG), synthetized by e-beam irradiation, alone and with covalently attached insulin (NG-In) were characterized for biocompatibility and brain delivery features in a mouse model. Preliminarily, the biodistribution of the "empty" nanocarrier after intraperitoneal (i.p.) injection was investigated by using a fluorescent-labeled NG. By fluorescence spectroscopy, SEM and dynamic light scattering analyses we established that urine clearance occurs in 24h. Histological liver and kidneys inspections indicated that no morphological alterations of tissues occurred and no immunological response was activated after NG injection. Furthermore, after administration of the insulin-conjugated nanogels (NG-In) through the intranasal route (i.n.) no alteration or immunogenic response of the nasal mucosa was observed, suggesting that the formulation is well tolerated in mouse. Moreover, an enhancement of NG-In delivery to the different brain areas and of its biological activity, measured as Akt activation levels, with reference to free insulin administration was demonstrated. Taken together, these results indicate that the synthesized NG-In enhances brain insulin delivery upon i.n. administration and strongly encourage its further evaluation as therapeutic agent against some neurodegenerative diseases.


Assuntos
Encéfalo/metabolismo , Portadores de Fármacos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Acrilatos/administração & dosagem , Acrilatos/farmacocinética , Administração Intranasal , Animais , Portadores de Fármacos/farmacocinética , Géis , Hipoglicemiantes/farmacocinética , Insulina/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Mucosa Nasal/metabolismo , Povidona/administração & dosagem , Povidona/farmacocinética
14.
Carbohydr Polym ; 179: 262-272, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29111050

RESUMO

Thin xyloglucan-based hydrogel films have been synthetized and characterized in the prospect of producing wound dressings. Polyvinyl alcohol (PVA) and glycerol (Gro) were added to have an optimal combination of softness, conformability and resilience. Physical hydrogels have been transformed into permanent covalent hydrogels by reaction with glutaraldehyde (GA). Network structure-process-property relationships are discussed on the account of the results of several complementary characterizations: FTIR, rheology, thermal analysis, morphological analysis, moisture retention and swelling measurements. Selected formulations were also subjected to preliminary in vitro cytotoxicity tests. The physical and mechanical properties of some of the xyloglucan-based hydrogel films produced, combined with absence of cytotoxicity, make them suitable candidates for integration with sensors to monitor the wound healing process and further biological investigations in animal models.


Assuntos
Curativos Hidrocoloides , Glucanos/química , Hidrogéis/química , Hidrogéis/farmacologia , Cicatrização/efeitos dos fármacos , Xilanos/química , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Glutaral/química , Glicerol/química , Humanos , Hidrogéis/síntese química , Álcool de Polivinil/química , Reologia , Relação Estrutura-Atividade , Termogravimetria
15.
Pharmaceutics ; 9(3)2017 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-28672810

RESUMO

Administered by an oral route, Furosemide (FUR), a diuretic used in several edematous states and hypertension, presents bioavailability problems, reported as a consequence of an erratic gastrointestinal absorption due to various existing polymorphic forms and low and pH-dependent solubility. A mucoadhesive sublingual fast-dissolving FUR based film has been developed and evaluated in order to optimize the bioavailability of FUR by increasing solubility and guaranteeing a good dissolution reproducibility. The Differential Scanning Calorimetry (DSC) analyses confirmed that the film prepared using the solvent casting method entrapped FUR in the amorphous state. As a solid dispersion, FUR increases its solubility up to 28.36 mg/mL. Drug content, thickness, and weight uniformity of film were also evaluated. The measured Young's Modulus, yield strength, and relative elongation of break percentage (EB%) allowed for the classification of the drug-loaded film as an elastomer. Mucoadhesive strength tests showed that the force to detach film from mucosa grew exponentially with increasing contact time up to 7667 N/m². FUR was quickly discharged from the film following a trend well fitted with the Weibull kinetic model. When applied on sublingual mucosa, the new formulation produced a massive drug flux in the systemic compartment. Overall, the proposed sublingual film enhances drug solubility and absorption, allowing for the prediction of a rapid onset of action and reproducible bioavailability in its clinical application.

16.
Biol Chem ; 398(2): 277-287, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27508963

RESUMO

Poly(N-vinyl pyrrolidone)-based-nanogels (NGs), produced by e-beam irradiation, are conjugated with monoclonal antibodies (mAb) for active targeting purposes. The uptake of immuno-functionalized nanogels is tested in an endothelial cell line, ECV304, using confocal and epifluorescence microscopy. Intracellular localization studies reveal a faster uptake of the immuno-nanogel conjugate with respect to the 'bare' nanogel. The specific internalization pathway of these immuno-nanogels is clarified by selective endocytosis inhibition experiments, flow cytometry and confocal microscopy. Active targeting ability is also verified by conjugating a monoclonal antibody which recognizes the αvß3 integrin on activated endothelial cells. Epifluorescence images of the 'wound healing assay' on ECV304 cells provide evidence of nanogels localization only in the target cells. Therefore, the immuno-nanogels produced have the potential to recognize specific cell types in heterogeneous systems, which makes them promising candidates for targeted drug delivery applications.


Assuntos
Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Portadores de Fármacos/química , Nanoestruturas/química , Anticorpos Monoclonais/metabolismo , Transporte Biológico , Linhagem Celular , Géis , Humanos , Povidona/química
17.
Mater Sci Eng C Mater Biol Appl ; 70(Pt 1): 745-752, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27770950

RESUMO

The development of growth factors is very promising in the field of tissue regeneration but specifically designed formulations have to be developed in order to enable such new biological entities (NBEs). In particular, the range of therapeutic concentrations is usually very low compared to other active proteins and the confinement in the target site can be of crucial importance. In-situ forming scaffolds are very promising solutions for minimally invasive intervention in cartilage reconstruction and targeting of NBEs. In this work injectable, in-situ forming gels of a temperature responsive partially degalactosylated xyloglucan (Deg-XG) incorporating the growth factor FGF-18 are formulated and characterized. In particular, injectability and shear viscosity at room temperature, time-to-gel at body temperature, morphology and mechanical properties of gels are investigated. The highly hydrophobic growth factor is favorably incorporated and retained by the gel. Gels undergo a slow erosion process when immersed in PBS at 37°C that opens up their porous structure. The prolonged hydrothermal treatment leads to structural rearrangements towards tougher networks with increased dynamic shear modulus. Preliminary biological evaluations confirm absence of cytotoxicity and the ability of these scaffolds to host cells and promote their proliferation.


Assuntos
Cartilagem/fisiologia , Fenômenos Químicos , Fatores de Crescimento de Fibroblastos/farmacologia , Géis/química , Glucanos/química , Fenômenos Mecânicos , Xilanos/química , Animais , Cartilagem/efeitos dos fármacos , Bovinos , Proliferação de Células/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Glucanos/síntese química , Injeções , Peso Molecular , Tecidos Suporte/química , Viscosidade , Xilanos/síntese química
18.
Molecules ; 21(11)2016 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-27886088

RESUMO

(1) Background: A new family of nanosystems able to discern between normal and tumor cells and to release a therapeutic agent in controlled way were synthetized by e-beam irradiation. This technique permits to obtain biocompatible, sterile, carboxyl-functionalized polyvinylpyrrolidone (PVP-co-acrylic acid) nanogels (NGs); (2) Methods: Here, we performed a targeting strategy based on the recognition of over-expressed proteins on tumor cells, like the folate receptor. The selective targeting was demonstrated by co-culture studies and flow cytometry analysis, using folate conjugated NGs. Moreover, nanoparticles were conjugated to a chemotherapeutic drug or to a pro-apoptotic siRNA through a glutathione sensitive spacer, in order to obtain a controlled release mechanism, specific for cancer cells. The drug efficiency was tested on tumor and healthy cells by flow cytometric analysis, confocal and epifluorescence microscopy and cytotoxicity assay; the siRNA effect was investigated by RNAi experiment; (3) Results: The data obtained showed that the use of NGs permits a faster cargo release in cancer cells, in response to high cytosolic glutathione level, also improving their efficacy; (4) Conclusion: The possibility of releasing biological molecules in a controlled way and to recognize a specific tumor target allows overcoming the typical limits of the classic cancer therapy.


Assuntos
Antioxidantes/farmacologia , Doxorrubicina/farmacologia , Neoplasias/metabolismo , Polietilenoglicóis/química , Polietilenoimina/química , RNA Interferente Pequeno/farmacologia , Animais , Antioxidantes/química , Linhagem Celular Tumoral , Ácido Fólico/química , Ácido Fólico/metabolismo , Transportadores de Ácido Fólico/antagonistas & inibidores , Células HeLa , Humanos , Camundongos , Células NIH 3T3 , Nanogéis , Nanopartículas/química , Neoplasias/tratamento farmacológico , Oxirredução/efeitos dos fármacos , Tamanho da Partícula , Polietilenoglicóis/farmacologia , Polietilenoimina/farmacologia , Povidona/química , Povidona/farmacologia
19.
Carbohydr Polym ; 152: 382-390, 2016 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-27516285

RESUMO

Partially degalactosylated xyloglucan from tamarind seeds (Deg-XG) is a very appealing biopolymer for the production of in situ gelling systems at physiological temperature. In this work, we observe that the morphology of hydrogels evolves towards high degrees of structural organization with time, yielding to dense stacks of thin membranes within 24h of incubation at 37°C. We also explore the possibility offered by gamma irradiation of controlling the time scale of this phenomenon, the final morphology and mechanical properties of the system. Structural and molecular modifications of Deg-XG with dose are investigated by FTIR, dynamic light scattering (DLS) and rotational viscosimetry. The impact on gelation ability and gel strength is studied by rheological analysis. The morphology evolution is investigated by SEM analysis, and absence of cytotoxicity verified by MTS assay and optical microscopy of neuroblastoma cells.


Assuntos
Biopolímeros , Raios gama , Glucanos/química , Glucanos/farmacocinética , Hidrogéis/síntese química , Hidrogéis/farmacocinética , Xilanos/química , Xilanos/farmacocinética , Biopolímeros/química , Biopolímeros/farmacocinética , Biopolímeros/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glucanos/síntese química , Glucanos/efeitos da radiação , Humanos , Hidrogéis/química , Teste de Materiais , Neuroblastoma/patologia , Polimerização/efeitos da radiação , Resistência ao Cisalhamento , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Fatores de Tempo , Viscosidade , Xilanos/síntese química , Xilanos/efeitos da radiação
20.
Biomaterials ; 80: 179-194, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26708643

RESUMO

A growing body of evidence shows the protective role of insulin in Alzheimer's disease (AD). A nanogel system (NG) to deliver insulin to the brain, as a tool for the development of a new therapy for Alzheimer's Disease (AD), is designed and synthetized. A carboxyl-functionalized poly(N-vinyl pyrrolidone) nanogel system produced by ionizing radiation is chosen as substrate for the covalent attachment of insulin or fluorescent molecules relevant for its characterization. Biocompatibility and hemocompatibility of the naked carrier is demonstrated. The insulin conjugated to the NG (NG-In) is protected by protease degradation and able to bind to insulin receptor (IR), as demonstrated by immunofluorescence measurements showing colocalization of NG-In(FITC) with IR. Moreover, after binding to the receptor, NG-In is able to trigger insulin signaling via AKT activation. Neuroprotection of NG-In against dysfunction induced by amyloid ß (Aß), a peptide mainly involved in AD, is verified. Finally, the potential of NG-In to be efficiently transported across the Blood Brain Barrier (BBB) is demonstrated. All together these results indicate that the synthesized NG-In is a suitable vehicle system for insulin deliver in biomedicine and a very promising tool to develop new therapies for neurodegenerative diseases.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Portadores de Fármacos/química , Insulina/administração & dosagem , Povidona/química , Doença de Alzheimer/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Insulina/farmacocinética , Insulina/farmacologia , Camundongos Endogâmicos C57BL , Nanoestruturas/química , Nanoestruturas/efeitos da radiação , Nanotecnologia/métodos , Radiação Ionizante , Receptor de Insulina/metabolismo
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