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Herein, we isolated five natural alkaloids, iso-corydine (iso-CORY), corydine (CORY), sanguinarine (SAN), chelerythrine (CHE) and magnoflorine (MAG), from traditional medicinal herb Dicranostigma leptopodum (Maxim.) Fedde (whole herb) and elucidated their structures. Then we synthesised G5. NHAc-PBA as targeting dendrimer platform to encapsulate the alkaloids into G5. NHAc-PBA-alkaloid complexes, which demonstrated alkaloid-dependent positive zeta potential and hydrodynamic particle size. G5. NHAc-PBA-alkaloid complexes demonstrated obvious breast cancer MCF-7 cell targeting effect. Among the G5. NHAc-PBA-alkaloid complexes, G5.NHAc-PBA-CHE (IC50=13.66 µM) demonstrated the highest MCF-7 cell inhibition capability and G5.NHAc-PBA-MAG (IC50=24.63 µM) had equivalent inhibitory effects on cell proliferation that comparable to the level of free MAG (IC50=23.74 µM), which made them the potential breast cancer targeting formulation for chemotherapeutic application. This work successfully demonstrated a pharmaceutical research model of 'natural bioactive product isolation-drug formulation preparation-breast cancer cell targeting inhibition'.
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Glioma, as a disease of the central nervous system, is difficult to be treated due to the presence of the blood-brain barrier (BBB) that can severely hamper the efficacy of most therapeutic agents. Hence, drug delivery to glioma in an efficient, safe, and specifically targeted manner is the key to effective treatment of glioma. With the advances in nanotechnology, targeted drug delivery systems have been extensively explored to deliver chemotherapeutic agents, nucleic acids, and contrast agents. Among these nanocarriers, dendrimers have played a significant role since they possess highly branched structures, and are easy to be decorated, thus offering numerous binding sites for various drugs and ligands. Dendrimers can be designed to cross the BBB for glioma targeting, therapy or theranostics. In this review, we provide a concise overview of dendrimer-based carrier designs including dendrimer surface modification with hydroxyl termini, peptides, and transferrin etc. for glioma imaging diagnostics, chemotherapy, gene therapy, or imaging-guided therapy. Finally, the future perspectives of dendrimer-based glioma theraputics are also briefly discussed.
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Dendrímeros , Glioma , Humanos , Barreira Hematoencefálica/metabolismo , Dendrímeros/química , Medicina de Precisão , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Glioma/metabolismo , Sistemas de Liberação de Medicamentos/métodosRESUMO
With the increasing and aging of global population, there is a dramatic rise in the demand for implants or substitutes to rehabilitate bone-related disorders which can considerably decrease quality of life and even endanger lives. Though titanium and its alloys have been applied as the mainstream material to fabricate implants for load-bearing bone defect restoration or temporary internal fixation devices for bone fractures, it is far from rare to encounter failed cases in clinical practice, particularly with pathological factors involved. In recent years, smart stimuli-responsive (SSR) strategies have been conducted to functionalize titanium implants to improve bone regeneration in pathological conditions, such as bacterial infection, chronic inflammation, tumor and diabetes mellitus, etc. SSR implants can exert on-demand therapeutic and/or pro-regenerative effects in response to externally applied stimuli (such as photostimulation, magnetic field, electrical and ultrasound stimulation) or internal pathology-related microenvironment changes (such as decreased pH value, specific enzyme secreted by bacterial and excessive production of reactive oxygen species). This review summarizes recent progress on the material design and fabrication, responsive mechanisms, and in vitro and in vivo evaluations for versatile clinical applications of SSR titanium implants. In addition, currently existing limitations and challenges and further prospective directions of these strategies are also discussed.
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Qualidade de Vida , Titânio , Próteses e Implantes , Regeneração Óssea , Fixadores InternosRESUMO
Cisplatin (cis-diamminedichloroplatinum(II)) is a potent chemotherapeutic agent commonly used to treat cancer. However, its use also leads to serious side effects, such as nephrotoxicity, ototoxicity, and cardiotoxicity, which limit the dose that can be safely administered to patients. To minimize these problems, dendrimers may be used as carriers for cisplatin through the coordination of their terminal functional groups to platinum. Here, cisplatin was conjugated to half-generation anionic PAMAM dendrimers in mono- and bidentate forms, and their biological effects were assessed in vitro. After preparation and characterization of the metallodendrimers, their cytotoxicity was evaluated against several cancer cell lines (A2780, A2780cisR, MCF-7, and CACO-2 cells) and a non-cancer cell line (BJ cells). The results showed that all the metallodendrimers were cytotoxic and that the cytotoxicity level depended on the cell line and the type of coordination mode (mono- or bidentate). Although, in this study, a correlation between dendrimer generation (number of carried metallic fragments) and cytotoxicity could not be completely established, the monodentate coordination form of cisplatin resulted in lower IC50 values, thus revealing a more accessible cisplatin release from the dendritic scaffold. Moreover, most of the metallodendrimers were more potent than the cisplatin, especially for the A2780 and A2780cisR cell lines, which showed higher selectivity than for non-cancer cells (BJ cells). The monodentate G0.5COO(Pt(NH3)2Cl)8 and G2.5COO(Pt(NH3)2Cl)32 metallodendrimers, as well as the bidentate G2.5COO(Pt(NH3)2)16 metallodendrimer, were even more active towards the cisplatin-resistant cell line (A2780cisR cells) than the correspondent cisplatin-sensitive one (A2780 cells). Finally, the effect of the metallodendrimers on the hemolysis of human erythrocytes was neglectable, and metallodendrimers' interaction with calf thymus DNA seemed to be stronger than that of free cisplatin.
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Dendrimers have been studied as promising materials for the delivery of anticancer drugs. In this work, low-generation (0-2) nitrile poly(alkylidenamine)-based dendrimers were explored as nanocarriers for the organometallic complex [Ru(η5-C5H5)(PPh3)2]+ (RuCp+) and investigated for their anticancer action and involved mechanisms, which were evaluated both in vitro and in vivo. It was observed that their biological behaviour is generation dependent, where the highest generation metallodendrimer (G2Ru) was overall more effective than the other metallodendrimers. G2Ru was active against a set of six cancer cell lines, revealing its important selectivity for these cells (the IC50 values were about 4-fold lower than that for non-cancer cells). Importantly, the in vivo studies with G2Ru in an MCF-7 xenograft mouse model showed that it exhibited low systemic toxicity, low accumulation in the main organs of the mice, preferential accumulation in the tumour, and remarkable capacity to limit tumour growth. The in vitro and in vivo studies revealed that G2Ru caused high levels of cell necrosis and apoptosis. The in vitro cell death mechanism studies showed the capacity of G2Ru to induce mitochondrial depolarization and ROS production. Altogether, pre-clinical results indicated G2Ru as a promising anticancer drug and the potential of low-generation poly(alkylidenamine)-based dendrimers as drug nanocarriers.
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Antineoplásicos , Dendrímeros , Rutênio , Humanos , Camundongos , Animais , Rutênio/farmacologia , Dendrímeros/farmacologia , Antineoplásicos/farmacologia , Apoptose , Morte CelularRESUMO
Currently, cancer chemotherapeutic drugs still have the defects of high toxicity and low bioavailability, so it is critical to design novel drug release systems for cancer chemotherapy. Here, we report a method to fabricate electrospun drug-loaded organic/inorganic hybrid nanofibrous system for antitumor therapy applications. In this work, rod-like attapulgite (ATT) was utilized to load a model anticancer drug doxorubicin (DOX), and mixed with poly(lactic-co-glycolic acid) (PLGA) to form electrospun hybrid nanofibers. The ATT/DOX/PLGA composite nanofibers were characterized through various techniques. It is feasible to load DOX onto ATT surfaces, and the ATT/DOX/PLGA nanofibers show a smooth and uniform morphology with improved mechanical durability. Under neutral and acidic pH conditions, the loaded DOX was released from ATT/DOX/PLGA nanofibers in a sustained manner. In addition, the released DOX from the nanofibers could significantly inhibit the growth of tumor cells. Owing to the significantly reduced burst release profile and increased mechanical durability of the ATT/DOX/PLGA nanofibers, the designed organic-inorganic hybrid nanofibers may hold great promise as a nanoplatform to encapsulate different drugs for enhanced local tumor therapy applications.
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Although doxorubicin (DOX) is one of the most used chemotherapeutic drugs due to its efficacy against a wide group of cancer types, it presents severe side effects. As such, intensive research is being carried out to find new nanoscale systems that can help to overcome this problem. Polyester dendrimers based on the monomer 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) are very promising systems for biomedical applications due to their biodegradability properties. In this study, bis-MPA-based dendrimers were, for the first time, evaluated as DOX delivery vehicles. Generations 4 and 5 of bis-MPA-based dendrimers with hydroxyl groups at the surface were used (B-G4-OH and B-G5-OH), together with dendrimers partially functionalized with amine groups (B-G4-NH2/OH and B-G5-NH2/OH). Partial functionalization was chosen because the main purpose was to compare the effect of different functional groups on dendrimers' drug delivery behavior without compromising cell viability, which is often affected by dendrimers' cationic charge. Results revealed that bis-MPA-based dendrimers were cytocompatible, independently of the chemical groups that were present at their surface. The B-G4-NH2/OH and B-G5-NH2/OH dendrimers were able to retain a higher number of DOX molecules, but the in vitro release of the drug was faster. On the contrary, the hydroxyl-terminated dendrimers exhibited a lower loading capacity but were able to deliver the drug in a more sustained manner. These results were in accordance with the cytotoxicity studies performed in several models of cancer cell lines and human mesenchymal stem cells. Overall, the results confirmed that it is possible to tune the drug delivery properties of bis-MPA-based dendrimers by modifying surface functionalization. Moreover, molecular modeling studies provided insights into the nature of the interactions established between the drug and the bis-MPA-based dendrimersâDOX molecules attach to their surface rather than being physically encapsulated.
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Dendrímeros , Cátions/química , Sobrevivência Celular , Dendrímeros/química , Dendrímeros/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Poliésteres/químicaRESUMO
The aim of this study was to promote bioactivity of the PEEK surface using sulfuric acid and piranha solution. PEEK was functionalized by a sulfuric acid treatment for 90 s and by piranha solution for 60 and 90 s. Chemical modification of the PEEK surface was evaluated by infrared spectroscopy, contact angle analysis, cytotoxicity, cell adhesion and proliferation. The spectroscopy characteristic band associated with sulfonation was observed in all treated samples. PEEK with piranha solution 60 s showed an increase in the intensity of the bands, which was even more significant for the longer treatment (90 s). The introduction of the sulfonic acid functional group reduced the contact angle. In cytotoxicity assays, for all treatments, the number of viable cells was higher when compared to those of untreated PEEK. PEEK treated with sulfuric acid and piranha solution for 60 s were the treatments that showed the highest percentage of cell viability with no statistically significant differences between them. The modified surfaces had a greater capacity for inducing cell growth, indicative of effective cell adhesion and proliferation. The proposed chemical modifications are promising for the functionalization of PEEK-based implants, as they were effective in promoting bioactivation of the PEEK surface and in stimulating cell growth and proliferation.
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Benzofenonas/química , Polímeros/química , Ácidos Sulfúricos/química , Adesão Celular , Morte Celular , Proliferação de Células , Fibroblastos/citologia , Humanos , Soluções , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
INTRODUCTION: Globally, breast cancer (BC) is leading at the top of women's diseases and, as a multifactorial disease, there is the need for the development of new approaches to aid clinicians on monitoring BC treatments. In this sense, metabolomic studies have become an essential tool allowing the establishment of interdependency among metabolites in biological samples. OBJECTIVE: The combination of nuclear magnetic resonance (NMR) and gas chromatography-quadrupole mass spectrometry (GC-qMS) based metabolomic analyses of urine and breast tissue samples from BC patients and cancer-free individuals was used. METHODS: Multivariate statistical tools were used in order to obtain a panel of metabolites that could discriminate malignant from healthy status assisting in the diagnostic field. Urine samples (n = 30), cancer tissues (n = 30) were collected from BC patients, cancer-free tissues were resected outside the tumor margin from the same donors (n = 30) while cancer-free urine samples (n = 40) where obtained from healthy subjects and analysed by NMR and GC-qMS methodologies. RESULTS: The orthogonal partial least square discriminant analysis model showed a clear separation between BC patients and cancer-free subjects for both classes of samples. Specifically, for urine samples, the goodness of fit (R2Y) and predictive ability (Q2) was 0.946 and 0.910, respectively, whereas for tissue was 0.888 and 0.813, revealing a good predictable accuracy. The discrimination efficiency and accuracy of tissue and urine metabolites was ascertained by receiver operating characteristic curve analysis that allowed the identification of metabolites with high sensitivity and specificity. The metabolomic pathway analysis identified several dysregulated pathways in BC, including those related with lactate, valine, aspartate and glutamine metabolism. Additionally, correlations between urine and tissue metabolites were investigated and five metabolites (e.g. acetone, 3-hexanone, 4-heptanone, 2-methyl-5-(methylthio)-furan and acetate) were found to be significant using a dual platform approach. CONCLUSION: Overall, this study suggests that an improved metabolic profile combining NMR and GC-qMS may be useful to achieve more insights regarding the mechanisms underlying cancer.
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Biomarcadores Tumorais , Neoplasias da Mama , Metabolômica , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/urina , Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/urina , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Espectroscopia de Ressonância Magnética/métodos , Metabolômica/métodos , Pessoa de Meia-Idade , Urina/químicaRESUMO
The DACHPtCl2 compound (trans-(R,R)-1,2-diaminocyclohexanedichloroplatinum(II)) is a potent anticancer drug with a broad spectrum of activity and is less toxic than oxaliplatin (trans-l-diaminocyclohexane oxalate platinum II), with which it shares the active metal fragment DACHPt. Nevertheless, due to poor water solubility, its use as a chemotherapeutic drug is limited. Here, DACHPtCl2 was conjugated, in a bidentate form, with half-generation PAMAM dendrimers (G0.5-G3.5) with carboxylate end-groups, and the resulting conjugates were evaluated against various types of cancer cell lines. In this way, we aimed at increasing the solubility and availability at the target site of DACHPt while potentially reducing the adverse side effects. DNA binding assays showed a hyperchromic effect compatible with DNA helix's disruption upon the interaction of the metallodendrimers and/or the released active metallic fragments with DNA. Furthermore, the prepared DACHPt metallodendrimers presented cytotoxicity in a wide set of cancer cell lines used (the relative potency regarding oxaliplatin was in general high) and were not hemotoxic. Importantly, their selectivity for A2780 and CACO-2 cancer cells with respect to non-cancer cells was particularly high. Subsequently, the anticancer drug 5-FU was loaded in a selected metallodendrimer (the G2.5COO(DACHPt)16) to investigate a possible synergistic effect between the two drugs carried by the same dendrimer scaffold and tested for cytotoxicity in A2780cisR and CACO-2 cancer cell lines. This combination resulted in IC50 values much lower than the IC50 for 5-FU but higher than those found for the metallodendrimers without 5-FU. It seems, thus, that the metallic fragment-induced cytotoxicity dominates over the cytotoxicity of 5-FU in the set of considered cell lines.
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Antineoplásicos/farmacologia , Dendrímeros/química , Fluoruracila/farmacologia , Compostos Organoplatínicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , DNA/metabolismo , Dendrímeros/síntese química , Liberação Controlada de Fármacos , Fluoruracila/síntese química , Fluoruracila/química , Humanos , Concentração Inibidora 50 , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria Ultravioleta , Eletricidade Estática , TermodinâmicaRESUMO
Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics. However, direct administration of "naked" immunotherapeutic agents (such as nucleic acids, cytokines, adjuvants or antigens without delivery vehicles) often results in: (1) an unsatisfactory efficacy due to suboptimal pharmacokinetics; (2) strong toxic and side effects due to low targeting (or off-target) efficiency. To overcome these shortcomings, a series of polysaccharide-based nanoparticles have been developed to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side effects. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, as they could interact with immune system to stimulate an enhanced immune response. Their structures offer versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on the use of polysaccharide-based immunotherapeutics.
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Nanomedicine represents a very significant contribution in current cancer treatment; in addition to surgical intervention, radiation and chemotherapeutic agents that unfortunately also kill healthy cells, inducing highly deleterious and often life-threatening side effects in the patient. Of the numerous nanoparticles used against cancer, gold nanoparticles had been developed for therapeutic applications. Inter alia, a large variety of dendrimers, i.e. soft artificial macromolecules, have turned up as non-viral functional nanocarriers for entrapping drugs, imaging agents, and targeting molecules. This review will provide insights into the design, synthesis, functionalization, and development in biomedicine of engineered functionalized hybrid dendrimer-tangled gold nanoparticles in the domain of cancer theranostic. Several aspects are highlighted and discussed such as 1) dendrimer-entrapped gold(0) hybrid nanoparticles for the targeted imaging and treatment of cancer cells, 2) dendrimer encapsulating gold(0) nanoparticles (Au DENPs) for the delivery of genes, 3) Au DENPs for drug delivery applications, 4) dendrimer encapsulating gold radioactive nanoparticles for radiotherapy, and 5) dendrimer/dendron-complexed gold(III) nanoparticles as technologies to take down cancer cells.
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Dendrímeros , Nanopartículas Metálicas , Neoplasias , Preparações Farmacêuticas , Ouro , Humanos , Neoplasias/tratamento farmacológico , Medicina de PrecisãoRESUMO
Like other bionanomaterials, dendrimers are usually labelled with fluorescent compounds in order to be optically detected within cells. However, this process can interfere with their biological properties, so it is crucial to find other solutions for their traceability. Here, the blue intrinsic fluorescence of amine-terminated poly(amidoamine) (PAMAM) dendrimers was enhanced using oxidative treatment with ammonium persulfate (APS). The effects of dendrimer generation (G3, G4, and G5) and pH on the spectroscopic behavior of both pristine and APS-treated PAMAM dendrimers were studied in aqueous solution. Overall, the results pointed out that there are at least two types of emitting electron-rich hetero-atomic sub-luminophores (HASLs) confined within the dendrimer scaffold that have very close maximum emission wavelengths and whose emission properties strongly depend on pH. The APS treatment significantly enhanced the fluorescence intensity by leading to the protonation of the interior of the dendrimer. However, fluorescence intensity was not only dependent on the number of HASLs in the dendrimer scaffold (i.e., on dendrimer generation), but also on the rigidification suffered by the dendrimer due to the acidic environment (at low pH values, APS-treated G4 was indeed the most emissive species). Moreover, photoluminescence studies with lyophilized samples were also conducted, which confirmed the coexistence of more than one type of HASLs emitting in the dendrimer structure. The APS treatment affected these HASLs to a different extent. Time-resolved fluorescence experiments always showed higher average lifetimes of HASLs for APS-treated dendrimers than for pristine ones, in accordance with the fluorescence intensity results. On the other hand, the fraction and lifetimes of HASLs in APS-treated dendrimers were similar in solution and the lyophilized form. This behaviour was different for the pristine dendrimers that presented increased luminescence upon aggregation. Finally, the highly emissive oxidized dendrimers were shown not only to be much less cytotoxic and hemotoxic than pristine dendrimers but also to be detectable inside cells upon excitation with UV light.
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Materiais Biocompatíveis/química , Dendrímeros/química , Corantes Fluorescentes/química , Animais , Linhagem Celular Tumoral , Fluorescência , Humanos , Camundongos , Células NIH 3T3 , OxirreduçãoRESUMO
To enhance the drug delivery efficiency of hyaluronic acid (HA), we designed and prepared glycodendron and pyropheophorbide-a (Ppa)-functionalized HA (HA-Ppa-Dendron) as a nanosystem for cancer photodynamic therapy. Linear Ppa-modified HA (HA-Ppa) was also prepared as a control. Cellular uptake of both polymers by MDA-MB-231 cells led to mitochondrial dysfunction and generation of reactive oxygen species under the irradiation of a laser. Compared to the linear polymer, HA-Ppa-Dendron had higher molecular weight, a more compact nanoscale particle size, and a dendritic structure, resulting in a much longer blood circulation time and higher tumor accumulation. HA-Ppa-Dendron outperformed HA-Ppa in inhibiting cell growth, with 60 % of tumors was eradicated under laser irradiation. Tumor growth inhibition (TGI) up to 99.2 % was achieved from HA-Ppa-Dendron, which was much higher than that of HA-Ppa (50.6 %). Therefore, glycodendron-functionalized HAs by integration of HA and dendritic polymers may act as efficient anti-cancer nanomedicine.
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Antracenos/química , Neoplasias da Mama/tratamento farmacológico , Clorofila/análogos & derivados , Ácido Hialurônico/química , Nanopartículas/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Clorofila/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Development of versatile nanoplatforms for cancer theranostics remains a hot topic in the area of nanomedicine. We report here a general approach to create polyethylenimine (PEI)-based hybrid nanogels (NGs) incorporated with ultrasmall iron oxide (Fe3O4) nanoparticles (NPs) and doxorubicin for T1-weighted MR imaging-guided chemotherapy of tumors. In this study, PEI NGs were first prepared using an inverse emulsion approach along with Michael addition reaction to cross-link the NGs, modified with citric acid-stabilized ultrasmall Fe3O4 NPs through 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC) coupling, and physically loaded with anticancer drug doxorubicin (DOX). The formed hybrid NGs possess good water dispersibility and colloidal stability, excellent DOX loading efficiency (51.4%), pH-dependent release profile of DOX with an accelerated release rate under acidic pH, and much higher r1 relaxivity (2.29 mM-1 s-1) than free ultrasmall Fe3O4 NPs (1.15 mM-1 s-1). In addition, in contrast to the drug-free NGs that possess good cytocompatibility, the DOX-loaded hybrid NGs display appreciable therapeutic activity and can be taken up by cancer cells in vitro. With these properties, the developed hybrid NGs enabled effective inhibition of tumor growth under the guidance of T1-weighted MR imaging. The developed hybrid NGs may be applied as a versatile nanoplatform for MR imaging-guided chemotherapy of tumors.
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Doxorrubicina/química , Compostos Férricos/química , Imageamento por Ressonância Magnética , Nanogéis/química , Nanopartículas/química , Tamanho da Partícula , Polietilenoimina/química , Animais , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Cinética , CamundongosRESUMO
Cancer is one of the leading causes of death worldwide and, as such, efforts are being done to find new chemotherapeutic drugs or, alternatively, novel approaches for the delivery of old ones. In this scope, when used as vehicles for drugs, nanomaterials may potentially maximize the efficacy of the treatment and reduce its side effects, for example by a change in drug's pharmacokinetics, cell targeting and/or specific stimuli-responsiveness. This is the case of doxorubicin (DOX) that presents a broad spectrum of activity and is one of the most widely used chemotherapeutic drugs as first-line treatment. Indeed, DOX is a very interesting example of a drug for which several nanosized delivery systems have been developed over the years. While it is true that some of these systems are already in the market, it is also true that research on this subject remains very active and that there is a continuing search for new solutions. In this sense, this review takes the example of doxorubicin, not so much with the focus on the drug itself, but rather as a case study around which very diverse and imaginative nanotechnology approaches have emerged.
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Nanoestruturas , Neoplasias , Linhagem Celular Tumoral , Doxorrubicina , Sistemas de Liberação de Medicamentos , Humanos , Nanotecnologia , Neoplasias/tratamento farmacológicoRESUMO
Breast cancer (BC) remains the second leading cause of death among women worldwide. An emerging approach based on the identification of endogenous metabolites (EMs) and the establishment of the metabolomic fingerprint of biological fluids constitutes a new frontier in medical diagnostics and a promising strategy to differentiate cancer patients from healthy individuals. In this work we aimed to establish the urinary metabolomic patterns from 40 BC patients and 38 healthy controls (CTL) using proton nuclear magnetic resonance spectroscopy (1H-NMR) as a powerful approach to identify a set of BC-specific metabolites which might be employed in the diagnosis of BC. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied to a 1H-NMR processed data matrix. Metabolomic patterns distinguished BC from CTL urine samples, suggesting a unique metabolite profile for each investigated group. A total of 10 metabolites exhibited the highest contribution towards discriminating BC patients from healthy controls (variable importance in projection (VIP) >1, p < 0.05). The discrimination efficiency and accuracy of the urinary EMs were ascertained by receiver operating characteristic curve (ROC) analysis that allowed the identification of some metabolites with the highest sensitivities and specificities to discriminate BC patients from healthy controls (e.g. creatine, glycine, trimethylamine N-oxide, and serine). The metabolomic pathway analysis indicated several metabolism pathway disruptions, including amino acid and carbohydrate metabolisms, in BC patients, namely, glycine and butanoate metabolisms. The obtained results support the high throughput potential of NMR-based urinary metabolomics patterns in discriminating BC patients from CTL. Further investigations could unravel novel mechanistic insights into disease pathophysiology, monitor disease recurrence, and predict patient response towards therapy.
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A novel bioactive macromolecule based on morpholino-functionalized phosphorus dendrimers (generation 2, G2-Mor+) was developed for osteogenic differentiation of mesenchymal stem cells (MSCs). Interestingly, through in vitro tests, it was shown that G2-Mor+ dendrimer can strongly promote the transformation of MSCs into osteoblasts, which implies the potential application of phosphorus dendrimers in bone regeneration for precision regenerative medicine.
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Diferenciação Celular/efeitos dos fármacos , Dendrímeros , Células-Tronco Mesenquimais/metabolismo , Morfolinos , Osteogênese/efeitos dos fármacos , Medicina Regenerativa , Células Cultivadas , Dendrímeros/química , Dendrímeros/farmacologia , Humanos , Células-Tronco Mesenquimais/citologia , Morfolinos/química , Morfolinos/farmacologiaRESUMO
We demonstrate a novel serum-enhanced gene delivery approach using zwitterion-functionalized dendrimer-entrapped gold nanoparticles (Au DENPs) as a non-viral vector for inhibition of cancer cell metastasis in vitro. Poly(amidoamine) dendrimers of generation 5 decorated with zwitterion carboxybetaine acrylamide (CBAA) and lysosome-targeting agent morpholine (Mor) were utilized to entrap gold NPs. We show that both Mor-modified and Mor-free Au DENPs are cytocompatible and can effectively deliver plasmid DNA encoding different reporter genes to cancer cells in medium with or without serum. Strikingly, due to the antifouling property exerted by the attached zwitterion CBAA, the gene delivery efficiency of Mor-modified Au DENPs and the Mor-free Au DENPs in the serum-containing medium are 1.4 and 1.7 times higher than the corresponding vector in serum-free medium, respectively. In addition, the Mor-free vector has a better gene expression efficiency than the Mor-modified one although the Mor modification enables the polyplexes to have enhanced cancer cell uptake. Wound healing and hypermethylated in cancer 1 (HIC1) protein expression assay data reveal that the expression of HIC1 gene in cancer cells enables effective inhibition of cell migration. Our findings suggest that the created zwitterion-functionalized Au DENPs may be employed as a powerful vector for serum-enhanced gene therapy of different diseases. STATEMENT OF SIGNIFICANCE: One major challenge in the non-viral gene delivery system is that the strong interaction between serum protein and the positively charged vector/gene polyplexes neutralize the positive charge of the polyplexes and form possible protein corona, thereby significantly reducing their cellular uptake efficiency and subsequent gene transfection outcome. Here we demonstrate the conceptual advances in the serum-enhanced gene delivery using zwitterionic modification of polycationic poly(amidoamine) (PAMAM) dendrimer-entrapped gold nanoparticles (Au DENPs). We demonstrate that partial zwitterionic modification of Au DENPs is able to confer them with antifouling property to resist serum protein adsorption. Hence the vector/DNA polyplexes are able to maintain their positive potentials and small hydrodynamic size in the serum environment, where serum solely play the role as a nutrition factor for enhanced gene delivery. We demonstrate that partial modification of zwitterion carboxybetaine acrylamide (CBAA) and morpholine (Mor) onto the surface Au DENPs renders the vector with both antifouling property and lysosome targeting ability, respectively. The generated functional Au DENPs can compact pDNA to form polyplexes that enable serum-enhanced gene expression. In particular, once complexed with hypermethylated in cancer 1 (HIC1) gene, the polyplexes can significantly inhibit cancer cell migration and metastasis.
Assuntos
Dendrímeros/química , Ouro/química , Íons , Nanopartículas Metálicas/química , Neoplasias/terapia , Acrilamida/química , Acrilamidas/química , Movimento Celular , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Ligantes , Lisossomos/metabolismo , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Morfolinas/química , Metástase Neoplásica , Neoplasias/patologia , CicatrizaçãoRESUMO
Breast cancer (BC), ranked as the fifth amongst all cancers, remains at the top of women's cancers worldwide followed by colorectal, lung, cervix, and stomach cancers. The main handicap of most of the screening/diagnostic methods is based on their low sensitivity and specificity and the invasive behavior of most sampling procedures. The aim of this study was to establish the volatomic pattern of BC and cancer-free (CF) tissues (n = 30) from the same patients, as a powerful tool to identify a set of volatile organic metabolite (VOM) potential BC biomarkers which might be used together or complement with the traditional BC diagnostics strategies, through the integration of chromatographic data, obtained by solid-phase microextraction followed by gas chromatography-mass spectrometry (SPME/GC-qMS), with chemometric tools. A total of four metabolites: limonene, decanoic acid, acetic acid and furfural presented the highest contribution towards discrimination of BC and CF tissues (VIP > 1, p < 0.05). The discrimination efficiency and accuracy of BC tissue metabolites was ascertained by ROC curve analysis that allowed the identification of some metabolites with high sensitivity and specificity. The results obtained with this approach suggest the possibility of identifying endogenous metabolites as a platform to find potential BC biomarkers and pave the way to investigate the related metabolomic pathways in order to improve BC diagnostic tools. Moreover, deeper investigations could unravel novel mechanistic insights into the disease pathophysiology.