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1.
Chem Commun (Camb) ; 55(82): 12352-12355, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31559405

RESUMO

We report a new biofunctionalized nanoplatform based on hyaluronic acid-coated gold-nano-dot-decorated hollow carbon nanospheres (AuHCNs-HA) for microRNA imaging in living cells. Importantly, the HA-coated nanoplatform could be internalized into target cells via CD44 receptor-mediated endocytosis. It can be further applied for intracellular miR-21 imaging in CD44-positive colorectal cancer cells.


Assuntos
Neoplasias Colorretais/metabolismo , Ouro/química , Nanopartículas Metálicas/química , MicroRNAs/análise , Imagem Óptica/métodos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Imagem Óptica/instrumentação , Tamanho da Partícula , Porosidade , Propriedades de Superfície
2.
Int J Nanomedicine ; 14: 6425-6437, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496695

RESUMO

Introduction: Curcumin (CUR) is a general ingredient of traditional Chinese medicine, which has potential antitumor effects. However, its use clinically has been limited due to its low aqueous solubility and bioavailability. In order to improve the therapeutic effect of CUR on osteosarcoma (i.e., bone cancer), a multifunctional micelle was developed here by combining active bone accumulating ability with tumor CD44 targeting capacity. Methods: The CUR loaded micelles were self-assembled by using alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18) as an amphiphilic material. The obtained micelles were characterized for size and drug loading. In addition, the in vitro release behavior of CUR was investigated under PBS (pH 5.7) medium containing 1% Tween 80 at 37℃. Furthermore, an hydroxyapatite (the major inorganic component of bone) affinity experiment was studied. In vitro antitumor activity was evaluated. Finally, the anti-tumor efficiency was studied. Results: The size and drug loading of the CUR loaded ALN-HA-C18 micelles were about 118 ± 3.6 nm and 6 ± 1.2%, respectively. CUR was released from the ALN-HA-C18 micelles in a sustained manner after 12 h. The hydroxyapatite affinity experiment indicated that CUR loaded ALN-HA-C18 micelles exhibited a high affinity to bone. CUR loaded ALN-HA-C18 micelles exhibited much higher cytotoxic activity against MG-63 cells compared to free CUR. Finally, CUR loaded ALN-HA-C18 micelles effectively delayed anti-tumor growth properties in osteosarcoma bearing mice as compared with free CUR. Conclusion: The present study suggested that ALN-HA-C18 is a novel promising micelle for osteosarcoma targeting and delivery of the hydrophobic anticancer drug CUR.


Assuntos
Alendronato/uso terapêutico , Curcumina/uso terapêutico , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Micelas , Osteossarcoma/tratamento farmacológico , Ácidos Esteáricos/química , Alendronato/química , Animais , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Curcumina/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Nus , Osteossarcoma/patologia , Tamanho da Partícula , Polímeros/química , Espectroscopia de Prótons por Ressonância Magnética
3.
Int J Nanomedicine ; 14: 5287-5301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31406460

RESUMO

Purpose: Nanoparticle (NP)-mediated targeted delivery of therapeutic genes or siRNAs to tumors has potential advantages. In this study, hyaluronic acid (HA)-modified chitosan nanoparticles (CS NPs-HA) loaded with cyanine 3 (Cy3)-labeled siRNA (sCS NPs-HA) were prepared and characterized. Methods: Human non-small cell lung cancer (NSCLC) A549 cells expressing receptor CD44 and tumor-bearing mice were used to evaluate the cytotoxic and antitumor effects of sCS NPs-HA in vitro and in vivo. Results: The results showed that noncytotoxic CS NPs-HA of small size (100-200 nm) effectively delivered the Cy3-labeled siRNA to A549 cells via receptor CD44 and inhibited cell proliferation by downregulating the target gene BCL2. In vivo experiment results revealed that sCS NPs-HA directly delivered greater amounts of Cy3-labeled siRNA to the tumor sites, resulting in the inhibition of tumor growth by downregulating BCL2, as compared to unmodified NPs loaded with siRNA (sCS NPs) and to naked Cy3-labeled siRNA. Conclusion: The HA-modified NPs based on chitosan could serve as a promising carrier for siRNA delivery and targeted therapy for NSCLC expressing CD44.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Quitosana/química , Ácido Hialurônico/química , Neoplasias Pulmonares/terapia , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Células A549 , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Fluorescência , Inativação Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem
4.
Int J Nanomedicine ; 14: 5785-5797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440047

RESUMO

Introduction: The targeted delivery of anti-cancer drugs to tumor tissue has been recognized as a promising strategy to increase their therapeutic efficacy and reduce side effects. Mesoporous silica-coated superparamagnetic Fe3O4 nanoparticles (NH2-MSNs), a kind of nanocarrier, can passively enter tumor tissues to enhance the permeability and retention of drugs. However, NH2-MSNs do not specifically bind to cancer cells. This drawback encouraged us to develop a more efficient nanocarrier for cancer therapy. Methods: Herein, we describe the development of an effective nanocarrier based on NH2-MSNs, which were modified with hyaluronic acid on their surface (HA-MSNs) and loaded with doxorubicin (DOX). We have successfully fabricated uniform spherical HA-MSNs nanocarriers. The targeting ability of this delivery system was evaluated through specific uptake by cells and IVIS imaging. Results: DOX-HA-MSNs nanocarriers displayed more dramatic cytotoxic activity against 4T1 breast cancer cells compared to GES-1 gastric mucosa cells. In vivo results revealed that once DOX-HA-MSNs nanocarriers are exposed to an external magnetic field, they could be rapidly attracted to the magnet and effectively cross the cytoplasmic membrane via CD44 receptor-mediated transcytosis. This allows them to access the cancer cell cytoplasm and release DOX based on changes in the physiological environment. Both in vitro and in vivo results demonstrated that the HA-MSNs nanocarriers provided better therapeutic efficacy. Conclusion: The HA-MSNs nanocarriers represent an effective new paradigm to treat cancers due to active targeting to the tumor cells. Moreover, the specific uptake by the tumor effectively protects normal tissues to reduce off-target side effects. The reported findings support further investigation of HA-MSNs for cancer therapy.


Assuntos
Dextranos/química , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Nanopartículas de Magnetita/química , Dióxido de Silício/química , Animais , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Humanos , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Espectroscopia Fotoeletrônica , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Eur J Pharm Biopharm ; 142: 498-505, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31330258

RESUMO

AIM: It was the aim of this study to assess in vitro methods for the characterization of mucoadhesive hydrogels for their potential to predict the residence time on human buccal mucosa. METHODS: Mixtures of hydrogels comprising hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose (CMC), xanthan gum (XTGM), hyaluronic acid sodium salt (HA), sodium alginate (ALG), carbopol (CP) as well as polycarbophil (PCP) and porcine mucus were analysed for relative rheological synergism. Furthermore, hydrogels were characterized for their texture and mechanical properties. For the assessment of mucoadhesive strength of formulations tensile studies were performed on porcine buccal mucosa. To facilitate a direct comparability of data the residence time of stained hydrogels was determined ex vivo on porcine buccal mucosa and in the oral cavity of volunteers. RESULTS: The extent of relative rheological synergism was in good agreement with data from in vivo residence time studies. Results of tensile studies were further effected by textural properties of hydrogels leading to a restricted correlation with data from the in vivo experiment. The resistance towards removal by artificial saliva flow ex vivo revealed the highest correlation to the in vivo experiment with increasing mucosal residence time in the rank order CP < HEC, HA, ALG, PCP < CMC < XTGM. CONCLUSIONS: This overview of measurement principles to predict the residence time of hydrogels for buccal application in humans may be a potent tool for the development of semisolid intraoral formulations.


Assuntos
Adesivos/química , Hidrogéis/química , Mucosa Bucal/metabolismo , Resinas Acrílicas/química , Administração Bucal , Adulto , Alginatos/química , Animais , Carboximetilcelulose Sódica/química , Celulose/análogos & derivados , Celulose/química , Correlação de Dados , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Ácido Hialurônico/química , Técnicas In Vitro/métodos , Boca , Polissacarídeos Bacterianos/química , Suínos , Adulto Jovem
6.
J Nanobiotechnology ; 17(1): 78, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269964

RESUMO

BACKGROUND: The construction of a multifunctional drug delivery system with a variety of advantageous features, including targeted delivery, controlled release and combined therapy, is highly attractive but remains a challenge. RESULTS: In this study, we developed a MoS2-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving targeted delivery of camptothecin (CPT) and dual-stimuli-responsive drug release. HA was connected to MoS2 via a disulfide linkage, forming a sheddable HA shell on the surface of MoS2. This unique design not only effectively prevented the encapsulated CPT from randomly leaking during blood circulation but also significantly accelerated the drug release in response to tumor-associated glutathione (GSH). Moreover, the MoS2-based generated heat upon near-infrared (NIR) irradiation could further increase the drug release rate as well as induce photothermal ablation of cancer cells. The results of in vitro and in vivo experiments revealed that MoS2-SS-HA-CPT effectively suppressed cell proliferation and inhibited tumor growth in lung cancer cell-bearing mice under NIR irradiation via synergetic chemo-photothermal therapy. CONCLUSIONS: The as-prepared MoS2-SS-HA-CPT with high targeting ability, dual-stimuli-responsive drug release, and synergistic chemo-photothermal therapy may provide a new strategy for cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Dissulfetos/química , Portadores de Fármacos/química , Molibdênio/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes/química , Humanos , Ácido Hialurônico/química , Hipertermia Induzida , Raios Infravermelhos , Camundongos Nus , Transplante de Neoplasias , Oxirredução , Fotoquimioterapia/métodos
7.
Chem Commun (Camb) ; 55(61): 9015-9018, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290867
8.
Carbohydr Polym ; 222: 114978, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31320056

RESUMO

The objective of present study was to explore whether polysaccharide could be employed as potential crystal growth inhibitor and provides synergistic effect on the supersaturation maintaining of lovastatin (LOV) in combination of nucleation inhibitor. Soluplus (SOL) and hyaluronic acid (HA) were selected as the most effective nucleation and crystal growth inhibitor respectively. The interaction between SOL and HA was elucidated via characterizing the particle size, zeta potential, surface hydrophobicity, solvent relaxation time (T2) and FT-IR. The supersaturated drug solution was spray dried into amorphous solid dispersion, then, the in vitro release, moisture uptake and physical stability were investigated. The synergistic effect between SOL and HA was dependent on drug concentration, drug/carrier and SOL/HA weight ratio, which facilitated both in vitro and in vivo performance. It was disclosed that HA could insert into SOL structure providing both electrostatic and steric stabilization. In conclusion, the combination of nucleation and crystal growth inhibitors is a promising approach for supersaturated drug delivery system.


Assuntos
Portadores de Fármacos/química , Composição de Medicamentos/métodos , Ácido Hialurônico/química , Lovastatina , Polietilenoglicóis/química , Polivinil/química , Animais , Cristalização , Estabilidade de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Lovastatina/administração & dosagem , Lovastatina/sangue , Ratos , Ratos Sprague-Dawley , Solubilidade
9.
Eur J Pharm Biopharm ; 142: 322-333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31295503

RESUMO

The purpose of this work was the development of antibacterial delivery systems for vancomycin, with potential application in the prevention or treatment of orthopedic implant infections. Previous studies have shown tandem thermal gelling and Michael addition cross-linking of hydrogels based on methacrylate, acrylate or vinylsulfone triblock copolymers of PEG-p(HPMAm-lac1-2) and thiolated hyaluronic acid. In this work we exploited these α-ß unsaturated derivatives of PEG-p(HPMAm-lac1-2) triblock copolymers and used them in combination with thiolated hyaluronic acid as controlled delivery systems for vancomycin. It was found that the antibiotic was sustainably released from the hydrogel networks for at least 5 days with release kinetics depending on diffusion and dissociation of the positively charged vancomycin from the negatively charged hyaluronic acid. The release of vancomycin could be tailored mainly by HA-SH solid content and degree of thiolation. The developed hydrogels were demonstrate efficacious in preserving the structural and functional integrity of the encapsulated drug by physical immobilization within the gel network and ionic interaction with hyaluronic acid, thereby preventing vancomycin deamidation processes. Furthermore, the antimicrobial activity of vancomycin loaded hydrogels was assessed, demonstrating retention of inhibitory activity towards Staphylococcus aureus during formulation and release, with slightly increased activity of vancomycin encapsulated in hydrogels of higher HA-SH content as compared to controls.


Assuntos
Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Hidrogéis/química , Infecções Relacionadas à Prótese/tratamento farmacológico , Vancomicina/química , Vancomicina/farmacologia , Acrilatos/química , Antibacterianos/química , Antibacterianos/farmacologia , Ácido Hialurônico/química , Metacrilatos/química , Ortopedia/métodos , Polietilenoglicóis/química , Polímeros/química , Próteses e Implantes/microbiologia , Infecções Relacionadas à Prótese/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos
10.
Chemphyschem ; 20(17): 2204-2209, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31298452

RESUMO

The efficiency of MRI contrast agents depends on the relaxation rate enhancement that they can induce at imaging fields. It is well known that, at these fields, large relaxation rates are obtained by binding of gadolinium(III) ions to large molecules. By the same token, the interaction of the gadolinium(III) complexes with macromolecules that are found in biological tissues can be responsible for an increase of the relaxation rate with respect to the value observed in liquids. We investigate here the relaxation enhancement of gadoteridol (Gd-HP-DO3A) in crosslinked hyaluronic acid, taken as model tissue, using fast field-cycling relaxometry. The analysis of the relaxation profiles as a function of the magnetic fields indicates that a sizable increase in the relaxation rates is due to a modest interaction of the contrast agent with the hydrogel and to the slower mobility of the water molecules outside the first-coordination sphere of the gadolinium(III) ion.


Assuntos
Meios de Contraste/química , Compostos Heterocíclicos/química , Ácido Hialurônico/química , Imagem por Ressonância Magnética/métodos , Modelos Biológicos , Compostos Organometálicos/química , Gadolínio/química , Água/química
11.
Life Sci ; 232: 116669, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31326566

RESUMO

AIMS: This study investigated the effects of hyaluronic acid (HA), a commonly used osteogenic medium referred to as DAG, and the combined administration of HA and DAG (CG) on the osteogenic differentiation of human amniotic mesenchymal stem cells (hAMSCs), and the underlying mechanism. MAIN METHODS: The phenotype of hAMSCs was detected by flow cytometry and immunocytochemical staining. Alkaline phosphatase (ALP) and calcium deposition assays were employed for evaluating the osteogenic differentiation of hAMSCs. The expression of osteogenesis-related genes and proteins was determined by quantitative reverse transcription PCR (qRT-PCR) and Western blotting, respectively. Meanwhile, the molecular mechanism of osteogenic differentiation of hAMSCs was detected by PCR array and qRT-PCR. KEY FINDINGS: The results showed that treatment with CG could significantly stimulate hAMSC ALP activity and calcium deposition compared to treatment with DAG, while HA had little effect. The expression of osteogenesis-related molecules and stemness-related molecules was up-regulated at the mRNA and protein levels in all three groups, and this up-regulation was most significant in the CG group. In addition, treatment with CG significantly increased the gene expressions involved in regulation of the TGF-ß/Smad signalling pathway compared to treatment with DAG. Furthermore, the pro-osteogenic differentiation effects as well as the up-regulated expression of genes observed in the CG treatment group were significantly inhibited when the cells were pre-treated with SB431542, an inhibitor of the TGF-ß/Smad pathway. SIGNIFICANCE: These results suggest that HA in combination with DAG could significantly enhance the osteogenic differentiation of hAMSCs, potentially via the TGF-ß/Smad signalling pathway.


Assuntos
Âmnio/citologia , Diferenciação Celular/efeitos dos fármacos , Ácido Hialurônico/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Cultivadas , Humanos , Ácido Hialurônico/química , Células-Tronco Mesenquimais/citologia , Peso Molecular
12.
Int J Nanomedicine ; 14: 4649-4666, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303753

RESUMO

Introduction: Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA). Materials and methods: The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments. Results: The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/química , Micelas , Neoplasias/tratamento farmacológico , Xantonas/administração & dosagem , Xantonas/uso terapêutico , Células A549 , Animais , Antineoplásicos/farmacologia , Apoptose , Varredura Diferencial de Calorimetria , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/síntese química , Humanos , Ácido Hialurônico/síntese química , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias/patologia , Oxirredução , Propionatos/síntese química , Propionatos/química , Espectroscopia de Prótons por Ressonância Magnética , Reprodutibilidade dos Testes , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Xantonas/farmacologia
13.
Carbohydr Polym ; 221: 84-93, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31227170

RESUMO

In this study, we report a novel pH and temperature responsive paclitaxel-loaded drug delivery system based on chitosan and di(ethylene glycol) methyl ether methacrylate. This was functionalized with hyaluronic acid to permit active targeting of CD44-overexpressing human breast cancer cells. The resultant HA-CS-g-PDEGMA-PTX nanoparticles (NPs) have small and uniform sizes (˜170 nm), a high drug loading (13.6 ±â€¯1.3%) and high encapsulation efficiency (76.2 ±â€¯8.5%). Cell viability and confocal microscopy experiments demonstrated that the NPs could effectively target and kill MDA-MB-231 human breast cancer cells, but were much less toxic to healthy human umbilical vein endothelial cells. In vivo biodistribution studies in mice showed that the NPs accumulated in the tumor site, while free drug was distributed more widely and rapidly cleared from the body. Histopathological studies revealed that the NPs led to enhanced apoptosis in the tumor site, which resulted in reduced tumor growth. The NPs prepared in this work have great potential for the treatment of breast cancers, and further offer a platform with which to target other cancers.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quitosana/química , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quitosana/síntese química , Quitosana/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Etilenoglicóis/síntese química , Etilenoglicóis/química , Etilenoglicóis/toxicidade , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Ácido Hialurônico/síntese química , Ácido Hialurônico/química , Ácido Hialurônico/toxicidade , Metacrilatos/síntese química , Metacrilatos/química , Metacrilatos/toxicidade , Camundongos , Nanopartículas/toxicidade , Paclitaxel/farmacologia , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Carbohydr Polym ; 218: 279-288, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31221331

RESUMO

Oral chemotherapy is preferred but challenged by low bioavailability of anticancer drugs. Self-assembled nanoparticles are promising in solving this problem but the design of appropriate nanocarrier remains a difficulty. Here, using doxorubicin (DOX) as a drug model, the objective of this study was to illustrate how to design an efficient drug delivery system using molecular simulation and elucidate the influence of fatty glyceride chain length in hyaluronic acid (HA) copolymers on peroral absorption of DOX. The compatibility between DOX and HA-g-glyceryl monocaprylate (HGC), HA-g-glyceryl monolaurate (HGL) and HA-g-glyceryl monostearate (HGS) was assessed by molecular simulation using solubility parameters and Flory-Huggins interaction parameters (χFH). Thereafter, HA copolymers were synthesized to verify the prediction. Among the copolymers, HGS showed the best compatibility with DOX followed by HGC and HGL. The physicochemical properties and stability of all the nanoparticles were copolymers structure dependent, with HGS-DOX nanoparticles showing the superior properties followed by HGC-DOX, HGL-DOX nanoparticles. The same order was found in cellular uptake, epithelial transport and in vivo absorption studies in rats, with HGS-DOX nanoparticles showing 7 times higher absorption after peroral administration than intravenous injection of DOX solution. In conclusion, molecular simulation is an effective strategy to the rational nanoparticle design for oral doxorubicin delivery.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Glicerídeos/química , Ácido Hialurônico/química , Nanopartículas/química , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Células CACO-2 , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Glicerídeos/síntese química , Glicerídeos/toxicidade , Humanos , Ácido Hialurônico/síntese química , Ácido Hialurônico/toxicidade , Masculino , Simulação de Dinâmica Molecular , Estrutura Molecular , Nanopartículas/toxicidade , Ratos Sprague-Dawley
15.
J Nanobiotechnology ; 17(1): 76, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217009

RESUMO

BACKGROUND: Molybdenum disulfide (MoS2) has been widely explored for biomedical applications due to its brilliant photothermal conversion ability. In this paper, we report a novel multifunctional MoS2-based drug delivery system (MoS2-SS-HA). By decorating MoS2 nanosheets with hyaluronic acid (HA), these functionalized MoS2 nanosheets have been developed as a tumor-targeting chemotherapeutic nanocarrier for near-infrared (NIR) photothermal-triggered drug delivery, facilitating the combination of chemotherapy and photothermal therapy into one system for cancer therapy. RESULTS: The nanocomposites (MoS2-SS-HA) generated a uniform diameter (ca. 125 nm), exhibited great biocompatibility as well as high stability in physiological solutions, and could be loaded with the insoluble anti-cancer drug erlotinib (Er). The release of Er was greatly accelerated under near infrared laser (NIR) irradiation, showing that the composites can be used as responsive systems, with Er release controllable through NIR irradiation. MTT assays and confocal imaging results showed that the MoS2-based nanoplatform could selectively target and kill CD44-positive lung cancer cells, especially drug resistant cells (A549 and H1975). In vivo tumor ablation studies prove a better synergistic therapeutic effect of the joint treatment, compared with either chemotherapy or photothermal therapy alone. CONCLUSION: The functionalized MoS2 nanoplatform developed in this work could be a potent system for targeted drug delivery and synergistic chemo-photothermal cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Dissulfetos/química , Portadores de Fármacos/química , Cloridrato de Erlotinib/farmacologia , Hipertermia Induzida , Molibdênio/química , Nanocompostos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Cloridrato de Erlotinib/química , Feminino , Humanos , Ácido Hialurônico/química , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fototerapia
16.
Biomed Res Int ; 2019: 4328219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179322

RESUMO

High molecular weight hyaluronan (H-HA) has a pivotal role in the maintenance of normal functions of synovial fluid and structure of the articular joint, but it has been shown that its concentration is reduced in patients affected by degenerative cartilage diseases, such as osteoarthritis (OA). The aim of this study was to investigate the anti-inflammatory effects and properties of hybrid cooperative complexes based on high and low molecular weight hyaluronan (HCC) compared to H-HA on human primary cells derived by pathological joints. In addition, the rheological behavior of HCC was evaluated in order to define their potential as viscosupplement gel in degenerated joints. The experiments were performed using an in vitro model of OA based on human chondrocytes and synoviocytes isolated from degenerated joints of patients hospitalized for surgical replacement. In order to assess the anti-inflammatory effects of HCC, we evaluated NF-kB, COMP-2, IL-6, and IL-8 as specific markers at the transcriptional and/or protein level. Moreover, the proliferative properties of HCC were assessed using time lapse video microscopy. We showed that chondrocytes and synoviocytes clearly presented an altered cytokine profile compatible with a severe ongoing inflammation status. H-HA and, above all, HCC significantly reduced levels of the specific biomarkers evaluated and improved cartilage healing. The rheological profile indicated HCC suitability for intra-articular injection in joint diseases. HCC viscoelastic properties and the protective/anti-inflammatory effect on human chondrocytes and synoviocytes suggest the novel HCC-based gels as a valid support for OA management.


Assuntos
Proliferação de Células/efeitos dos fármacos , Condrócitos/metabolismo , Ácido Hialurônico , Modelos Biológicos , Osteoartrite/tratamento farmacológico , Sinoviócitos/metabolismo , Condrócitos/patologia , Géis , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Peso Molecular , Osteoartrite/metabolismo , Osteoartrite/patologia , Sinoviócitos/patologia
17.
Carbohydr Polym ; 220: 185-190, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31196539

RESUMO

Posterior eye segment diseases are treated through monthly intravitreal injections, that evoke serious side effects. A promising approach to reduce injection frequency consists in producing biodegradable microspheres (MPs) releasing the protein in the vitreous body for long times. Moreover, a rational design of these MPs requires a discouraged diffusion/sedimentation within the intravitreal space, which are detrimental for the vision and the control over drug release kinetics. In this work, poly(lactic-co-glycolic acid) (PLGA)-based MPs encapsulating bovine serum albumin (BSA) were coated with hyaluronic acid (HA) at two molecular weights and tested for their release, diffusion and degradation features in simulated vitreous body (SVB). Results indicate that HA corona prolongs MP degradation time and BSA release. Furthermore, HA coating increased the affinity between MPs and SVB, thereby repressing device transport compared to control PLGA MPs. Results hold promise for the possible application of HA-decorated MPs for intravitreal injection of protein drugs.


Assuntos
Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Injeções Intravítreas/métodos , Microesferas , Corpo Vítreo/efeitos dos fármacos , Difusão , Sistemas de Liberação de Medicamentos/métodos , Oftalmopatias/tratamento farmacológico , Humanos , Ácido Hialurônico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Soroalbumina Bovina/química
18.
Carbohydr Polym ; 220: 219-227, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31196543

RESUMO

Burns and chronic wounds, often related to chronic diseases (as diabetes and cancer), are challenging lesions, difficult to heal. The prompt and full reconstitution of a functional skin is at the basis of the development of biopolymer-based scaffolds, representing a 3D substrate mimicking the dermal extracellular matrix. Aim of the work was to develop scaffolds intended for skin regeneration, according to: fabrication by electrospinning from aqueous polysaccharide solutions; prompt and easy treatment to obtain scaffolds insoluble in aqueous fluids; best performance in supporting wound healing. Three formulations were tested, based on chitosan (CH) and pullulan (P), associated with glycosaminoglycans (chondroitin sulfate - CS or hyaluronic acid - HA). A multidisciplinary approach has been used: chemico-physical characterization and preclinical evaluation allowed to obtain integrated information. This supports that CS gives distinctive properties and optimal features to the scaffold structure for promoting cell proliferation leading tissue reparation towards a complete skin restore.


Assuntos
Materiais Biocompatíveis/química , Quitosana/química , Sulfatos de Condroitina/química , Glucanos/química , Ácido Hialurônico/química , Engenharia Tecidual , Tecidos Suporte , Cicatrização , Materiais Biocompatíveis/uso terapêutico , Queimaduras/terapia , Humanos , Pele Artificial
19.
Adv Mater ; 31(30): e1901051, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31165524

RESUMO

Insulin-dependent patients with diabetes mellitus require multiple daily injections of exogenous insulin to combat hyperglycemia. However, administration of excess insulin can lead to hypoglycemia, a life-threatening condition characterized by abnormally low blood glucose levels (BGLs). To prevent hypoglycemia associated with intensive insulin therapy, a "smart" composite microneedle (cMN) patch is developed, which releases native glucagon at low glucose levels. The cMN patch is composed of a photo-crosslinked methacrylated hyaluronic acid (MeHA) microneedle array with embedded multifunctional microgels. The microgels incorporate zwitterionic moieties that stabilize loaded glucagon and phenylboronic acid moieties that provide glucose-dependent volume change to facilitate glucagon release. Hypoglycemia-triggered release of structurally unchanged glucagon from the cMN patch is demonstrated in vitro and in a rat model of type 1 diabetes (T1D). Transdermal application of the patch prevented insulin-induced hypoglycemia in the diabetic rats. This work is the first demonstration of a glucose-responsive glucagon-delivery MN patch for the prevention of hypoglycemia, which has a tremendous potential to reduce the dangers of intensive insulin therapy and improve the quality of life of patients with diabetes and their caregivers.


Assuntos
Glicemia/metabolismo , Glucagon/administração & dosagem , Hipoglicemia/tratamento farmacológico , Agulhas , Animais , Reagentes para Ligações Cruzadas/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Liberação Controlada de Fármacos , Géis , Humanos , Ácido Hialurônico/análogos & derivados , Ácido Hialurônico/química , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Metacrilatos/química , Processos Fotoquímicos , Polimerização , Ratos , Adesivo Transdérmico
20.
Carbohydr Polym ; 219: 423-430, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151543

RESUMO

Colloidal polyaniline dispersions stabilized with biocompatible polysaccharides, sodium hyaluronate and chitosan (both with two different molecular weights), were successfully formulated. The colloids were characterized by UV-vis spectra, particle-size distributions and morphology, as well as by their biological properties in terms of cytotoxicity and antibacterial activity. Colloids containing both chitosan and hyaluronate showed only mild cytotoxicities, which were mainly governed by the concentration of conducting polyaniline in the colloid. Antibacterial activity of the samples, however, depended both on the type of polysaccharide and the ratio between the stabilizer and polyaniline mass. The colloid synthetized using 0.2 M aniline hydrochloride, 0.1 M ammonium persulfate, and 1 wt.% sodium hyaluronate of molecular weight of 1.8-2.1 × 106 exhibited the highest antibacterial activity against both gram positive and gram negative bacteria. This formulation, therefore, allowed for the formation of potentially stimuli-responsive antibacterial colloidal particles with low cytotoxicity.


Assuntos
Compostos de Anilina , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Coloides , Ácido Hialurônico/química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Coloides/química , Coloides/farmacologia , Escherichia coli/efeitos dos fármacos , Camundongos , Células NIH 3T3 , Nanocompostos/química , Staphylococcus aureus/efeitos dos fármacos
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