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1.
Chem Commun (Camb) ; 55(61): 9039-9042, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292589
2.
Chem Commun (Camb) ; 55(60): 8876-8879, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31286121

RESUMO

Here we report template-free synthesis of imine-linked calix[4]arene hollow nanocapsules and their utility in the effective delivery of a poorly soluble cancer drug into tumor cells. These stimuli-responsive nanocapsules show high drug loading and release which resulted in a 40-fold higher cytotoxicity for breast cancer cell line over normal cells.


Assuntos
Antineoplásicos/farmacologia , Calixarenos/química , Camptotecina/farmacologia , Portadores de Fármacos/química , Nanocápsulas/química , Fenóis/química , Antineoplásicos/química , Calixarenos/síntese química , Calixarenos/toxicidade , Camptotecina/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Nanocápsulas/toxicidade , Fenóis/síntese química , Fenóis/toxicidade
4.
Nat Commun ; 10(1): 2566, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189915

RESUMO

There is clinical and scientific interest in developing local anesthetics with prolonged durations of effect from single injections. The need for such is highlighted by the current opioid epidemic. Site 1 sodium channel blockers such as tetrodotoxin (TTX) are extremely potent, and can provide very long nerve blocks but the duration is limited by the associated systemic toxicity. Here we report a system where slow release of TTX conjugated to a biocompatible and biodegradable polymer, poly(triol dicarboxylic acid)-co-poly(ethylene glycol) (TDP), is achieved by hydrolysis of ester linkages. Nerve block by the released TTX is enhanced by administration in a carrier with chemical permeation enhancer (CPE) properties. TTX release can be adjusted by tuning the hydrophilicity of the TDP polymer backbone. In vivo, 1.0-80.0 µg of TTX released from these polymers produced a range of durations of nerve block, from several hours to 3 days, with minimal systemic or local toxicity.


Assuntos
Anestésicos Locais/administração & dosagem , Portadores de Fármacos/química , Bloqueio Nervoso/métodos , Bloqueadores dos Canais de Sódio/administração & dosagem , Tetrodotoxina/administração & dosagem , Anestesia Local/métodos , Anestésicos Locais/farmacocinética , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/toxicidade , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Masculino , Camundongos , Permeabilidade , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacocinética , Tetrodotoxina/farmacocinética , Fatores de Tempo , Resultado do Tratamento
6.
Pharm Res ; 36(8): 115, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31161432

RESUMO

PURPOSE: Fibrin gels (FBGs) are potential delivery vehicles for many drugs, and can be easily prepared from purified components. We previously demonstrated their applicability for the release of different doxorubicin (Dox) nanoparticles used clinically or in an experimental stage, such as its inclusion complex with the amino ß-cyclodextrin polymer (oCD-NH2/Dox). Here we extend these studies by in vitro and in vivo evaluations. METHODS: An in vitro cytotoxicity model consisting of an overlay of a neuroblastoma (NB) cell-containing agar layer above a drug-loaded FBG layer was used. Local toxicity in vivo (histology and blood analysis) was studied in a mouse orthotopic NB model (SHSY5YLuc+ cells implanted into the left adrenal gland). RESULTS: In vitro data show that FBGs loaded with oCD-NH2/Dox have a slightly lower cytotoxicity against NB cell lines than those loaded with Dox. Fibrinogen (FG), and Ca2+ concentrations may modify this activity. In vivo data support a lower general and local toxicity for FBGs loaded with oCD-NH2/Dox than those loaded with Dox. CONCLUSION: Our results suggest a possible increase of the therapeutic index of Dox when locally administered through FBGs loaded with oCD-NH2/Dox, opening the possibility of using these releasing systems for the treatment of neuroblastoma.


Assuntos
Antineoplásicos/farmacologia , Celulose/química , Ciclodextrinas/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Fibrina/química , Nanopartículas/química , Neuroblastoma/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Portadores de Fármacos/toxicidade , Feminino , Géis , Xenoenxertos , Humanos , Camundongos Nus , Nanopartículas/toxicidade
7.
Carbohydr Polym ; 216: 1-16, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047045

RESUMO

Sinapic acid (SA) is a plant-derived phenolic compound known for its multiple biological properties, but its role in the promotion of bone formation is not yet well-studied. Moreover, the delivery of SA is hindered by its complex hydrophobic nature, limiting its bioavailability. In this study, we fabricated a drug delivery system using chitosan nanoparticles (nCS) loaded with SA at different concentrations. These were incorporated into polycaprolactone (PCL) fibers via an electrospinning method. nCS loaded with 50 µM SA in PCL fibers promoted osteoblast differentiation. Furthermore, SA treatment activated the osteogenesis signaling pathways in mouse mesenchymal stem cells. A critical-sized rat calvarial bone defect model system identified that the inclusion of SA into PCL/nCS fibers accelerated bone formation. Collectively, these data suggest that SA promoted osteoblast differentiation in vitro and bone formation in vivo, possibly by activating the TGF-ß1/BMP/Smads/Runx2 signaling pathways, suggesting SA might have therapeutic benefits in bone regeneration.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Quitosana/química , Ácidos Cumáricos/farmacologia , Portadores de Fármacos/química , Nanopartículas/química , Poliésteres/química , Animais , Diferenciação Celular/efeitos dos fármacos , Quitosana/toxicidade , Ácidos Cumáricos/toxicidade , Portadores de Fármacos/toxicidade , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Nanopartículas/toxicidade , Osteogênese/efeitos dos fármacos , Poliésteres/toxicidade , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Crânio/efeitos dos fármacos , Crânio/patologia , Resistência à Tração
8.
Carbohydr Polym ; 216: 129-139, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047049

RESUMO

A novel biotin and arginine modified hydroxypropyl-ß-cyclodextrin (biotin-Arg(pbf)-HP-ß-CD) was successfully synthesized. The hydroxyl groups of HP-ß-CD on the primary faces were coupled with carboxyl groups of biotin using arginine as the functional spacer. Using biotin-Arg(pbf)-HP-ß-CD as the carrier, paclitaxel (PTX)-loaded nanoparticles were developed by modified emulsion solvent evaporation method. The optimized PTX-loaded biotin-Arg(pbf)-HP-ß-CD nanoparticles had a mean diameter of 121.9 nm and zeta potential of -57.7 mV. Transmission electron microscopy (TEM) observation revealed that the nanoparticles were spherical in shape. XRD spectra confirmed the successful encapsulation of PTX. Moreover, in vitro and in vivo evaluations were performed to demonstrate the superior antitumor activity of the PTX-loaded nanoparticles. The cellular uptake study demonstrated the biotin receptor-mediated endocytosis of biotin-Arg(pbf)-HP-ß-CD nanoparticles and the increase of cellular uptake by introduction of biotin and arginine. It can be concluded that the biotin-Arg(pbf)-HP-ß-CD nanoparticles are efficient tumor-targeting drug delivery systems for PTX.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/uso terapêutico , 2-Hidroxipropil-beta-Ciclodextrina/síntese química , 2-Hidroxipropil-beta-Ciclodextrina/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Arginina/análogos & derivados , Arginina/síntese química , Arginina/toxicidade , Biotina/análogos & derivados , Biotina/síntese química , Biotina/toxicidade , Carcinoma/tratamento farmacológico , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Feminino , Humanos , Células MCF-7 , Camundongos , Nanopartículas/toxicidade , Paclitaxel/química , Paclitaxel/farmacologia , Tamanho da Partícula , Neoplasias do Colo do Útero/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Carbohydr Polym ; 216: 332-342, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047074

RESUMO

Chitosan has received a lot of attention as a carrier for small interfering RNA (siRNA), due to its capacity for complexation and intracellular release of these molecules. However, one of its limitations is its insolubility at neutral pH and the tendency towards aggregation of its nanoparticles in isotonic ionic strength. In this study, a series of amphipathic chitosans were synthesized by varying the degree of acetylation (DA) from ˜2 to ˜30 mol% and the degree of substitution (DS) from 5 to 25%. by tertiary amino groups (DEAE) The results showed that the adjustment of these parameters decreases the interparticle interactions mediated by hydrogen bonding to obtain nanoparticles with improved colloidal stability. siRNA-containing nanoparticles of 100 to 150 nm with low polydispersities (0.15-0.2) and slightly positive zeta potentials (˜+ 5 mV) were resistant to aggregation at pH 7.4 and ionic strength of 150 mM. This resistance to aggregation is provided by changes on the nanoparticle surface and highlights the importance of more organized self-assembly in providing colloidal stability at physiological conditions. Additionally, the PEGylation of the most promising vectors conferred favorable physicochemical properties to nanoparticles. The chitosans and their nanoparticles exhibited low toxicity and an efficient cell uptake, as probed by confocal microscopy of rhodamine labeled vectors. The results provide a new approach to overcome the limited stability of chitosan nanoparticles at physiological conditions and show the potential of these amphipathic chitosans as siRNA carriers.


Assuntos
Quitosana/análogos & derivados , Portadores de Fármacos/química , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Tensoativos/química , Anidridos Acéticos/química , Acetilação , Animais , Quitosana/síntese química , Quitosana/metabolismo , Quitosana/toxicidade , Dietilaminas/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Fluorescência , Corantes Fluorescentes/química , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Polietilenoglicóis/toxicidade , Células RAW 264.7 , RNA Interferente Pequeno/química , Rodaminas/química , Tensoativos/síntese química , Tensoativos/metabolismo , Tensoativos/toxicidade
10.
Carbohydr Polym ; 217: 35-45, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31079683

RESUMO

One of the most effective strategies to enhance the bioavailability and the therapeutic effect of hydrophobic drugs is the use of nanocarriers. We have used κ-carrageenan extracted from Kappaphycus alvarezii to produce oligocarrageenan via an enzymatic degradation process. Polycaprolactone (PCL) chains were grafted onto the oligocarrageenans using a protection/deprotection technique yielding polycaprolactone-grafted oligocarrageenan. The resulting amphiphilic copolymers formed spherical nanomicelles with a mean size of 187 ± 21 nm. Hydrophobic drugs such as curcumin were efficiently encapsulated in the micelles and released within 24-72 h in solution. The micelles were non-cytotoxic and facilitated the uptake of curcumin by endothelial EA-hy926 cells. They also increased the anti-inflammatory effect of curcumin in TNF-alpha-induced inflammation experiments. Finally, in vivo experiments supported a lack of toxicity in zebrafish and thus the potential use of polycaprolactone-grafted oligocarrageenan to improve the delivery of hydrophobic compounds to different organs, including liver, lung and brain as shown in mice.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Curcumina/farmacologia , Portadores de Fármacos/química , Micelas , Oligossacarídeos/química , Poliésteres/química , Acetilação , Animais , Anti-Inflamatórios não Esteroides/química , Carragenina/química , Carragenina/isolamento & purificação , Linhagem Celular , Curcumina/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Feminino , Gammaproteobacteria/enzimologia , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/isolamento & purificação , Humanos , Hidrólise , Masculino , Camundongos Endogâmicos C57BL , Oligossacarídeos/síntese química , Oligossacarídeos/isolamento & purificação , Oligossacarídeos/toxicidade , Oxazinas/química , Tamanho da Partícula , Poliésteres/síntese química , Poliésteres/toxicidade , Rodófitas/química , Rifampina/química , Peixe-Zebra
11.
Artif Cells Nanomed Biotechnol ; 47(1): 1702-1709, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062603

RESUMO

The objective of this study was to hydrophobically modify fenugreek gum (FG) and to further evaluate the potential application of the obtained derivative in liver-targeted drug delivery system. Stearic acid (C18) was conjugated with FG (FG-C18) by a simple esterification reaction. The obtained FG-C18 was then characterized on its chemical structure by Fourier transform infrared spectroscopy and 1H-nuclear magnetic resonance. The self-assembled nanomicelles (NMs) of FG-C18 in water were prepared by an ultrasonication method. The average diameter and zeta potential of FG-C18 NMs were 196.70 ± 6.12 nm and -31.79 ± 1.58 mV, respectively. FG-C18 NMs appeared as spherical particles under transmission electron microscopy and possessed a critical micellar concentration of 0.042 mg/ml by pyrene fluorescence probe method. A low toxicity of FG-C18 was revealed on both HepG2 and MCF-7 cells at 0.1-100 mg/ml. Haemolysis of FG-C18 was less than 5%. Cellular uptake of coumarin-6 into HepG2 cells was enhanced by treating with C6-loaded FG-C18 NMs compared to free coumarin-6. These results suggest that FG-C18 have a potential application for a liver targeted drug delivery.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Interações Hidrofóbicas e Hidrofílicas , Fígado/metabolismo , Gomas Vegetais/química , Gomas Vegetais/síntese química , Trigonella/química , Transporte Biológico , Técnicas de Química Sintética , Cumarínicos/química , Cumarínicos/metabolismo , Portadores de Fármacos/toxicidade , Hemólise/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Gomas Vegetais/toxicidade
12.
J Nanobiotechnology ; 17(1): 56, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992030

RESUMO

BACKGROUND: The increasing development and use of nanobiomaterials raises questions about their potential adverse effects on the environment after excretion and release. Published ecotoxicological data was searched for five polymeric nanobiomaterials [chitosan, polylactic acid (PLA), polyacrylonitrile (PAN), polyhydroxyalkanoates (PHA), and poly(lactic-glycolic acid) (PLGA)] and one inorganic nanobiomaterial [hydroxyapatite (HAP)] to evaluate the environmental hazards for freshwater and soil using a meta-analysis. If enough data was available, a probabilistic species sensitivity distribution (pSSD) and from this a predicted no effect concentration (PNEC) was calculated. If only one data point was available, a PNEC was calculated based on the most sensitive endpoint. Each material was classified either as "nano" or "non-nano", depending on the categorization in the original articles. When the original article specified that the material consisted of nanoparticles, the material was classified as nano; when nothing was mentioned, the material was classified as "non-nano". RESULTS: For PLA, PHA and PLGA, no published data on ecotoxicity was found and therefore no hazard assessment could be conducted. In soils, HAP was found to have the lowest PNEC with 0.3 mg/kg, followed by PAN and chitosan. In freshwater, chitosan was found to have the lowest PNEC with 5 µg/l, followed by nano-chitosan, HAP and PAN. CONCLUSION: Compared with other common pollutants, even the most sensitive of the selected nanobiomaterials, chitosan, is less toxic than engineered nanomaterials such as nano-ZnO and nano-Ag, some common antibiotics, heavy metals or organic pollutants such as triclosan. Given the current knowledge, the nanobiomaterials covered in this work therefore pose only little or no environmental hazard.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Durapatita/toxicidade , Substâncias Perigosas/toxicidade , Nanoestruturas/toxicidade , Polímeros/toxicidade , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Liberação Controlada de Fármacos , Durapatita/química , Água Doce/química , Substâncias Perigosas/química , Humanos , Modelos Estatísticos , Nanoestruturas/química , Polímeros/química , Poluentes do Solo/química , Poluentes do Solo/toxicidade , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidade
13.
Eur J Pharm Biopharm ; 139: 232-239, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954658

RESUMO

Fast in situ forming, chemically crosslinked hydrogels were prepared by the amidation reaction between N-succinimidyl ester end groups of multi-armed poly(ethylene glycol) (PEG) and amino surface groups of poly(amido amine) (PAMAM) dendrimer generation 2.0. To control the properties of the PEG/PAMAM hydrogels, PEGs were used with different arm numbers (4 or 8) as well as different linkers (amide or ester) between the PEG arms and their terminal N-succinimidyl ester groups. Oscillatory rheology measurements showed that the hydrogels form within seconds after mixing the PEG and PAMAM precursor solutions. The storage moduli increased with crosslink density and reached values up to 2.3 kPa for hydrogels based on 4-armed PEG. Gravimetrical degradation experiments demonstrated that hydrogels with ester linkages between PEG and PAMAM degrade within 2 days, whereas amide-linked hydrogels were stable for several months. The release of two different model drugs (fluorescein isothiocyanate-dextran with molecular weights of 4·103 and 2·106 g/mol, FITC-DEX4K and FITC-DEX2000K, respectively) from amide-linked hydrogels was characterized by an initial burst followed by diffusion-controlled release, of which the rate depended on the size of the drug. In contrast, the release of FITC-DEX2000K from ester-containing hydrogels was governed mainly by degradation of the hydrogels and could be modulated via the ratio between ester and amide linkages. In vitro cytotoxicity experiments indicated that the PEG/PAMAM hydrogels are non-toxic to mouse fibroblasts. These in situ forming PEG/PAMAM hydrogels can be tuned with a broad range of mechanical, degradation and release properties and therefore hold promise as a platform for the delivery of therapeutic agents.


Assuntos
Dendrímeros/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Hidrogéis/química , Polietilenoglicóis/química , Animais , Linhagem Celular , Dendrímeros/toxicidade , Dextranos/administração & dosagem , Dextranos/farmacocinética , Portadores de Fármacos/toxicidade , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Fibroblastos , Fluoresceína-5-Isotiocianato/administração & dosagem , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Hidrogéis/toxicidade , Camundongos , Polietilenoglicóis/toxicidade , Reologia , Fatores de Tempo , Testes de Toxicidade
14.
Carbohydr Polym ; 215: 160-169, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981341

RESUMO

Inulin has interesting physicochemical and functional properties, and therefore a wide range of applications in the food and medical industries. It has gained great traction due to its ability to form nanoparticles and its possible application as nanovehicle for drug delivery. In this work, we demonstrated that the enzymatically-synthesized high molecular weight (HMW) inulin forms stable spherical nanoparticles with an average diameter of 112 ± 5 nm. The self-assemblage of HMW inulin nanoparticles is carried out during enzymatic synthesis of the polymer, and become detectable after a certain critical aggregation concentration (CAC) is reached. Both, the CAC and nanoparticle size are influenced by the reaction temperature. These nanoparticles are not toxic for peripheral blood mononuclear cells, at concentrations below 200 µg/mL; no significant prebiotic potential was detected in cultures of 13 probiotic strains. This work contributes to a better understanding of the formation of HMW inulin nanoparticles and their biological properties.


Assuntos
Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Hexosiltransferases/química , Inulina/síntese química , Inulina/toxicidade , Leuconostoc/enzimologia , Nanopartículas/química , Nanopartículas/toxicidade , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Inulina/química , Leucócitos Mononucleares/efeitos dos fármacos , Peso Molecular , Prebióticos , Probióticos
15.
Artif Cells Nanomed Biotechnol ; 47(1): 1428-1436, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31007068

RESUMO

Nanoparticles (NPs) have gained importance in addressing drug delivery challenges across biological barriers. Here, we reformulated pentamidine, a drug used to treat Human African Trypanosomiasis (HAT) in polymer based nanoparticles and liposomes and compared their capability to enhance pentamidine penetration across blood brain barrier (BBB). Size, polydispersity index, zeta potential, morphology, pentamidine loading and drug release profiles were determined by various methods. Cytotoxicity was tested against the immortalized mouse brain endothelioma cells over 96 h. Moreover, cells monolayer integrity and transportation ability were examined for 24 h. Pentamidine-loaded polycaprolactone (PCL) nanoparticles had a mean size of 267.58, PDI of 0.25 and zeta potential of -28.1 mV and pentamidine-loaded liposomes had a mean size of 119.61 nm, PDI of 0.25 and zeta potential 11.78. Pentamidine loading was 0.16 µg/mg (w/w) and 0.17 µg/mg (w/w) in PCL NPs and liposomes respectively. PCL nanoparticles and liposomes released 12.13% and 22.21% of pentamidine respectively after 24 h. Liposomes transported 87% of the dose, PCL NPs 66% of the dose and free pentamidine penetration was 63% of the dose. These results suggest that liposomes are comparatively promising nanocarriers for transportation of pentamidine across BBB.


Assuntos
Barreira Hematoencefálica/metabolismo , Portadores de Fármacos/química , Lipossomos/química , Nanopartículas/química , Pentamidina/metabolismo , Fosfatidilcolinas/química , Poliésteres/química , Animais , Linhagem Celular , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Camundongos , Pentamidina/química
16.
Artif Cells Nanomed Biotechnol ; 47(1): 1543-1558, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31007088

RESUMO

Mannosylation of nanovaccine is an appropriate strategy for targeting the mannose receptors on DCs. Here, HBsAg and mannose loaded on the surface of iron oxide nanoparticles to increases HBsAg vaccine potency. Nanoparticles are made by co-precipitation method and bonded to the HBsAg and mannose by chemical bonding. The physicochemical properties of nano-vaccines, their toxicity and antigenicity were determined. The synthesized nano-vaccine showed spherical shape with a mean particle size of 60 nm, a zeta potential of -44 mV, an antigen-binding efficiency of around 100% and for mannose 78%. In vitro release of nanoparticles exhibited about 30% at the first day and about 60% until the third day. SDSPAGE analysis confirmed structural integrity of HBsAg loaded on nanoparticles. The HBsAg-loaded LCMNP and MLCMNP nanoparticles had no toxic effects on HEK293 cell line. The quantification of the intracellular Fe by ICP-OES as a criterion of nano-vaccine uptake revealed mannose intensify uptake of MLCMNP. In addition, mannose in the structure of MLCMNP improved IL-6, TNF-α and IFN-γ (>16 fold) cytokines genes expression by macrophage/dendritic cells after exposure in 12 h. Immunization of experimental mice (subcutaneously, two times with 2-week intervals) with 5 µg of HBsAg loaded on MLCMNP nanoparticles increased specific total IgG and IgG2a/IgG1 ratio. In addition, TNF-α, IL-12, IL-2 and IL-4 cytokines in mannosylated nano-vaccine increased versus nano-vaccine group while lymphocyte proliferation and IFN-γ responses in the targeted nano-vaccine group show a tiny increase versus the nano-vaccine group. The results show that mannosylated nano-vaccine promotes higher level of cellular and humoural immune responses against HBsAg nano-vaccine.


Assuntos
Portadores de Fármacos/química , Compostos Férricos/química , Antígenos de Superfície da Hepatite B/química , Antígenos de Superfície da Hepatite B/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Manose/química , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Portadores de Fármacos/toxicidade , Feminino , Células HEK293 , Humanos , Imunoglobulina G/metabolismo , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Vacinas/química , Vacinas/farmacologia
17.
Biomater Sci ; 7(5): 1984-1994, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30834395

RESUMO

Zwitterionic complexes in aqueous solutions have been extensively explored as the most promising candidate in drug delivery systems for targeted cancer chemotherapy. A POSS-based supramolecular AD-POSS-(sulfobetaine)7/CD-PLLA zwitterionic complex has been fabricated via a combination of efficient click chemistry and host-guest interaction. The well-defined POSS-based zwitterionic polymer could self-assemble into spherical nanoparticles that encapsulated a model cancer drug (DOX) and exhibited drug release in a controlled manner in a faintly acidic environment. On account of the hydrophilic block with cationic and anionic groups in the microscopic range that can form a hydration layer via electrostatic interactions, these drug-loaded nanoparticles exhibited excellent stability in a tumor intracellular microenvironment or under other pH conditions as revealed by dynamic light scattering (DLS) and zeta potential measurements. In vitro experiments demonstrated that these POSS-based nanoparticles had high resistance to non-specific protein absorption and low cytotoxicity against normal cells. Moreover, these DOX-loaded aggregates could be accumulated and effectively internalized by HeLa and MCF-7 tumor cells, exhibiting effective cellular proliferation inhibition via the release of anticancer agents. Therefore, these POSS-based supramolecular amphiphilic zwitterionic complexes, relying on the simple supramolecular interaction and efficient click reaction, could further emerge as a potential universal anticancer drug nanocarrier system for multifunctional cancer chemotherapy.


Assuntos
Portadores de Fármacos/química , Interações Hidrofóbicas e Hidrofílicas , Compostos de Organossilício/química , Células 3T3 , Absorção Fisico-Química , Animais , Transporte Biológico , Bovinos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Teste de Materiais , Camundongos , Nanopartículas/química , Compostos de Organossilício/metabolismo , Compostos de Organossilício/toxicidade , Poliésteres/química , Soroalbumina Bovina/química
18.
Biomater Sci ; 7(5): 2023-2036, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30839983

RESUMO

Intratumoral delivery of chemotherapeutic agents may permit the localization of drugs in tumors, decrease nonspecific targeting and increase efficacy. The pH-responsive peptide hydrogel is considered a suitable carrier for chemotherapeutics via intratumoral injection. Thus, a study was carried out to develop a paclitaxel (PTX) drug delivery system using a pH-responsive FER-8 peptide hydrogel for tumor targeting. The pH-sensitive hydrogel system was characterized for loading capacity, acid sensitivity, structure, rheology, morphology, drug release, in vitro cytotoxicity and in vivo efficacy in H22 tumor-bearing mice. The stable FER-8 peptide hydrogel with high drug-loading capacity was formed at pH 7.4 by the self-assembly of peptide, whereas higher degradation was observed at an acidic pH. Circular dichroism and rheology confirmed the suitable meshwork structure and enhanced mechanical properties of the hydrogel. The FER-8 peptide hydrogel fibers were found to have an average size less than 500 nm at pH 7.4, which was confirmed by TEM and DLS analysis. Sustained release of PTX at pH 5.5 was observed for the FER-8 peptide hydrogel (HG-PTX) for almost 1 week. In vitro cytotoxicity studies indicated that the FER-8 peptide hydrogel increased the drug accumulation in HepG2 cells and effectively inhibited the growth of HepG2 tumor cells compared with free drugs. Furthermore, in vivo studies using H22-bearing mice indicated that the paclitaxel-loaded FER-8 peptide hydrogel significantly increased the amount of drugs in tumor tissues and showed prolonged retention (96 hours) at the tumor site by intratumoral injection. The in vivo anti-tumor studies confirmed the pH-sensitive properties of HG-PTX, which allowed the drug to be triggered by the acidic pH environment at tumor sites, provided sustained delivery of the drug and enhanced tumor inhibition. In conclusion, HG-PTX provides an attractive strategy and potential vehicle for efficient anti-cancer drug delivery. The carrier can enhance tumor targeting, prolong retention, reduce systemic side effects and increase the accumulation of drugs at the tumor site.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Hidrogéis/química , Paclitaxel/química , Paclitaxel/farmacologia , Peptídeos/química , Animais , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Teste de Materiais , Camundongos , Peptídeos/farmacocinética , Peptídeos/toxicidade , Distribuição Tecidual
19.
Biomater Sci ; 7(5): 2134-2143, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30869660

RESUMO

Smart micelles which undergo dramatic property changes in response to temperature have aroused extensive interest in specific cancer therapy. To date, studies on thermosensitive polymers have mainly focused on lower critical solution temperature (LCST) polymers. Materials with upper critical solution temperature (UCST) which can swell and disassemble at elevated temperatures have much less been documented, although they have been reported to be ideal carriers for quick and complete drug release upon applying a stimulus. Here, magnetic micelles with UCST are developed for doxorubicin (DOX) delivery. Hydrophobic Fe3O4 magnetic nanoparticles with a particle size of 8 nm are fabricated and enveloped in an amphiphilic polymer, poly(AAm-co-AN)-g-PEG (PAAP), to form UCST micelles (Fe3O4@PAAP). The resulting micelles exhibit excellent photothermal effects and burst drug release in response to near infrared (NIR) laser irradiation. The in vitro and in vivo antitumor experiments indicate that DOX-Fe3O4@PAAP micelles can significantly enhance the therapeutic effect upon NIR light irradiation. A novel thermosensitive platform is thus offered for in situ drug release and combined photothermal-chemotherapy, holding a favorable prospect for cancer therapy.


Assuntos
Portadores de Fármacos/química , Liberação Controlada de Fármacos , Raios Infravermelhos , Fenômenos Magnéticos , Micelas , Temperatura Ambiente , Animais , Compostos Azo/química , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Nanopartículas de Magnetita/química , Camundongos , Piridinas/química , Soluções , Distribuição Tecidual
20.
Carbohydr Polym ; 214: 221-233, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30925992

RESUMO

This study has developed a versatile nano-system with the combined advantages of photothermal effect, active tumor-targeting, temperature-sensitive drug release, and photoacoustic imaging. The nano-system consists of the core of the phase change material (PCM), the outer polypyrrole (PPY) shell and the hyaluronic acid (HA) modified in the PPY shell. The obtained composite nanoparticles (denoted as DTX/PPN@PPY@HA) were spherical with a mean diameter of about 232.7 nm. In vivo and in vitro photoacoustic imaging experiments show that DTX/PPN@PPY@HA is an effective photoacoustic contrast agent, which can be used for accurate localization of tumor region and real-time guidance of photothermal chemotherapy. DTX/PPN@PPY@HA shows good photothermal effects and temperature-sensitive drug release. In addition, cellular experiments showed that DTX/PPN@PPY@HA could be efficiently internalized into tumor cells and produce significant cytotoxicity with the help of near-infrared (NIR) laser. Furthermore, the remarkable inhibition of DTX/PPN@PPY@HA against tumor growth was achieved in 4T1 tumor-bearing mice model.


Assuntos
Antineoplásicos/farmacologia , Meios de Contraste/química , Docetaxel/farmacologia , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Animais , Antineoplásicos/administração & dosagem , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Meios de Contraste/administração & dosagem , Meios de Contraste/efeitos da radiação , Meios de Contraste/toxicidade , Docetaxel/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/efeitos da radiação , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes/química , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/efeitos da radiação , Ácido Hialurônico/toxicidade , Raios Infravermelhos , Injeções Intravenosas , Pulmão/patologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/efeitos da radiação , Nanopartículas/toxicidade , Tamanho da Partícula , Fosfolipídeos/administração & dosagem , Fosfolipídeos/química , Fosfolipídeos/efeitos da radiação , Fosfolipídeos/toxicidade , Técnicas Fotoacústicas/métodos , Polímeros/administração & dosagem , Polímeros/química , Polímeros/efeitos da radiação , Polímeros/toxicidade , Pirróis/administração & dosagem , Pirróis/química , Pirróis/efeitos da radiação , Pirróis/toxicidade , Temperatura Ambiente , Nanomedicina Teranóstica/métodos
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