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1.
AAPS PharmSciTech ; 20(8): 320, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646399

RESUMO

The in vitro drug release in an aqueous medium is a critical performance metric for a sustained release drug product. During long-term release studies, drugs may degrade in the release medium, and such degradation can lead to errors in drug release quantitation. Using dexamethasone as a model drug and LC-MS/MS methods employing dexamethasone-d4 as an internal standard, this study identified that dexamethasone can degrade into 13 major degradation products in phosphate buffered saline (PBS) as a function of time, temperature (25, 37, and 45°C), and light exposure. A putative scheme for dexamethasone degradation pathways in PBS has been proposed. In proof-of-concept studies, the analytical method was used to quantitate dexamethasone and its degradation products during in vitro release studies with sustained release dexamethasone-poly(D,L-lactide-co-glycolide) (PLGA) implants incubated in phosphate buffer saline (PBS). Further, mathematical approaches were developed to estimate drug release from implants after accounting for drug degradation in PBS. The LC-MS/MS analytical method and the mathematical approaches developed could be used for assessing the stability and/or release of dexamethasone during manufacturing, storage, and use of various dosage forms.


Assuntos
Anti-Inflamatórios/farmacocinética , Dexametasona/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Água/metabolismo , Anti-Inflamatórios/administração & dosagem , Cromatografia Líquida/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Dexametasona/administração & dosagem , Implantes de Medicamento , Liberação Controlada de Fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Espectrometria de Massas em Tandem/métodos
2.
Biomater Sci ; 7(10): 4060-4074, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31475710

RESUMO

Combined photothermal-chemotherapy guided by multimodal imaging is a promising strategy for cancer diagnosis and treatment. Multifunctional nanoparticles, such as those comprising organic and inorganic compounds, have been extensively investigated for combined photothermal-chemotherapy; however, their application is still limited by their potential long-term toxicity and lack of contrast properties. To solve these problems, in this study, a new type of multifunctional nanoparticle for combined photothermal-chemotherapy guided by dual-modality imaging was prepared with endogenous melanin by multistep emulsification to enhance tumor ablation. The nanoparticles were coated with poly(lactide-co-glycolic acid) (PLGA) and loaded with paclitaxel (PTX), encapsulated melanin and perfluoropentane (PFP). The materials in the nanoparticles were endogenous, ensuring high stability, biocompatibility, and biosafety. Nanoparticles irradiated with a laser, which induced their phase transformation into microbubbles, exhibited high photothermal conversion efficiency, thereby achieving photoacoustic (PA)/ultrasound (US) dual-modality imaging to determine tumor location, boundary, and size and to monitor drug distribution. Furthermore, optical droplet vaporization (ODV) of the nanoparticles could trigger the release of PTX; thus, these nanoparticles are a useful drug carrier. In vivo and in vitro experiments revealed that a strong synergistic antitumor effect was achieved by combining the photothermal properties of the nanoparticles with a chemotherapy drug. Importantly, the cavitation, thermoelastic expansion, and sonoporation caused by the phase transformation of the nanoparticles could directly damage the tumors. These processes also promoted the release, penetration and absorption of the drug, further enhancing the effect of combined photothermal-chemotherapy on tumor suppression. Therefore, the multifunctional nanoparticles prepared in this study provide a new strategy of using endogenous materials for controlled near-infrared (NIR)-responsive drug release and combined photothermal-chemotherapy guided by multimodal imaging.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Fluorcarbonetos/administração & dosagem , Melaninas/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/terapia , Paclitaxel/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Preparações de Ação Retardada/administração & dosagem , Feminino , Fluorcarbonetos/farmacocinética , Células Endoteliais da Veia Umbilical Humana , Humanos , Melaninas/farmacocinética , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Técnicas Fotoacústicas , Fototerapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Distribuição Tecidual , Ultrassonografia
3.
Biomater Sci ; 7(10): 4299-4309, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408067

RESUMO

To effectively alleviate acute severe ulcerative colitis (ASUC), we developed a colon-specific delivery system-PLGA-KPV/MMT/CS multifunctional medicinal nanoparticles loaded with cyclosporine A (CyA). The lysine-proline-valine (KPV) tripeptide, which possesses anti-inflammatory properties and high affinity to peptide transporter 1 (PepT1), can target therapy-related cells (colonic epithelial cells and macrophages) via overexpression of PepT1. Montmorillonite (MMT)/chitosan (CS) coating can reduce CyA leakage in the upper gastrointestinal tract (GIT) and enhance nanoparticle adhesion to the inflamed colon. The bio-distribution demonstrated that nanoparticles can specifically accumulate in the inflamed tissues and can be retained for up to 36 h. After being treated with the CyA-PLGA-KPV/MMT/CS nanoparticles (PKMCN), the mice with DSS-induced ulcerative colitis exhibited significant improvements in body weight, colon length, and disease activity index. Moreover, biochemistry and immunohistochemical analysis showed that the PKMCN treatment group performed as well as the healthy group. Intriguingly, PKMCN without CyA also presented marked therapeutic effects. Our results suggested that PKMCN could be a promising drug delivery system for ASUC therapy by targeting inflamed cells, prolonging curative time, and mitigating colitis.


Assuntos
Anti-Inflamatórios/administração & dosagem , Colite Ulcerativa/metabolismo , Ciclosporina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Oligopeptídeos/administração & dosagem , Transportador 1 de Peptídeos/metabolismo , Animais , Anti-Inflamatórios/química , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/patologia , Ciclosporina/química , Sulfato de Dextrana , Portadores de Fármacos/química , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Oligopeptídeos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
4.
Int J Pharm ; 568: 118508, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299337

RESUMO

Imatinib (IMT) is a selective tyrosine kinase inhibitor clinically used for treating chronic myeloid leukemia and malignant gastrointestinal stromal tumors. However, oral administration of IMT is challenged by its high oral dose, low intestinal solubility and adverse reactions. This work aimed to investigate the effect of galactose ligand on polymeric nanoparticles-facilitated oral absorption of IMT. N-oleoyl-D-galactosamine was synthesized for fabricating biomimetic galactose-modified nanoparticles (GNPs) in an attempt to improve the oral bioavailability of IMT. IMT-loaded GNPs (IMT-GNPs) were prepared using a solvent diffusion technique and characterized by particle size, morphology, and entrapment efficiency (EE). The in vitro release and in vivo oral bioavailability of IMT-GNPs were comparatively studied with bulk IMT and IMT-loaded nanoparticles (IMT-NPs), respectively. The resultant IMT-GNPs were 122.0 nm around in particle size with a polydispersity index (PDI) of 0.201. IMT-GNPs possessed a high EE (93.06%) and exhibited a sustained effect on drug release. After oral administration, IMT-GNPs significantly enhanced the oral bioavailability of IMT, up to 152.3% relative to IMT suspensions, whereas IMT-NPs merely resulted in an increase to 115.2%. Cellular uptake and ex vivo intestinal transport imaging demonstrated that GNPs were armed with higher cellular affinity and intestinal epithelial permeability compared with galactose-free IMT-NPs. These results provide solid evidence that galactose modification has great potential to ulteriorly promote the oral absorption of IMT on the base of nanoparticles, which may be conducive to achieve the synergy and attenuation of IMT.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Galactose/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Galactose/análogos & derivados , Galactose/farmacocinética , Humanos , Mesilato de Imatinib/química , Mesilato de Imatinib/farmacocinética , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos Sprague-Dawley
5.
AAPS PharmSciTech ; 20(6): 228, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227940

RESUMO

In order to obtain sustained release of biodegradable microspheres, the purpose of this study was to design and characterize an injectable octreotide microsphere-gel composite system. The octreotide microspheres were prepared by phase separation method, which used PLGA as a carrier material, dimethyl silicone oil as a phase separation reagent, and n-heptane-Span 80 as a hardener. In addition, we used poloxamer 407 (PL 407) and poloxamer 188 (PL 188) as the thermosensitive gel matrix material. The composite system was obtained by scattering octreotide microspheres in a poloxamer gel. In vitro data showed that the release time of the composite system could last for about 50 days. Because of the blocking and control actions of the poloxamer gel, the initial burst release was significantly reduced and the plateau phase was eliminated. Pharmacokinetic data showed that the burst release of the composite system was significantly less than that of the microspheres, i.e., Cmax1 was reduced by about half. From day 2 to day 50, higher plasma concentration levels and more stable drug release behavior were exhibited. In addition, the good biocompatibility of the composite system in vivo was also demonstrated by hematoxylin-eosin (HE) staining. Therefore, the octreotide microsphere-gel composite system will be a new direction for hydrophilic polypeptide/protein-loaded sustained release dosage forms with high pharmacological activity.


Assuntos
Géis/química , Microesferas , Octreotida/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Animais , Liberação Controlada de Fármacos , Masculino , Octreotida/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos , Ratos Sprague-Dawley
6.
Int J Pharm ; 567: 118449, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226473

RESUMO

In the present study, we have prepared microRNA(miR)-124-loaded Rabies virus glycoprotein (RVG)29 surface-conjugated polymeric nanoparticles (NPs) to improve neuroinflammation in Parkinson's disease (PD). We hypothesize that an increase in the intracellular concentration of miR-124 will result in a better prognosis for Parkinson's disease. Minimal toxicity for the RVG29 NPs was observed at concentrations <100 µg/mL, while the cell viability of cells treated with blank NPs at concentrations of 200 µg/mL markedly decreased, indicating the safety of the carrier system. Results showed that mRNA levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-6, significantly increased upon lipopolysaccharide (LPS) administration. However, the mRNA levels of these cytokines reflected those of the miR-NPs-treated control group, indicating the influence of miR-124 exposure. After transfection with miR-NPs, levels of pro-inflammatory cytokines and neuroprotective molecules were reduced and increased, respectively. Administration of LPS significantly increased the levels of mitogen activated protein kinase kinase kinase (MEKK)3 and P-P65 levels, while transfection with miR-NPs significantly reduced the expression of both MEKK3 and P-P65, reflecting that of the control. This research has revealed that miR-124 could target both the MEKK3 and nuclear factor kappa light chain enhancer of activated B cell (NF-Kb) pathways, while also reducing inflammatory cytokine levels. In addition, a 3-fold decrease in apoptosis was observed in miR-NP transfected cells. The exogenous delivery of miR-NPs significantly downregulated MEKK3 expression in animal studies, as outlined by immunohistochemical staining (IHC). Overall, miR-NPs have the potential to inhibit pro-inflammatory signaling and enhance neuroprotection in PD.


Assuntos
MicroRNAs/administração & dosagem , Nanopartículas/administração & dosagem , Transtornos Parkinsonianos/terapia , Fragmentos de Peptídeos/administração & dosagem , Proteínas do Envelope Viral/administração & dosagem , Animais , Liberação Controlada de Fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/química , Nanopartículas/química , Fragmentos de Peptídeos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteínas do Envelope Viral/química
7.
Int J Pharm ; 566: 541-548, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31173801

RESUMO

The effect of mild hyperthermia (MHT) on nanoparticle (NP) accumulation in rat model liver metastasis and the contribution of neoplastic and non-neoplastic cells were characterized. CdSe/ZnS QD-doped poly(lactic-co-glycolic acid) (PLGA) NPs (155 ±â€¯10 nm) were delivered via the ileocolic vein to metastatic livers 15 min after localized MW irradiation (1 min, 41 °C) or in normothermia (37 °C, NT). Quantitative analysis of tissue sections by confocal fluorescence microscopy 1 h after NP injection showed no NP tumor accumulation in NT. On the contrary, MHT increased NP association with tumor, compared to normal tissue. Counterstaining of specific markers showed that the MHT effect is due to an increased NP endocytosis not only by tumor cells, but also by hepatocytes at the growing tumor edge and, to a minor extent, by tumor-associated macrophages. High-NP capturing hepatocytes, close to the tumor, may be a relevant phenomenon in MHT-induced increased targeting of NPs to liver metastasis, influencing their therapeutic efficacy.


Assuntos
Portadores de Fármacos/administração & dosagem , Hepatócitos/metabolismo , Hipertermia Induzida , Neoplasias Hepáticas/metabolismo , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Animais , Compostos de Cádmio/administração & dosagem , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Macrófagos do Fígado/metabolismo , Neoplasias Hepáticas/secundário , Macrófagos/metabolismo , Masculino , Ratos , Compostos de Selênio/administração & dosagem , Sulfetos/administração & dosagem , Compostos de Zinco/administração & dosagem
8.
J Bone Miner Metab ; 37(6): 1026-1035, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31076895

RESUMO

Composite materials ß-tricalcium phosphate (ß-TCP) and poly-lactic-co-glycolic acid (PLGA) have achieved stable bone regeneration without cell transplantation in previous studies. Recent research shows that aspirin (ASP) has great potential in promoting bone regeneration. The objective of the present study was to incorporate PLGA into ß-TCP combined with a lower single-dose local administration of ASP to enhance its in vivo biodegradation and bone tissue growth. After the creation of a rodent critical-sized femoral metaphyseal bone defect, PLGA -modified ß-TCP (TP) was prepared by mixing sieved granules of ß-TCP and PLGA (50:50, v/v) for medical use, then TP with dripped 50 µg/0.1 ml and 100 µg/0.1 ml aspirin solution was implanted into the defect of OVX rats until death at 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, biomechanics and real time RT-PCR. The results of our study show that a single-dose local administration of ASP combined with the local usage of TP can increase the healing of defects in OVX rats. Single-dose local administration of aspirin can improve the transcription of genes involved in the regulation of bone formation and vascularization in the defect area, and inhibits osteoclast activity. Furthermore, treatments with a higher single-dose local administration of ASP and TP showed a stronger effect on accelerating the local bone formation than while using a lower dose of ASP. The results from our study demonstrate that the combination of a single-dose local administration of ASP and ß-TCP/PLGA had an additive effect on local bone formation in osteoporosis rats, and bone regeneration by PLGA/ß-TCP/ASP occured in a dose-dependent manner.


Assuntos
Aspirina/administração & dosagem , Aspirina/uso terapêutico , Regeneração Óssea , Fosfatos de Cálcio/administração & dosagem , Osteoporose/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Animais , Aspirina/farmacologia , Biomarcadores/metabolismo , Fenômenos Biomecânicos , Regeneração Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/diagnóstico por imagem , Ovariectomia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Microtomografia por Raio-X
9.
Int J Pharm ; 565: 242-257, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31077762

RESUMO

Encapsulation of protein vaccines in biodegradable nanoparticles (NP) increases T-cell expansion after mucosal immunization but requires incorporating a suitable immunostimulant to increase long-lived memory T-cells. EP67 is a clinically viable, host-derived peptide agonist of the C5a receptor that selectively activates antigen presenting cells over neutrophils. We previously found that encapsulating EP67-conjugated CTL peptide vaccines in NP increases long-lived memory subsets of CTL after respiratory immunization. Thus, we hypothesized that alternatively conjugating EP67 to the NP surface can increase long-lived mucosal and systemic memory T-cells generated by encapsulated protein vaccines. We found that respiratory immunization of naïve female C57BL/6 mice with LPS-free ovalbumin (OVA) encapsulated in PLGA 50:50 NP (∼380 nm diameter) surface-conjugated with ∼0.1 wt% EP67 through 2 kDa PEG linkers (i) increased T-cell expansion and long-lived memory subsets of OVA323-339-specific CD4+ and OVA257-264-specific CD8a+ T-cells in the lungs (CD44HI/CD127/KLRG1) and spleen (CD44HI/CD127/KLRG1/CD62L) and (ii) decreased peak CFU of OVA-expressing L. monocytogenes (LM-OVA) in the lungs, liver, and spleen after respiratory challenge vs. encapsulation in unmodified NP. Thus, conjugating EP67 to the NP surface is one approach to increase the generation of long-lived mucosal and systemic memory T-cells by encapsulated protein vaccines after respiratory immunization.


Assuntos
Nanopartículas/administração & dosagem , Oligopeptídeos/administração & dosagem , Ovalbumina/administração & dosagem , Infecções Respiratórias/prevenção & controle , Linfócitos T/efeitos dos fármacos , Vacinas/administração & dosagem , Animais , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Imunização , Memória Imunológica , Masculino , Camundongos Endogâmicos C57BL , Membrana Mucosa/imunologia , Nanopartículas/química , Oligopeptídeos/química , Ovalbumina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Baço/citologia , Propriedades de Superfície , Linfócitos T/imunologia , Vacinas/química
10.
Int J Pharm ; 565: 95-107, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31071416

RESUMO

Polymer/bioceramic composite micro-particles have been used for bone regeneration in order to address weak mechanical properties/bioactivity of polymers and to enable easy filling of irregular bone defects through minimally invasive injection procedure. The purpose of this study was to determine whether injectable apatite-coated atorvastatin (AT) loaded Poly (d,l-lactide-co-glycolide) (PLGA) micro-particles can support osteogenic differentiation of adipose derived mesenchymal stem cells(ADMSCs). Particle preparation conditions (oil-in-water (O/W) emulsion), were carefully adjusted to yield uniform particles of about 20-50 µm in diameter. Taking a solid in oil-in water (S/O/W) emulsion strategy, it became possible to load atorvastatin (10 wt%) in the micro-particles without deformation. The particles were then coated with HAp by incubation in 10X simulated body fluid (SBF). The apatite coating layer was similar to apatite in natural bone, as demonstrated by SEM, XRD, and FTIR analyses. Adipose derived mesenchymal stem cells (ADMSCs), were cultured on the micro-particles and calcium deposition measurement was performed through Alizarin Red assay. Initial cell adhesion did not differ significantly between the samples and the control. The strongest osteogenic differentiation was observed on PLGA-AT-HAp in both the osteogenic and non osteogenic culture media, while PLGA-AT slightly decreased and PLGA-HAp slightly increased osteogenic differentiation of the cells, indicating suitability of PLGA-AT-HAp as an injectable tissue engineering system.


Assuntos
Atorvastatina/administração & dosagem , Durapatita/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Células-Tronco Mesenquimais/efeitos dos fármacos , Microesferas , Osteogênese/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Animais , Atorvastatina/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Liberação Controlada de Fármacos , Durapatita/química , Fibroblastos/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Células-Tronco Mesenquimais/citologia , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
11.
Drug Deliv Transl Res ; 9(3): 707-720, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30949939

RESUMO

Dexamethasone is a widely used drug in medical and biological applications. Since the systematic and controllable release of this drug is of significant importance, encapsulation of this anti-inflammatory drug in poly(lactic-co-glycolic acid) (PLGA) nanoparticles can minimize uncontrolled issues. As dexamethasone-encapsulated PLGA nanoparticles are synthesized in the presence of organic solvents, poly(dimethylsiloxane) (PDMS)-based microchannels collapse due to the swelling problem. In present study, PTFE nanoparticles were used for the surface modification of the microchannels to prevent absorption and adhesion of solvents into the microchannels' wall. The contact angle analysis of microchips after coating showed that the surface of microchannels bear the superhydrophobicity feature (140.30°) and SEM images revealed that PTFE covered the surface of PDMS, favorably. Then, the prepared microchip was tested for the synthesis of dexamethasone-loaded nanoparticles. SEM and atomic force microscopy (AFM) images of the synthesized nanoparticles represented that there was not any evidence of adhesion or absorption of nanoparticles. Furthermore, the monodispersity of nanoparticles was discernible. As AFM results revealed, the average diameters of 47, 63, and 82 nm were achieved for flow ratios of 0.01, 0.05, and 0.1, respectively. To evaluate the drug efficiency, cumulative release and encapsulation efficiency were analyzed which showed much more efficiency than the synthesized nanoparticles in the bulk mode. In addition, MTT test revealed that nanoparticles could be considered as a non-toxic material. Since the synthesis of drug-loaded nanoparticles is ubiquitous in laboratory experiments, the approach presented in this study can render more versatility in this regard.


Assuntos
Anti-Inflamatórios/química , Dexametasona/química , Dimetilpolisiloxanos/química , Dispositivos Lab-On-A-Chip , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Politetrafluoretileno/química , Anti-Inflamatórios/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dexametasona/administração & dosagem , Dimetilpolisiloxanos/administração & dosagem , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Politetrafluoretileno/administração & dosagem
12.
Int J Pharm ; 563: 228-236, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30959236

RESUMO

Bevacizumab, a vascular endothelial growth factor (VEGF)-targeting drug, is widely used as an off-label therapeutic for age-related macular degeneration (AMD). To reduce the monthly administration frequency, this study investigated microspheres comprising a poly(d, l-lactide-co-glycolide)/poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PLGA/PCADK) blend that could be loaded with bevacizumab-dextran particles using solid-in-oil-in-water (S/O/W) emulsification. Control microspheres were also prepared through water-in-oil-in-water (W/O/W) emulsification. The structural stability of bevacizumab in the polymer monomers was analyzed using dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size exclusion chromatography (SEC-HPLC), circular dichroism (CD) and fluorescence spectroscopy. Subsequently, microspheres were prepared and evaluated in terms of their morphology, encapsulation efficiency and release behavior. PLGA/PCADK microspheres prepared by the S/O/W method with <20% PCADK showed a smooth spherical structure with a uniform distribution of bevacizumab. The microspheres exhibited a release behavior comprising a slight initial burst and an increasing total release over 50 days both in vitro and in vivo. Additionally, the microspheres were well tolerated by ocular tissue. Finally, a chorioallantoic membrane (CAM) assay revealed that the bioactivity of bevacizumab was retained by PCADK. In conclusion, these results suggest the potential for bevacizumab-loaded PLGA/PCADK microspheres prepared by the S/O/W method as a means of intravitreal therapy for ocular diseases.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Polímeros/administração & dosagem , Inibidores da Angiogênese/química , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/química , Bevacizumab/química , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Dextranos/administração & dosagem , Dextranos/química , Liberação Controlada de Fármacos , Oftalmopatias/tratamento farmacológico , Injeções Intravítreas , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Coelhos
13.
Int J Pharm ; 565: 41-49, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31022503

RESUMO

The aim of the present study was to assess the potential of biocompatible polymeric nanosheets as topical and transdermal drug-delivery devices. Nanosheets are two-dimensional nanostructures with a thickness in the nanometer order, and their extremely large aspect ratios result in unique properties, including high transparency, flexibility, and adhesiveness. Nanosheet formulations containing betamethasone valerate (BV) as a model drug and consisting of poly (L-lactic acid) or poly (lactic-co-glycolic) acid were fabricated through a spin-coating-assisted layer-by-layer method using a water-soluble sacrificial membrane. The fabricated formulations could incorporate and release higher amounts of BV compared with a commercial ointment, and the amounts could be controlled by the polymers used, the amount of BV added, and the use of controlled-release membranes. The presence of BV had a minimal effect on thickness, transparency, adhesiveness, and moisture permeability of nanosheets, permitting their application to any area of skin for a long period of time. Therefore, this biocompatible polymeric nanosheet formulation represents a novel and promising topical and transdermal drug delivery device, which has potential to deliver drugs regardless of the area of skin.


Assuntos
Sistemas de Liberação de Medicamentos , Nanoestruturas/administração & dosagem , Poliésteres/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Administração Tópica , Adulto , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Valerato de Betametasona/administração & dosagem , Valerato de Betametasona/química , Liberação Controlada de Fármacos , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/química , Humanos , Masculino , Nanoestruturas/química , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos Pelados , Pele/metabolismo , Suínos , Adulto Jovem
14.
Carbohydr Polym ; 211: 217-226, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30824082

RESUMO

Alhagi honey polysaccharides (AHP) have been widely studied as immunomodulators. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles have been frequently used to control the release of drugs. In this study, AHP was extracted and encapsulated within PLGA (AHPP). Enhancement of immune activity in vitro and the adjuvanticity when inoculated with OVA were evaluated. The results demonstrated that the average molecular weight of AHP was 46.8 kDa and possessed typical polysaccharide absorption peaks. The entrapment efficiency for AHP within AHPP was 65.76 ± 3.31%. AHPP significantly stimulated phagocytic activity, MHCII and CD86 expression in macrophages. Further investigation showed that AHPP/OVA significantly enhanced lymphocyte proliferation and improved the CD4+/CD8+ T cell ratio. Moreover, AHPP/OVA treatment significantly increased IgG levels and up-regulated Th-associated cytokines with overall Th1 polarization. These studies demonstrated that AHP encapsulated within PLGA as a vaccine delivery system enhanced adaptive immunity.


Assuntos
Mel , Fatores Imunológicos/administração & dosagem , Nanopartículas/administração & dosagem , Ovalbumina/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Polissacarídeos/administração & dosagem , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Sistemas de Liberação de Medicamentos , Linfócitos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/fisiologia , Camundongos Endogâmicos ICR , Fagocitose/efeitos dos fármacos , Vacinas/administração & dosagem
15.
AAPS PharmSciTech ; 20(3): 133, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30820689

RESUMO

Irinotecan (IRT), the pro-drug of SN-38, has exhibited potent cytotoxicity against various tumors. In order to enhance the anti-tumor effect of IRT, we prepared IRT-loaded PLGA nanoparticles (IRT-PLGA-NPs) by emulsion-solvent evaporation method. Firstly, IRT-PLGA-NPs were characterized through drug loading (DL), entrapment efficiency (EE), particle size, zeta potential, transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). We next studied the in vitro release characteristics of IRT-PLGA-NPs. Finally, the pharmacokinetics and pharmacodynamics profiles of IRT-PLGA-NPs were investigated. The results revealed that IRT-PLGA-NPs were spherical with an average size of (169.97 ± 6.29) nm and its EE and DL were (52.22 ± 2.41)% and (4.75 ± 0.22)%, respectively. IRT-PLGA-NPs could continuously release drug for 14 days in vitro. In pharmacokinetics studies, for pro-drug IRT, the t1/2ß of IRT-PLGA-NPs was extended from 0.483 to 3.327 h compared with irinotecan solution (IRT-Sol), and for its active metabolite SN-38, the t1/2ß was extended from 1.889 to 4.811 h, which indicated that IRT-PLGA-NPs could prolong the retention times of both IRT and SN-38. The pharmacodynamics results revealed that the tumor doubling time, growth inhibition rate, and specific growth rate of IRT-PLGA-NPs were 2.13-, 1.30-, and 0.47-fold those of IRT-Sol, respectively, which demonstrated that IRT-PLGA-NPs could significantly inhibit the growth of tumor. In summary, IRT-PLGA-NPs, which exhibited excellent therapeutic effect against tumors, might be used as a potential carrier for tumor treatment in clinic.


Assuntos
Antineoplásicos/síntese química , Irinotecano/síntese química , Nanopartículas/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/análise , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/análise , Materiais Biocompatíveis/síntese química , Varredura Diferencial de Calorimetria/métodos , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/análise , Portadores de Fármacos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Irinotecano/administração & dosagem , Irinotecano/análise , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/análise , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/análise , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/análise , Inibidores da Topoisomerase I/síntese química , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia
16.
Eur J Pharm Sci ; 133: 28-39, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30885784

RESUMO

Over the last years nanoparticles (NP) have become a promising vehicle as drug delivery systems for photodynamic therapy (PDT), combining the advantages of an effective drug transport to the target cells and the reduction of undesired side effects. The in vitro evaluation of new nanoparticulate formulations has become a rising problem since cell culture models differ from the in vivo situation of the human body to a large extent. Particularly, in case of gastrointestinal tumors, after peroral application nanoparticles are challenged by overcoming the mucus layer as a first physical barrier before reaching the target cells, an aspect often neglected in literature. However, the presence of mucus is crucial for in vitro models to evaluate mucus-penetrating potential of surface-modified nanoparticulate drug carrier systems. Biodegradable poly(dl-lactide-co-glycolide) (PLGA) NP loaded with the model photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)porphyrin (mTHPP) were surface modified with either poly(ethylene glycol) (PEG) or chitosan (CS) to gain mucus-penetrating or mucoadhesive particle properties. All NP systems were compared to each other and to free mTHPP regarding cytotoxicity and cellular uptake in HT-29 cells and mucus producing HT-29-MTX cells. For PEGylated mTHPP-PLGA-PEG-NP a significantly higher accumulation was obtained in HT-29-MTX cells compared to all other tested nanoparticles and the free drug. Additionally, a mucus-containing Transwell® model, consisting of HT-29-MTX cells, confirmed these results, representing a promising in vitro screening method for mucus-penetrating particle properties.


Assuntos
Muco/metabolismo , Nanopartículas/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Polietilenoglicóis/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Porfirinas/administração & dosagem , Linhagem Celular Tumoral , Trato Gastrointestinal/metabolismo , Humanos , Fotoquimioterapia
17.
Drug Deliv ; 26(1): 199-207, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30835586

RESUMO

The multidrug resistance in tumor (MDR) is a major barrier to efficient cancer therapy. Modern pharmacological studies have proven that tetrandrine (TET) has great potential in reversing MDR. However, it has a series of medication problems in clinic such as poor water solubility, low oral bioavailability and short half-life in vivo. Aiming at the above problems, red blood cell membrane-camouflaged TET-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (RPTNs) had been developed. The RPTNs had spherical shell-core double layer structure with average particle size of 164.1 ± 1.65 nm and encapsulation efficiency of 84.1% ± 0.41%. Compared with TET-PLGA nanoparticles (PTNs), the RPTNs reduced RAW 264.7 macrophages' swallowing by 32% due to its retention of natural membrane proteins. The cumulative drug release of RPTNs was 81.88% within 120 h. And pharmacokinetic study showed that the blood half-life of RPTNs was 19.38 h, which was 2.95 times of free drug. When RPTNs of 2 µg/mL TET were administered in combination with adriamycin (ADR), significant MDR reversal effect was observed in drug-resistant cells MCF-7/ADR. In a word, the RPTNs hold potential to improve its efficacy and broaden its clinical application.


Assuntos
Benzilisoquinolinas/síntese química , Membrana Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Animais , Benzilisoquinolinas/administração & dosagem , Benzilisoquinolinas/metabolismo , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/fisiologia , Eritrócitos/metabolismo , Células HEK293 , Humanos , Células MCF-7 , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Células RAW 264.7
18.
Drug Deliv ; 26(1): 34-44, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30744436

RESUMO

The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH2s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Glioma/terapia , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Radiossensibilizantes/administração & dosagem , Temozolomida/administração & dosagem , Animais , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/metabolismo , Linhagem Celular Tumoral , Terapia Combinada/métodos , Sistemas de Liberação de Medicamentos/métodos , Glioma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Nanopartículas/química , Nanopartículas/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Radiossensibilizantes/síntese química , Radiossensibilizantes/metabolismo , Radioterapia/métodos , Temozolomida/síntese química , Temozolomida/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
Crit Rev Ther Drug Carrier Syst ; 36(2): 93-136, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30806210

RESUMO

In situ forming systems can serve as promising alternative to existing long acting injectables like disperse systems and microspheres, owing to their biocompatibility, stability, ease of administration and scale up. Microspheres based on long-acting parenteral systems pose challenges in scaling up and process changes with the drug and polymer selected. In situ gelling systems are having low viscosity which is very conducive during various manufacturing unit operations and passing the formulation through hypodermic needle with lower applied pressure. Different mechanisms such as physical or physiological stimuli and cross linking reactions are involved in the gelling of in situ forming systems at the site of injection. Drug release from in situ forming systems can be altered according to the need by using different polymers, lipids and fatty acids. In situ forming systems can be evaluated by sol-gel transition time, temperature and pH, rheology, gel strength, texture analysis, syringeability and injectability. The present paper is an overview of the various in situ gelling polymers and their application in the preparation of depot formulations. Numerous products based on in situ forming systems such as Eligard®, Atridox® are available in market.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Animais , Sistemas de Liberação de Medicamentos/tendências , Géis/administração & dosagem , Géis/farmacocinética , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Polímeros/administração & dosagem , Polímeros/farmacocinética , Reologia/métodos , Reologia/tendências
20.
Eur J Pharm Biopharm ; 136: 240-249, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30630062

RESUMO

In this study, we investigated the feasibility of incorporating protein drugs into electrospun fibrous mats (EFMs) for wound healing using lysozyme as a model drug. Lysozyme nanoparticles (Lyso- NPs) were first obtained by electrospray. Lysozyme solutions were prepared with a binary solvent mixture of ethanol (EtOH)-water (H2O) at varied volume ratios. Subsequently, Lyso-NPs were suspended in poly(lactic-co-glycolic acid) (PLGA) solutions using trifluoroethanol (TFE) as a solvent. Lyso-NPs loaded EFMs were obtained by electrospinning of the aforementioned suspensions, and the bioactivity of lysozyme in the EFMs was investigated using fluorescence-based assay kit. The electrosprayed Lyso-NPs were spherical with barely altered bioactivity as compared to the untreated raw material when using EtOH- H2O (30:70, v/v) as the solvent. After the subsequent electrospinning process, more than 90% of the bioactivity of lysozyme was retained compared to the raw material. The cytotoxicity of the produced EFMs was evaluated by thiazolyl blue tetrazolium bromide (MTT) study and the proliferation and distribution of mouse fibroblast cells (L929) growing on EFMs were investigated using 4,6-diamidino-2-phenylindol dihydrochloride (DAPI) for nucleic acid staining. Nearly negligible cytotoxicity of all the EFMs was observed according to the MTT study. Furthermore, it was observed that the L929 cells grew well on the Lyso-EFMs, especially those with the modification of polyethylene glycol (PEG) that was added to improve the hydrophilicity of EFMs. This study demonstrated that the electrospray/electrospinning processes are suitable for loading biomacromolecules to produce functionalized wound dressings to promote wound healing.


Assuntos
Bandagens , Fibroblastos/efeitos dos fármacos , Muramidase/administração & dosagem , Nanofibras/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Galinhas , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Fibroblastos/metabolismo , Camundongos , Muramidase/química , Muramidase/farmacocinética , Nanofibras/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Cicatrização/fisiologia
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