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1.
Nat Protoc ; 15(9): 3064-3087, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32807907

RESUMO

Targeted downregulation of select endogenous plant genes is known to confer disease or pest resistance in crops and is routinely accomplished via transgenic modification of plants for constitutive gene silencing. An attractive alternative to the use of transgenics or pesticides in agriculture is the use of a 'green' alternative known as RNAi, which involves the delivery of siRNAs that downregulate endogenous genes to confer resistance. However, siRNA is a molecule that is highly susceptible to enzymatic degradation and is difficult to deliver across the lignin-rich and multi-layered plant cell wall that poses the dominant physical barrier to biomolecule delivery in plants. We have demonstrated that DNA nanostructures can be utilized as a cargo carrier for direct siRNA delivery and gene silencing in mature plants. The size, shape, compactness and stiffness of the DNA nanostructure affect both internalization into plant cells and subsequent gene silencing efficiency. Herein, we provide a detailed protocol that can be readily adopted with standard biology benchtop equipment to generate geometrically optimized DNA nanostructures for transgene-free and force-independent siRNA delivery and gene silencing in mature plants. We further discuss how such DNA nanostructures can be rationally designed to efficiently enter plant cells and deliver cargoes to mature plants, and provide guidance for DNA nanostructure characterization, storage and use. The protocol described herein can be completed in 4 d.


Assuntos
DNA/química , Portadores de Fármacos/química , Engenharia , Nanoestruturas/química , RNA Interferente Pequeno/metabolismo , Tabaco/metabolismo , DNA/metabolismo , Portadores de Fármacos/metabolismo , RNA Interferente Pequeno/genética , Tabaco/genética
2.
AAPS PharmSciTech ; 21(5): 183, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632576

RESUMO

Pulmonary drug delivery is a noninvasive therapeutic approach that offers many advantages including localized drug delivery and higher patient compliance. As with all formulations, the low aqueous solubility of a drug often poses a challenge in the formulation development. Thus, strategies such as cyclodextrin (CD) complexation have been utilized to overcome this challenge. Resveratrol (RES), a natural stilbene, has shown abundant anti-cancer properties. Due to many drawbacks of conventional chemotherapeutics, RES has been proposed as an emerging alternative with promising pharmacological effects. However, RES has limited therapeutic applications due to low water solubility, chemical stability, and bioavailability. This study was aimed at developing an inhalable therapy that would increase the aqueous solubility and stability of RES by complexation with sulfobutylether-ß-cyclodextrin (SBECD). Phase solubility profiles indicated an optimal stoichiometric inclusion complex at 1:1 (SBECD:RES) ratio for formulation considerations. Physiochemical characterizations were performed to analyze CD-RES. Stability studies at pH 7.4 and in plasma indicated significant improvement in RES stability after complexation, with a much longer half-life. The mass median aerodynamic diameter (MMAD) of CD-RES was 2.6 ± 0.7 µm and fine particle fraction (FPF) of 83.4 ± 3.0% are suitable for pulmonary delivery and efficient deposition. Lung cancer was selected as the respiratory model disease, owing to its high relevance as the major cause of cancer deaths worldwide. Cell viability studies in 5 non-small-cell-lung-cancer (NSCLC) cell lines suggest CD-RES retained significant cytotoxic potential of RES. Taken together, CD-RES proves to be a promising inhalation treatment for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ciclodextrinas/química , Neoplasias Pulmonares/tratamento farmacológico , Resveratrol/administração & dosagem , Administração por Inalação , Disponibilidade Biológica , Portadores de Fármacos/metabolismo , Estabilidade de Medicamentos , Humanos , Pulmão/metabolismo , Solubilidade
3.
Proc Natl Acad Sci U S A ; 117(32): 19141-19150, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32703811

RESUMO

Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood-brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal "off-target" accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/instrumentação , Células Endoteliais/metabolismo , Nanopartículas/metabolismo , Animais , Transporte Biológico , Encéfalo/irrigação sanguínea , Endotélio/metabolismo , Humanos , Ratos , Ratos Sprague-Dawley
4.
AAPS PharmSciTech ; 21(4): 123, 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32337654

RESUMO

The objective of this work was to investigate the capacity of mogroside V (MOG-V), a food additive, as a novel carrier to improve the bioavailability and liver distribution of silybin (SLY). Solid dispersion particles (SDPs) of SLY/MOG-V were prepared utilizing the solvent evaporation method. The physicochemical characterizations of SDPs were evaluated by using dynamic light scattering (DLS), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) measurements. DLS results demonstrated the formation of nanoparticles (206 nm) of SDPs in water. DSC and PXRD analysis revealed that SLY was in amorphous form or molecularly dispersed in SDPs. SDPs also exhibited a major increase in both dissolution rate and saturation solubility, as evidenced by a 1931-fold improvement (2201 µg/mL) in solubility compared with pure SLY (1.14 µg/mL). The pharmacokinetic study in rats showed that oral absorption of SLY/MOG-V SDPs was dramatically increased. The mean value of AUC until 12 h for SLY/MOG-V SDPs (27,481 ng·min/mL) was 24.5-fold higher than that of pure SLY (1122 ng·min/mL). In vivo tissue distribution experiment in mice confirmed that the major distribution tissue was changed from lungs to liver after SLY was loaded into MOG-V. In addition, even orally administrated to mice at a high dose (4.2 g/kg), MOG-V exhibited no undesirable effect on the plasma glucose concentrations. Thus, MOG-V may have the applicability to serve as an ideal excipient for solubilization or as a novel liver targeting carrier for the delivery of SLY.


Assuntos
Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Fígado/metabolismo , Silibina/metabolismo , Triterpenos/metabolismo , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/metabolismo , Disponibilidade Biológica , Portadores de Fármacos/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Sprague-Dawley , Silibina/administração & dosagem , Edulcorantes/administração & dosagem , Edulcorantes/metabolismo , Triterpenos/administração & dosagem , Difração de Raios X/métodos
5.
Org Biomol Chem ; 18(10): 1978-1986, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32104826

RESUMO

Development of an intracellular delivery method for functional peptides via cell-penetrating peptides (CPPs) expands peptide use in basic research and therapeutic applications. Although direct conjugation of a functional peptide with a CPP is the simplest method for delivery, this method has not always been reliable. CPPs usually contain several positively charged amino acids that potentially interact non-specifically with negatively charged molecules in cells and subsequently interfere with conjugated functional peptide function. Here we demonstrate a new intracellular delivery method for peptides in which a functional peptide is released from a positively charged CPP via peptide nucleic acids (PNAs). We prepared an 8-mer PNA conjugated to octa-arginine in tandem (PNA1-CPP) and linked its complementary PNA to an autophagy inducing peptide (PNA2-AIP) by solid-phase peptide synthesis. PNA1-CPP and PNA2-AIP formed a 1 : 1 hybrid via PNA1/PNA2 interaction, thereby indirectly but stably connecting the AIP to the CPP. PNA2-AIP was successfully delivered into cells in a hybrid formation-dependent manner and at least some portion of the PNA1-CPP/PNA2-AIP hybrids dissociated into PNA2-AIP and PNA1-CPP inside the cells. Notably, PNA2-AIP delivered to cells induced more autophagy than AIP directly conjugated to CPP (CPP-AIP). Further, the PNA hybrid did not induce significant cell death. These findings indicate that the PNA1/PNA2 hybrid can function as a molecular glue enabling the delivery of functional peptides into cells.


Assuntos
Proteína Beclina-1/farmacologia , Peptídeos Penetradores de Células/metabolismo , Portadores de Fármacos/metabolismo , Fragmentos de Peptídeos/farmacologia , Ácidos Nucleicos Peptídicos/metabolismo , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Proteína Beclina-1/toxicidade , Peptídeos Penetradores de Células/toxicidade , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Células HeLa , Humanos , Zíper de Leucina , Oligopeptídeos/metabolismo , Oligopeptídeos/toxicidade , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Ácidos Nucleicos Peptídicos/toxicidade , Ligação Proteica
6.
Nanoscale ; 12(9): 5587-5600, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32100776

RESUMO

As one of the most promising noninvasive therapeutic modalities, sonodynamic therapy (SDT) can focus the ultrasound energy on tumor sites located in deep tissue and locally activate the preloaded sonosensitizer to kill tumor cells. However, exploring sonosensitizers with high SDT efficacy and desirable biosafety is still a significant challenge. Herein, we utilized the hydrophilic-hydrophobic self-assembly technology to assemble the hydrophobic organic dye Ce6 and broad spectral anti-cancer agent Paclitaxel with hydrophilic organic dye IR783 to generate a nanoscale sonosensitizer, Ce6-PTX@IR783, without the introduction of extra nanomaterials into the fabrication to guarantee high therapeutic biosafety and further potential clinical translation. The constructed nanodrug was endowed with an external ultrasound-activatable chemo-sonodynamic effect and photoacoustic imaging performance via integrating multiple moieties into one nanosystem. Ce6 could enhance the sonodynamic effect, while PTX exerted a chemotherapeutic effect, and IR783 was applied to increase tumor-specific accumulation and assist in fulfilling photoacoustic imaging. In particular, the small particle size (70 nm) of Ce6-PTX@IR783 contributed to the increased tumor accumulation via the enhanced permeability and retention effect. The high synergistically chemo-sonodynamic therapeutic efficacy has been successfully demonstrated in vitro and in vivo, in addition to the demonstrated high biodegradability, biocompatibility and biosafety. This facile self-assembly procedure provides an intriguing strategy for highly efficient utilization of hydrophobic drugs and is liable to realize large-scale production and further clinical translation.


Assuntos
Antineoplásicos Fitogênicos/química , Nanopartículas/química , Paclitaxel/química , Porfirinas/química , Radiossensibilizantes/química , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Endocitose , Feminino , Corantes Fluorescentes/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Oxigênio Singlete/metabolismo , Distribuição Tecidual , Transplante Heterólogo
7.
AAPS PharmSciTech ; 21(3): 77, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970527

RESUMO

Previously, we developed a solid lipid nanoparticle (SLN) formulation of 4-(N)-docosahexaenoyl 2', 2'-difluorodeoxycytidine (DHA-dFdC), a compound with promising antitumor activity. Herein, we studied the feasibility of administering the DHA-dFdC by the oral route using the solid lipid nanoparticles (i.e., DHA-dFdC-SLNs). In simulated gastrointestinal fluids, the DHA-dFdC-SLNs did not aggregate. The release of the DHA-dFdC from the solid lipid nanoparticles in simulated gastrointestinal fluid was slow, but was slightly faster in simulated intestinal fluid than in simulated gastric fluid. In mice orally administered with DHA-dFdC-SLNs, plasma DHA-dFdC concentration vs. time curve has a Tmax of ~ 1.7 h and a Cmax of 17.01 µg/mL. The absolute oral bioavailability of DHA-dFdC when given as DHA-dFdC-SLNs was ~ 68% (based on AUC0-24 h values), while the relative oral bioavailability DHA-dFdC (compared with DHA-dFdC in a Tween 80/ethanol-in-water solution) was 126%. Finally, in mice with pre-establish B16-F10 murine melanoma, oral DHA-dFdC-SLNs increased their survival significantly, as compared with oral administration of the DHA-dFdC solution. It is concluded that the solid lipid nanoparticle formulation increased the bioavailability of the DHA-dFdC upon oral administration, as compared with the DHA-dFdC solution.


Assuntos
Ácidos Docosa-Hexaenoicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Polissorbatos/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Composição de Medicamentos/métodos , Feminino , Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/metabolismo , Polissorbatos/química , Polissorbatos/metabolismo , Taxa de Sobrevida/tendências , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
AAPS PharmSciTech ; 21(3): 78, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970547

RESUMO

Protein drugs were considered to be the first choice to treat many human diseases, but their clinical application was usually limited by their short half-life and lack of validated targeted therapy. Here, a series of folate-functionalized poly(ethylene glycol)-b-(poly(2-aminoethyl-L-glutamate)-g-poly(L-glutamic acid))s (FA-PEG-b-(PELG-g-PLGA)s) were designed as tumor-targeted carriers for cationic protein delivery. Compared with traditional copolymers consisting of PEG and linear charged hydrophilic blocks, FA-PEG-b-(PELG-g-PLGA) with brush-like polyelectrolyte segments were beneficial to improving their electrostatic interactions with loading protein molecules, thus increasing drug-loading stability and protecting encapsulated proteins from degradation. The designed polymer brushes could efficiently encapsulate cytochrome C (CytC), a cationic model protein, to form polyion complex (PIC) micelles with an average particle size of approximately 200 nm. An in vitro drug release study showed that the drug-loading stability of the formed PIC micelles was largely improved. The functionalization of the block copolymer carriers with a targeting folate group enhanced the tumor cell growth inhibition and total apoptotic rates induced by CytC. Our results shed light on the unique advantages of brush-like polymer carriers in delivering cationic proteins, and the poly(L-glutamic acid)-based linear-brush diblock copolymers could be applied as a versatile delivery platform for molecular targeting in cancer therapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Ácido Glutâmico/síntese química , Poliésteres/síntese química , Polietilenoglicóis/síntese química , Proteínas/síntese química , Animais , Cátions , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/metabolismo , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Células NIH 3T3 , Tamanho da Partícula , Poliésteres/administração & dosagem , Poliésteres/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Polímeros/administração & dosagem , Polímeros/síntese química , Polímeros/metabolismo , Proteínas/administração & dosagem , Proteínas/metabolismo
9.
Carbohydr Polym ; 229: 115435, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826424

RESUMO

Micelles are one of the most investigated nanocarriers for drug delivery. In this study, polymeric micelles based on chitosan were prepared to explore the delivery mechanism which was critical for enhancing tumor targeting but still remain elusive. The chitosan polymer COSA was synthesized and the polymeric micelles showed good self-assembly ability, good dispersion stability and low toxicity. After being intravenously administered, the micelles were selectively taken up by circulating monocytes in a receptor-mediated way (almost 94% uptake in Ly-6Chi monocytes, below 7% in all other circulating cells) and reach the tumor with the subsequent travel of these cells. In addition, the micelles in macrophages (differentiated from circulating monocytes) can be exocytosed and subsequently taken up by cancer cells. The delivery mechanism of COSA micelles is directional for the novel strategies to enhance tumor targeting and the micelles are promising candidates for diseases in which monocytes are directly implicated.


Assuntos
Quitosana/metabolismo , Portadores de Fármacos/metabolismo , Micelas , Monócitos/metabolismo , Animais , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Endocitose , Exocitose , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Células RAW 264.7
10.
Carbohydr Polym ; 229: 115437, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826460

RESUMO

Chitosan nanosystems have been widely explored to deliver therapeutic into cells. The cationic nature of the polymer facilitates its entry into the cell via the negatively charged lipid bilayer. Though the interaction is feasible for successful payload delivery, very little is known about the mechanistic aspects and kinetics of interaction of chitosan nanoparticles (Chnps) with the cellular bilayer membrane. Moreover, the precise mechanism of delivery of therapeutic agents by the Chnps is unknown. The polymerbilayer membrane is anticipated to play a crucial role in deciding its ultimate intracellular fate, while delivering its therapeutic payload. Here, we have made an attempt to understand the interaction of Chnps with the cellular membrane for delivering payload, through experimental analysis and predictive mathematical modeling. We observed that the positively charged, mucoadhesive Chnps lack specificity towards a particular cell type, but are rather successful in the intracellular delivery of nucleic acids.


Assuntos
Quitosana/metabolismo , Portadores de Fármacos/metabolismo , Nanopartículas/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Quitosana/química , Portadores de Fármacos/química , Endocitose/fisiologia , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Humanos , Cinética , Lisossomos/metabolismo , Fluidez de Membrana , Modelos Biológicos , Nanopartículas/química
11.
J Pharm Biomed Anal ; 177: 112852, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31499432

RESUMO

The effect of insertion of SH and S-protected groups on the binding and mucoadhesion properties of quaternary ammonium-chitosans and their nanoparticulate forms has been investigated by NMR spectroscopy. Diclofenac sodium salt has been assumed as low molecular weight probe to detect the different binding behaviour of polymeric materials; mucin from bovine submaxillary glands was selected as the model protein for differentiating their mucoadhesion. NMR proton selective relaxation rates of the probe molecule were remarkably sensitive to the presence of very low amounts of sulfurated moieties. Impact of supramolecular aggregation in nanostructured species was demonstrated as well as the relevance of S-protection.


Assuntos
Diclofenaco/administração & dosagem , Portadores de Fármacos/química , Membrana Mucosa/metabolismo , Nanopartículas/química , Adesividade , Animais , Bovinos , Quitosana/química , Quitosana/metabolismo , Portadores de Fármacos/metabolismo , Peso Molecular , Mucinas/metabolismo , Nanopartículas/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/metabolismo , Enxofre/química
12.
Carbohydr Polym ; 229: 115511, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826400

RESUMO

An ultrafast (e.g. 75 s) synthesis of carboxymethyl xanthan gum (CMXG) capped gold nanoparticles (AuNPs) (CMXG@AuNPs) was developed using microwave irradiation (MWI) method. The synthesis of AuNPs was optimized by varying CMXG amount, gold ion concentration, and MWI time. The CMXG@AuNPs exhibited a spherical shape, high crystallinity, and narrow size distribution (i.e. 8-10 nm). The electrostatic interaction-mediated the loading of doxorubicin (DOX) onto CMXG@AuNPs. The release of DOX, loaded on CMXG@AuNPs was extensive in an acidic condition but negligible at physiological pH value. The in vitro anticancer efficacy of DOX loaded on CMXG@AuNPs (i.e. DOX@CMXG@AuNPs) in the presence of an ionophore (i.e. nigericin) was about 4.6 folds higher than that of free DOX. Flow cytometry revealed that DOX@CMXG@AuNPs exhibited a higher cellular uptake under an acidic condition than free DOX. CMXG@AuNPs showed unique excellence in the pH-responsive DOX-releasing property and the cancer cell-killing capability.


Assuntos
Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Ouro/química , Nanopartículas Metálicas/química , Micro-Ondas , Polissacarídeos Bacterianos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Transporte Biológico , Linhagem Celular Tumoral , Técnicas de Química Sintética , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Humanos
13.
Carbohydr Polym ; 229: 115479, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826506

RESUMO

Antibiotics are powerful weapons to fight against bacterial infections, while most of them lack of selective targeting towards pathological site which could restrict their antibacterial efficacy. To overcome this challenge, an antimicrobial levofloxacin(LF)was conjugated onto hyaluronic acid (HA) moieties via an o-phenylenediamine linker to prepare a NO-sensitive nanosystem (HA-NO-LF) in this study. The HA-NO-LF nanomicelles could enter host cells via a CD44 mediated endocytosis and release drug gradually upon exposure to endogenous NO. Furthermore, the more promising therapeutic effect of the nanomicelles in ameliorating inflammatory levels was observed in a mouse pneumonia model than that of LF. These results suggest that the HA-NO-LF nanomicelles may exert potent curative effect in infectious diseases.


Assuntos
Portadores de Fármacos/química , Ácido Hialurônico/química , Levofloxacino/química , Levofloxacino/farmacologia , Micelas , Nanoestruturas/química , Óxido Nítrico/metabolismo , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Transporte Biológico , Portadores de Fármacos/metabolismo , Feminino , Ácido Hialurônico/metabolismo , Espaço Intracelular/metabolismo , Camundongos , Células RAW 264.7 , Staphylococcus aureus/efeitos dos fármacos
15.
AAPS PharmSciTech ; 21(1): 32, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863211

RESUMO

Lipid nanoparticles (LNs) are traditional systems able to effectively increase skin hydration. However, due to its reduced viscosity, LNs suspensions are less attractive for skin administration. To overcome this disadvantage, the LN were incorporated in the semi-solid formulation is easy manipulation. This study demonstrated that it is possible to obtain novel LN-loaded fucoxanthin (LN-FUCO) for topical administration containing a combination of bacuri butter and tucumã oil prepared by high shear homogenization for improved stability. The particle size was found to be 243.0 nm and the entrapment efficiency up to 98% of FUCO was incorporated and achieved the suitability of formula. The LN-FUCO hydrogel characteristics of slight acidity, drug content near 100%, and nanometric mean size assure to this formulation high compatibility to dermal application. Photostability assay by UVA, LN-FUCO, and LN-FUCO hydrogel improved photostability and conferred greater protection against FUCO degradation. The results obtained from in vitro skin permeation studies presented a significant difference between LN-FUCO hydrogel and FUCO (p < 0.05), with no detection of the drug in the receptor medium. Therefore, high shear homogenization is demonstrated to be a simple, available, and effective method to prepare high-quality LN-FUCO hydrogel for topical application.


Assuntos
Lipídeos/química , Nanopartículas , Xantofilas/química , Administração Cutânea , Animais , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos , Hidrogéis/metabolismo , Tamanho da Partícula , Absorção Cutânea
16.
PLoS One ; 14(12): e0226639, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31881053

RESUMO

Raloxifene is commonly used for breast cancer protection. The low bioavailability of raloxifene (2%) is the result of its low solubility and intestinal glucuronidation. The nano-lipid carriers are characterized by small particle size, biocompatibility, and sustainable properties that improve cellular uptake of the loaded drug. The aim of this study was the improvement of raloxifene bioavailability by enhancing its solubility and cellular penetration through formulation of D-α-tocopheryl polyethylene glycol 1000 succinate based transferosomes and augmenting their effect with the cationic cell-penetrating peptide transactivator of transcription of the human immunodeficiency virus. Particle size, zeta potential, and transmission electron microscope investigation of the formed nanocarriers were carried out. Ex vivo raloxifene permeation through rat skin and cell viability studies was investigated. The results of D-α-tocopheryl polyethylene glycol 1000 succinate- transactivator of transcription of the human immunodeficiency virus transferosomes showed an average vesicle size of 96.05 nm with positively charged vesicles 39.4 mV of zeta potential value. The results revealed significant (p < 0.05) enhancement of raloxifene permeation from raloxifene transferosomes- loaded film when compared with raw raloxifene film. IC50 results showed significant improvement of formulated raloxifene cytotoxicity by 1.42-fold in comparison with raw raloxifene against MCF-7 cell lines. The developed raloxifene-transferosomes are considered promising nano-lipid carriers for the enhancement delivery of raloxifene.


Assuntos
Portadores de Fármacos/metabolismo , Cloridrato de Raloxifeno/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Vitamina E/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Administração Cutânea , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacocinética , Anticarcinógenos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Células MCF-7 , Cloridrato de Raloxifeno/farmacocinética , Cloridrato de Raloxifeno/farmacologia , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Absorção Cutânea
17.
Pharm Res ; 36(12): 185, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31773287

RESUMO

PURPOSE: Nanoparticle-mediated drug delivery and efficacy for cancer applications depends on systemic as well as local microenvironment characteristics. Here, a novel coupling of a nanoparticle (NP) kinetic model with a drug pharmacokinetic/pharmacodynamics model evaluates efficacy of cisplatin-loaded poly lactic-co-glycolic acid (PLGA) NPs in heterogeneously vascularized tumor tissue. METHODS: Tumor lesions are modeled with various levels of vascular heterogeneity, as would be encountered with different types of tumors. The magnitude of the extracellular to cytosolic NP transport is varied to assess tumor-dependent cellular uptake. NP aggregation is simulated to evaluate its effects on drug distribution and tumor response. RESULTS: Cisplatin-loaded PLGA NPs are most effective in decreasing tumor size in the case of high vascular-induced heterogeneity, a high NP cytosolic transfer coefficient, and no NP aggregation. Depending on the level of tissue heterogeneity, NP cytosolic transfer and drug half-life, NP aggregation yielding only extracellular drug release could be more effective than unaggregated NPs uptaken by cells and releasing drug both extra- and intra-cellularly. CONCLUSIONS: Model-based customization of PLGA NP and drug design parameters, including cellular uptake and aggregation, tailored to patient tumor tissue characteristics such as proportion of viable tissue and vascular heterogeneity, could help optimize the NP-mediated tumor drug response.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Nanopartículas/metabolismo , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacocinética , Cisplatino/farmacologia , Citosol/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Nanopartículas/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Distribuição Tecidual
18.
Artif Cells Nanomed Biotechnol ; 47(1): 4211-4221, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713444

RESUMO

At present, cancer is the first cause of death for humans, but early detection and treatment can help improve prognoses and reduce mortality. However, further development of carrier-assistant drug delivery systems (DDSs) is retarded by the aspects such as the low drug-carrying capacity, carrier-induced toxicity and immunogenicity, complex synthesis manipulation. The development of nanoscale drug delivery systems (NDDS) have been rapidly developed to address these issues. In this article, we used PLGA-PEG with good biocompatibility to encapsulate Fe3O4 nanoparticles (a magnetic resonance imaging contrast agent) and DOX (an antitumour drug) via the emulsion-solvent evaporation method, aimed at achieving a dual function of the early detection and the treatment of mammary cancer. The results showed that the Fe3O4/DOX/PLGA-PEG nanoparticles had a relatively uniform size, a high carrier rate of Fe3O4 and high encapsulation efficiency of DOX, and a relatively high activity of released DOX within 120 h. In addition, in vitro studies showed that the Fe3O4/DOX/PLGA-PEG nanoparticles were cytocompatibility in NIH 3T3 fibroblast cells culture study while had a special effect on destroying human breast cancer MCF-7 cells compared with pure DOX solution. In vitro studies revealed that the Fe3O4/DOX/PLGA-PEG enabled enhanced T2 contrast magnetic resonance. Overall, our multifunctional Fe3O4/DOX/PLGA-PEG nanoparticles, composed of biocompatible substances and therapeutic/imaging materials, have great potential for the early detection of cancer and accurate drug delivery via the dynamic monitoring using MRI.


Assuntos
Materiais Biocompatíveis/química , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Detecção Precoce de Câncer , Nanopartículas de Magnetita/química , Poliésteres/química , Polietilenoglicóis/química , Células 3T3 , Animais , Materiais Biocompatíveis/metabolismo , Transporte Biológico , Cápsulas , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Imagem por Ressonância Magnética , Camundongos , Tamanho da Partícula , Solventes/química
19.
Artif Cells Nanomed Biotechnol ; 47(1): 4222-4233, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713452

RESUMO

Gold nanoparticles (AuNPs), as a kind of inorganic nanoparticle, have been gradually recognized as one of the most promising nanomaterials, which is attributed to their unique optical, electronic, sensing and biochemical characteristics. Due to such unique characteristics, AuNPs have been widely applied in biomedical fields such as diagnosis, biosensing and drug delivery. Except for their use in cancer treatment alone with their photothermal ablation of solid tumours, when used with anticancer drugs, AuNPs can exert a dual role in treating cancer. With the advantages of protecting drugs from degradation and leakage in the physiological environment, tuneable modification in size, surface and shape, and biocompatibility, AuNPs can be used as promising drug carriers in anticancer drug design. However, there are still many aspects that need to be improved during the usage of drug carriers in pharmacology including the following aspects: prolongation in the plasma, enhancement in targeting accumulation, improvement in cellular uptake and the control of intracellular release. AuNPs are important drug carriers.


Assuntos
Portadores de Fármacos/química , Ouro/química , Nanopartículas Metálicas/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Portadores de Fármacos/metabolismo , Ouro/metabolismo , Humanos , Ligantes
20.
AAPS PharmSciTech ; 20(8): 331, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677012

RESUMO

Because spray-dried dispersion (SDD) performance depends on polymer selection and drug load, time- and resource-sparing methods to screen drug/polymer combinations before spray drying are desirable. The primary objective was to assess the utility of films to anticipate the effects of drug load and polymer grade on dissolution performance of tablets containing SDDs of itraconazole (ITZ). A secondary objective was to characterize the solid-state attributes of films and SDDs to explain drug load and polymer effects on dissolution performance. SDDs employed three different grades of hypromellose acetate succinate (i.e., either HPMCAS-L, HPMCAS-M, or HPMCAS-H). Solid-state characterization employed differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Results indicate that films correctly anticipated the effects of drug load and polymer on dissolution performance. The best dissolution profiles were observed under the following conditions: 20% drug loading performed better than 30% for both films and SDDs, and the polymer grade rank order was HPMCAS-L > HPMCAS-M > HPMCAS-H for both films and SDDs. No dissolution was detected from films or SDDs containing HPMCAS-H. Solid-state characterization revealed percent crystallinity and phase miscibility as contributing factors to dissolution, but were not the sole factors. Amorphous content in films varied with drug load (10% > 20% > 30%) and polymer grades (HPMCAS-L > HPMCAS-M > HPMCAS-H), in agreement with dissolution. In conclusion, films anticipated the rank-order effects of drug load and polymer grade on dissolution performance from SDDs of ITZ, in part through percent crystallinity and phase miscibility influences.


Assuntos
Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Itraconazol/síntese química , Itraconazol/metabolismo , Metilcelulose/análogos & derivados , Antifúngicos/síntese química , Antifúngicos/metabolismo , Varredura Diferencial de Calorimetria , Dessecação , Metilcelulose/síntese química , Metilcelulose/metabolismo , Polímeros , Solubilidade , Comprimidos , Difração de Raios X/métodos
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