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1.
Nat Commun ; 11(1): 4909, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999291

RESUMO

Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.


Assuntos
Micropartículas Derivadas de Células/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Melanoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno CD47/metabolismo , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/secundário , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Camundongos , Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/imunologia , Nucleotídeos Cíclicos/administração & dosagem , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
2.
Crit Rev Ther Drug Carrier Syst ; 37(3): 205-227, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749138

RESUMO

In this review, we describe the advances in oral drug delivery approaches for taxanes for successful therapeutic outcome. Taxanes (paclitaxel and docetaxel) have unwanted pharmacokinetic profiles when they are given in their current dosage forms. Taxanes have low bioavailability, are extensively metabolized by CYP3A, and have a high affinity for P-glycoprotein. Regardless of dosage schedule, the overall docetaxel or paclitaxel dose that a patient can tolerate at a given interval remains similar. Currently, there are no commercially available oral taxane nanoformulations, and there are still several challenges to overcome. Nano-based formulations may offer the best solutions to problems involving the safety and effectiveness of taxane delivery. Thus, further research is necessary before such taxane nanoformulations can be manufactured for clinical use.


Assuntos
Docetaxel/administração & dosagem , Paclitaxel/administração & dosagem , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Ensaios Clínicos como Assunto , Docetaxel/química , Docetaxel/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Micelas , Nanopartículas/administração & dosagem , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacocinética
3.
Crit Rev Ther Drug Carrier Syst ; 37(3): 271-303, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749140

RESUMO

Nanotechnology has made great contributions in the development of materials with potential application in different areas, especially in the pharmaceutical sector, where nano-systems are being intensely studied for controlled drug release. These innovative systems are composed of structures such as nanoparticles, nanoemulsions, and cyclodextrins, with the aim of promoting enhanced bioavailability of bioactive molecules. Among these nanocarriers, vesicles such as liposomes and polymersomes are considered to be promising alternatives in delivering hydrophilic and lipophilic drugs. They have different classifications according to their composition, among which are hybrid vesicles, which unlike liposomes are composed of both lipids and polymers. These vesicular systems stand out for combining the advantages of both components, overcoming the limitations of traditional systems imposed by low stability and premature release of the encapsulated active substance. The polymers applied in hybrid vesicles can make up the membrane structure itself or be employed to coat preformed vesicles. Due to the relevance of these systems, this work covers their characteristics and summarizes recent articles about them in the literature.


Assuntos
Cosméticos/administração & dosagem , Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , Nanotecnologia/métodos , Polímeros/administração & dosagem , Nanomedicina Teranóstica/métodos , Animais , Cosméticos/química , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos/métodos , Humanos , Lipídeos/química , Lipossomos/administração & dosagem , Lipossomos/química , Nanopartículas/química , Polímeros/química
4.
Nat Commun ; 11(1): 3858, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737343

RESUMO

Checkpoint blockade therapy has provided noteworthy benefits in multiple cancers in recent years; however, its clinical benefits remain confined to 10-40% of patients with extremely high costs. Here, we design an ultrafast, low-temperature, and universal self-assembly route to integrate immunology-associated large molecules into metal-organic-framework (MOF)-gated mesoporous silica (MS) as cancer vaccines. Core MS nanoparticles, acting as an intrinsic immunopotentiator, provide the niche, void, and space to accommodate antigens, soluble immunopotentiators, and so on, whereas the MOF gatekeeper protects the interiors from robust and off-target release. A combination of MOF-gated MS cancer vaccines with systemic programmed cell death 1 (PD-1) blockade therapy generates synergistic effects that potentiate antitumour immunity and reduce the effective dose of an anti-PD-1 antibody to as low as 1/10 of that for PD-1 blockade monotherapy in E.G7-OVA tumour-bearing mice, with eliciting the robust adaptive OVA-specific CD8+ T-cell responses, reversing the immunosuppressive pathway and inducing durable tumour suppression.


Assuntos
Anticorpos Neutralizantes/farmacologia , Vacinas Anticâncer/farmacologia , Linfoma/terapia , Estruturas Metalorgânicas/farmacologia , Nanopartículas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/química , Citotoxicidade Imunológica , Composição de Medicamentos , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Estruturas Metalorgânicas/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptor de Morte Celular Programada 1/imunologia , Dióxido de Silício/química , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Nat Commun ; 11(1): 4249, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843618

RESUMO

Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). However, a vast majority of PDAC cases do not harbor a durable response to monotherapy of CDK4/6 inhibitor. Utilizing remote loading to co-encapsulate CDK4/6 inhibitor palbociclib (PAL) and an autophagy inhibitor hydroxychloroquine (HCQ), we demonstrate a ratiometrically designed mesoporous silica nanoformulation with synergistic efficacy in subcutaneous and orthotopic PDAC mouse models. The synergism is attributed to the effective intratumoral buildup of PAL/HCQ, which otherwise exhibit distinctly different circulatory and biodistribution profile. PAL/HCQ co-delivery nanoparticles lead to the most effective shrinkage of PDAC compared to various controls, including free drug mixture. Immunohistochemistry reveals that PAL/HCQ co-delivery nanoparticles trigger anti-apoptotic pathway after repetitive intravenous administrations in mice. When combined with a Bcl inhibitor, the performance of co-delivery nanoparticles is further improved, leading to a long-lasting anti-PDAC effect in vivo.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/química , Hidroxicloroquina/farmacologia , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Piperazinas/administração & dosagem , Piperazinas/química , Piperazinas/farmacologia , Piridinas/administração & dosagem , Piridinas/química , Piridinas/farmacologia , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Resultado do Tratamento
6.
Int J Nanomedicine ; 15: 5017-5026, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764933

RESUMO

Background: Molecular imaging is of great benefit to early disease diagnosis and timely treatment. One of the most striking innovations is the development of multimodal molecular imaging technology, which integrates two or more imaging modalities, largely in view of making the best of the advantages of each modality while overcoming their respective shortcomings. Hence, engineering a versatile and easily prepared nanomaterial with integrating multimodal molecular imaging function holds great promise, but is still a great challenge. Materials and Methods: We firstly designed and synthesized a BDT-DPP conjugated polymer and then noncovalent self-assembly with phospholipid-polyethylene glycol endowed BDT-DPP with water solubility and biocompatibility. Followed by [Cu] labeling, the acquired multifunctional nanoparticles (NPs) were studied in detail for the photophysical property. The cytotoxicity and biocompatibility of DPP-BDT NPs were examined through MTT assay and H&E stained analysis. In addition, we investigated the accumulation of the NPs in HepG2 tumor models by positron emission tomography (PET) and photoacoustic (PA) dual-mode imaging. Results and Discussion: The DPP-BDT NPs exhibited excellent optical stability, strong near-infrared (NIR) light absorption as well as fine biocompatibility. After tail vein injection into the living mice, the PA signals in the neoplastic tissues were gradually increased and reached to the maximum at the 4-h post-injection, which was consistent with the PET analysis. Such strong PA and PET signals were attributed to the efficient NPs accumulation resulting from the enhanced permeability and retention (EPR) effect. Conclusion: The biocompatible DPP-BDT NPs demonstrated to be strong NIR absorption property and PAI sensitivity. Besides, these novel DPP-BDT NPs can act not only as a PA imaging contrast agent but also as an imaging agent for PET.


Assuntos
Cetonas/química , Nanopartículas/química , Neoplasias Experimentais/diagnóstico por imagem , Técnicas Fotoacústicas/métodos , Tomografia por Emissão de Pósitrons/métodos , Pirróis/química , Animais , Meios de Contraste/química , Radioisótopos de Cobre/administração & dosagem , Radioisótopos de Cobre/farmacocinética , Feminino , Células Hep G2 , Humanos , Injeções , Camundongos , Camundongos Nus , Imagem Multimodal/métodos , Células NIH 3T3 , Nanopartículas/administração & dosagem , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Polímeros/química , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Int J Nanomedicine ; 15: 5083-5095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764938

RESUMO

Background: ß-glucans are chiral polysaccharides with well-defined immunological properties and supramolecular wrapping ability of its chiral feature. However, the exploitation of chiral properties of these nanoparticles in drug delivery systems was seldom conducted. Methods: ß-glucan molecules with different chain lengths were extracted from yeast Saccharomyces cerevisiae and thereafter modified. In a conformation transition process, these ß-glucan molecules were then self-assembled with anti-cancer drug doxorubicin into nanoparticles to construct drug delivery systems. The chiral interactions between the drug and carriers were revealed by circular dichroism spectra, ultraviolet and visible spectrum, fourier transform infrared spectroscopy, dynamic light scattering and transmission electron microscope. The immune-potentiation properties of modified ß-glucan nanoparticles were evaluated by analysis of the mRNA expression in RAW264.7 cell model. Further, the antitumor efficacy of the nanoparticles against the human breast cancer were studied in MCF-7 cell model by cellular uptake and cytotoxicity experiments. Results: ß-glucan nanoparticles can activate macrophages to produce immune enhancing cytokines (IL-1ß, IL-6, TNF-α, IFN-γ). A special chirality of the carriers in diameter of 50~160 nm can also associate with higher drug loading ability of 13.9% ~38.2% and pH-sensitive release with a change of pH from 7.4 to 5.0. Cellular uptake and cytotoxicity experiments also prove that the chiral-active ß-glucan nanoparticles can be used in anti-cancer nanomedicine. Conclusion: This work demonstrates that ß-glucans nanoparticles with special chiral feature which leading to strong immunopotentiation ability and high drug loading efficiency can be developed as a novel type of nanomedicine for anti-cancer treatment.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , beta-Glucanas/imunologia , Adjuvantes Imunológicos/química , Animais , Antineoplásicos/imunologia , Dicroísmo Circular , Portadores de Fármacos/química , Humanos , Células MCF-7 , Camundongos , Nanopartículas/química , Células RAW 264.7 , Saccharomyces cerevisiae/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , beta-Glucanas/química
8.
Int J Nanomedicine ; 15: 5389-5403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801695

RESUMO

Hypothesis: Developing oral formulations to enable effective release of poorly water-soluble drugs like progesterone is a major challenge in pharmaceutics. Coaxial electrospray can generate drug-loaded nanoparticles of strategic compositions and configurations to enhance physiological dissolution and bioavailability of poorly water-soluble drug progesterone. Experiments: Six formulations comprising nanoparticles encapsulating progesterone in different poly(lactide-co-glycolide) (PLGA) matrix configurations and compositions were fabricated and characterized in terms of morphology, molecular crystallinity, drug encapsulation efficiency and release behavior. Findings: A protocol of fabrication conditions to achieve 100% drug encapsulation efficiency in nanoparticles was developed. Scanning electron microscopy shows smooth and spherical morphology of 472.1±54.8 to 588.0±92.1 nm in diameter. Multiphoton Airyscan super-resolution confocal microscopy revealed core-shell nanoparticle configuration. Fourier transform infrared spectroscopy confirmed presence of PLGA and progesterone in all formulations. Diffractometry indicated amorphous state of the encapsulated drug. UV-vis spectroscopy showed drug release increased with hydrophilic copolymer glycolide ratio while core-shell formulations with progesterone co-dissolved in PLGA core exhibited enhanced release over five hours at 79.9±1.4% and 70.7±3.5% for LA:GA 50:50 and 75:25 in comparison with pure progesterone without polymer matrix in the core at 67.0±1.7% and 57.5±2.8%, respectively. Computational modeling showed good agreement with the experimental drug release behavior in vitro.


Assuntos
Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Progesterona/administração & dosagem , Progesterona/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Microscopia Eletrônica de Varredura , Nanopartículas/administração & dosagem , Tamanho da Partícula , Solubilidade , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química , Difração de Raios X
9.
Int J Nanomedicine ; 15: 5517-5526, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801703

RESUMO

Introduction: Hypertension is a major health problem worldwide and is typically treated using oral drugs. However, the frequency of oral administration may result in poor patient compliance, and reduced bioavailability owing to the first-pass effect can also prove problematic. Methods: In this study, we developed a new transdermal-drug-delivery system (TDDS) for the treatment of hypertension using atenolol (ATE) based on poly(acrylic acid) (PAA)-decorated three-dimensional (3D) flower-like MoS2 nanoparticles (PAA-MoS2 NPs) that respond to NIR laser irradiation. The PAA-modified MoS2 NPs were synthesized and characterized using attenuated total reflection Fourier-transform infrared spectroscopy, X-ray diffraction measurements, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, and the sedimentation equilibrium method. The drug-loading efficiency and photothermal conversion effect were also explored. Results: The results showed that the colloidally stable PAA-MoS2 NPs exhibited a high drug-loading capacity of 54.99% and high photothermal conversion ability. Further, the capacity of the PAA-MoS2 NPs for controlled release was explored using in vitro drug-release and skin-penetration studies. The drug-release percentage was 44.72 ± 1.04%, and skin penetration was enhanced by a factor of 1.85 in the laser-stimulated group. Sustained and controlled release by the developed TDDS were observed with laser stimulation. Moreover, in vivo erythema index analysis verified that the PAA-MoS2 NPs did not cause skin irritation. Discussion: Our findings demonstrate that PAA-MoS2 NPs can be used as a new carrier for transdermal drug delivery for the first time.


Assuntos
Anti-Hipertensivos/administração & dosagem , Atenolol/administração & dosagem , Dissulfetos/química , Sistemas de Liberação de Medicamentos/métodos , Molibdênio/química , Nanopartículas/administração & dosagem , Resinas Acrílicas/química , Administração Cutânea , Animais , Anti-Hipertensivos/farmacocinética , Atenolol/efeitos adversos , Atenolol/farmacocinética , Sistemas de Liberação de Medicamentos/efeitos adversos , Liberação Controlada de Fármacos , Difusão Dinâmica da Luz , Eritema/induzido quimicamente , Humanos , Lasers , Masculino , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Coelhos , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
10.
Int J Nanomedicine ; 15: 5629-5643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801706

RESUMO

Purpose: Lecithin/chitosan nanoparticles have shown great promise in the transdermal delivery of therapeutic agents. Baicalein, a natural bioactive flavonoid, possesses multiple biological activities against dermatosis. However, its topical application is limited due to its inherently poor hydrophilicity and lipophilicity. In this study, the baicalein-phospholipid complex was prepared to enhance the lipophilicity of baicalein and then lecithin/chitosan nanoparticles loaded with the baicalein-phospholipid complex were developed to improve the transdermal retention and permeability of baicalein. Methods: Lecithin/chitosan nanoparticles were prepared by the solvent-injection method and characterized in terms of particle size distribution, zeta potential, and morphology. The in vitro release, the ex vivo and in vivo permeation studies, and safety evaluation of lecithin/chitosan nanoparticles were performed to evaluate the effectiveness in enhancing transdermal retention and permeability of baicalein. Results: The lecithin/chitosan nanoparticles obtained by the self-assembled interaction of chitosan and lecithin not only efficiently encapsulated the drug with high entrapment efficiency (84.5%) but also provided sustained release of baicalein without initial burst release. Importantly, analysis of the permeation profile ex vivo and in vivo demonstrated that lecithin/chitosan nanoparticles prolonged the retention of baicalein in the skin and efficiently penetrated the barrier of stratum corneum without displaying skin irritation. Conclusion: These results indicate the potential of drug-phospholipid complexes in enhancing the entrapment efficiency and self-assembled lecithin/chitosan nanoparticles based on phospholipid complexes in the design of a rational transdermal delivery platform to improve the efficiency of transdermal therapy by enhancing its percutaneous retention and penetration in the skin.


Assuntos
Flavanonas/administração & dosagem , Nanopartículas/administração & dosagem , Fosfolipídeos/química , Administração Cutânea , Animais , Quitosana/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Flavanonas/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Lecitinas/química , Masculino , Nanopartículas/efeitos adversos , Nanopartículas/química , Permeabilidade , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Testes de Irritação da Pele
11.
Life Sci ; 259: 118287, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32814066

RESUMO

Alzheimer's disease (AD) is a fatal neurodegenerative disease that requires immediate attention. Oxidative stress that leads to the generation of reactive oxygen species is a contributing factor to the disease progression by promoting synthesis and deposition of amyloid-ß, the main hallmark protein in AD. It has been previously demonstrated that nanoyttria possesses antioxidant properties and can alleviate cellular oxidative injury in various toxicity and disease models. This review proposed that nanoyttria could be used for the treatment of AD. In this paper, the evidence on the antioxidant potential of nanoyttria is presented and its prospects on AD therapy are discussed.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Depuradores de Radicais Livres/farmacologia , Nanopartículas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Ítrio/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Humanos , Ratos , Ítrio/administração & dosagem
12.
Proc Natl Acad Sci U S A ; 117(33): 19737-19745, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32732430

RESUMO

Immunotherapy is emerging as one of the most effective methods for treating many cancers. However, immunotherapy can still introduce significant off-target toxicity, and methods are sought to enable targeted immunotherapy at tumor sites. Here, we show that relatively large (>100-nm) anionic nanoparticles administered intraperitoneally (i.p.) selectively accumulate in tumor-associated macrophages (TAMs). In a mouse model of metastatic ovarian cancer, fluorescently labeled silica, poly(lactic-co-glycolic acid), and polystyrene nanoparticles administered i.p. were all found to selectively accumulate in TAMs. Quantifying silica particle uptake indicated that >80% of the injected dose was in TAMs. Particles that were smaller than 100 nm or cationic or administered intravenously (i.v.) showed no TAM targeting. Moreover, this phenomenon is likely to occur in humans because when freshly excised human surgical samples were treated with the fluorescent silica nanoparticles no interaction with healthy tissue was seen but selective uptake by TAMs was seen in 13 different patient samples. Ovarian cancer is a deadly disease that afflicts ∼22,000 women per year in the United States, and the presence of immunosuppressive TAMs at tumors is correlated with decreased survival. The ability to selectively target TAMs opens the door to targeted immunotherapy for ovarian cancer.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Imunoterapia , Macrófagos/efeitos dos fármacos , Nanopartículas/administração & dosagem , Neoplasias Ovarianas/terapia , Animais , Sistemas de Liberação de Medicamentos/instrumentação , Feminino , Humanos , Macrófagos/imunologia , Camundongos Nus , Nanopartículas/química , Neoplasias Ovarianas/imunologia , Poliestirenos/administração & dosagem , Poliestirenos/química
13.
PLoS One ; 15(8): e0237726, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813737

RESUMO

In this in vitro study, spherical mesoporous bioactive glass nanoparticle (MBGN) and non-porous bioactive glass nanoparticle (BGN) were fabricated. The impact of mesopores on dentinal tubule occlusion and bioactivity was compared to examine the potential of these materials in alleviating dentine hypersensitivity (DH). MBGN, dense BGN were synthesized by sol-gel methods and characterized. Bioactivity and ion dissolution ability were analyzed. Twenty-four simulated sensitive dentin discs were prepared and randomly divided into three groups (n = 8 each); Group 1, no treatment; Group 2, Dense BGN; Group 3, MBGN. Then, four discs per group were treated with 6wt.% citric acid challenge to determine the acidic resistance. The effects on dentinal tubule occlusion were observed by FESEM. The microtensile bond strength (MTBS) was also measured. Cytotoxicity was examined using the MTT assay. According to the results, dense BGN without mesopore and MBGN with mesopore were successfully fabricated. Dense BGN and MBGN occluded the dentinal tubule before and after acid challenge. However, only MBGN formed a membrane-like layer and showed hydroxyapatite formation after soaking SBF solution. There were no significant differences in MTBS among dense BGN, MBGN (P>0.05). The cell viability was above 72% of both materials. The higher bioactivity of MBGN compared with that of dense BGN arises from the structural difference and it is anticipated to facilitate dentin remineralization by inducing hydroxyapatite deposition within the dentinal tubule.


Assuntos
Dessensibilizantes Dentinários/administração & dosagem , Sensibilidade da Dentina/terapia , Dentina/efeitos dos fármacos , Vidro/química , Nanopartículas/administração & dosagem , Dente Pré-Molar , Dentina/metabolismo , Dessensibilizantes Dentinários/química , Dessensibilizantes Dentinários/farmacocinética , Permeabilidade da Dentina/efeitos dos fármacos , Sensibilidade da Dentina/patologia , Liberação Controlada de Fármacos , Durapatita/metabolismo , Humanos , Teste de Materiais , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanopartículas/ultraestrutura , Porosidade , Propriedades de Superfície , Resistência à Tração , Remineralização Dentária/métodos , Difração de Raios X
14.
PLoS Pathog ; 16(8): e1008665, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32780770

RESUMO

Two-component, self-assembling nanoparticles represent a versatile platform for multivalent presentation of viral antigens. Computational design of protein nanoparticles with differing sizes and geometries enables combination with antigens of choice to test novel multimerization concepts in immunization strategies where the goal is to improve the induction and maturation of neutralizing antibody lineages. Here, we describe detailed antigenic, structural, and functional characterization of computationally designed tetrahedral, octahedral, and icosahedral nanoparticle immunogens displaying trimeric HIV envelope glycoprotein (Env) ectodomains. Env trimers, based on subtype A (BG505) or consensus group M (ConM) sequences and engineered with SOSIP stabilizing mutations, were fused to an underlying trimeric building block of each nanoparticle. Initial screening yielded one icosahedral and two tetrahedral nanoparticle candidates, capable of presenting twenty or four copies of the Env trimer. A number of analyses, including detailed structural characterization by cryo-EM, demonstrated that the nanoparticle immunogens possessed the intended structural and antigenic properties. When the immunogenicity of ConM-SOSIP trimers presented on a two-component tetrahedral nanoparticle or as soluble proteins were compared in rabbits, the two immunogens elicited similar serum antibody binding titers against the trimer component. Neutralizing antibody titers were slightly elevated in the animals given the nanoparticle immunogen and were initially more focused to the trimer apex. Altogether, our findings indicate that tetrahedral nanoparticles can be successfully applied for presentation of HIV Env trimer immunogens; however, the optimal implementation to different immunization strategies remains to be determined.


Assuntos
Anticorpos Anti-HIV/imunologia , Antígenos HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Nanopartículas/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Epitopos/imunologia , Feminino , Infecções por HIV/virologia , Humanos , Imunização , Nanopartículas/administração & dosagem , Coelhos , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
15.
PLoS One ; 15(8): e0237218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760143

RESUMO

Influenza is an infectious respiratory illness caused by influenza viruses. Despite yearly updates, the efficacy of influenza vaccines is significantly curtailed by the virus antigenic drift and antigenic shift. These constant changes to the influenza virus make-up also challenge the development of a universal flu vaccine, which requires conserved antigenic regions shared by influenza viruses of different subtypes. We propose that it is possible to bypass these challenges by the development of an influenza vaccine based on conserved proteins delivered in an adjuvanted nanoparticle system. In this study, we generated influenza nanoparticle constructs using trimethyl chitosan nanoparticles (TMC nPs) as the carrier of recombinant influenza hemagglutinin subunit 2 (HA2) and nucleoprotein (NP). The purified HA2 and NP recombinant proteins were encapsulated into TMC nPs to form HA2-TMC nPs and NP-TMC nPs, respectively. Primary human intranasal epithelium cells (HNEpCs) were used as an in vitro model to measure immunity responses. HA2-TMC nPs, NP-TMC nPs, and HA2-NP-TMC nPs (influenza nanoparticle constructs) showed no toxicity in HNEpCs. The loading efficiency of HA2 and NP into the TMC nPs was 97.9% and 98.5%, respectively. HA2-TMC nPs and NP-TMC nPs more efficiently delivered HA2 and NP proteins to HNEpCs than soluble HA2 and NP proteins alone. The induction of various cytokines and chemokines was more evident in influenza nanoparticle construct-treated HNEpCs than in soluble protein-treated HNEpCs. In addition, soluble factors secreted by influenza nanoparticle construct-treated HNEpCs significantly induced MoDCs maturation markers (CD80, CD83, CD86 and HLA-DR), as compared to soluble factors secreted by protein-treated HNEpCs. HNEpCs treated with the influenza nanoparticle constructs significantly reduced influenza virus replication in an in vitro challenge assay. The results indicate that TMC nPs can be used as influenza vaccine adjuvants and carriers capable of delivering HA2 and NP proteins to HNEpCs.


Assuntos
Adjuvantes Imunológicos/farmacologia , Quitosana/farmacologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/farmacologia , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Animais , Linhagem Celular , Células Cultivadas , Quitosana/administração & dosagem , Cães , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/farmacologia , Humanos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Células Madin Darby de Rim Canino , Nanopartículas/administração & dosagem , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Proteínas de Ligação a RNA/administração & dosagem , Proteínas de Ligação a RNA/farmacologia , Proteínas do Core Viral/administração & dosagem , Proteínas do Core Viral/farmacologia
16.
Int J Nanomedicine ; 15: 5203-5215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801686

RESUMO

Introduction: Metformin is an ideal candidate to treat the liver tumor with insulin resistance because of its good performance in the treatment of type 2 diabetes and the advantage in cancer therapy. We aim to develop a delivery system with higher efficiency than free drug. Methods: Metformin-bovine serum albumin (met-BSA) nanoparticles (NPs) were prepared using the anti-solvent precipitation method with a stabilizer of BSA for particle growth. The therapeutic effect of the drug was tested by the insulin-resistant HepG2 cells and C57BL/6J mice at a glucose starvation condition. The interaction mechanism of the drug and the protein during the formation of the NPs was tested using a series of spectroscopy. Results: Metformin and BSA formed nonporous and spherical particles of about 200 nm with proper lognormal distribution and thermostability. The cellular uptake, as well as the anti-liver cancer activities of met-BSA, was enhanced dramatically compared with the free drug. The thermodynamic studies suggested that the weak binding of metformin to BSA was governed by hydrogen bonds and van der Waals forces. Moreover, the results of synchronous, circular dichroism (CD) and three-dimensional fluorescence demonstrated that the BSA skeleton and chromophore microenvironments were changed in the presence of metformin. Conclusion: Therefore, met-BSA has been proved as a simple yet effective therapeutic agent for cancer with insulin resistance, promising for future clinic translations in cancer treatment.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Resistência à Insulina , Metformina/farmacologia , Nanopartículas/administração & dosagem , Soroalbumina Bovina/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Dicroísmo Circular , Diabetes Mellitus Tipo 2 , Células Hep G2 , Humanos , Ligação de Hidrogênio , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Metformina/administração & dosagem , Metformina/química , Camundongos Endogâmicos C57BL , Nanopartículas/química , Soroalbumina Bovina/química , Termodinâmica , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Nanomedicine ; 15: 5239-5252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801689

RESUMO

Introduction: The main pathological mechanism of restenosis after percutaneous coronary intervention (PCI) is intimal hyperplasia, which is mainly caused by proliferation and migration of vascular smooth muscle cells (VSMCs). Our previous study found that honokiol (HNK), a small-molecule polyphenol, can inhibit neointimal hyperplasia after balloon injury, but its specific mechanism is still unclear. Moreover, poor water solubility as well as low bioavailability of honokiol has limited its practical use. Methods: We used mesoporous silica nanoparticles (MSNPs) as a standard substance to encapsulate HNK and then assemble into honokiol-mesoporous silica nanoparticles, and we investigated the effect of these nanoparticles on the process of restenosis after common carotid artery injury in rats. Results: We report a promising delivery system that loads HNK into MSNPs and finally assembles it into a nanocomposite particle. These HNK-MSNPs not merely inhibited proliferation and migration of VSMCs by reducing phosphorylation of Smad3, but also showed a higher suppression of intimal thickening than the free-honokiol-treated group in a rat model of balloon injury. Conclusion: To sum up, this drug delivery system supplies a potent nano-platform for improving the biological effects of HNK and provides a promising strategy for preventing vascular restenosis.


Assuntos
Compostos de Bifenilo/farmacologia , Reestenose Coronária/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Lignanas/farmacologia , Nanopartículas/química , Intervenção Coronária Percutânea/efeitos adversos , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Reestenose Coronária/metabolismo , Modelos Animais de Doenças , Humanos , Lignanas/administração & dosagem , Lignanas/farmacocinética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nanopartículas/administração & dosagem , Poloxâmero/química , Ratos Sprague-Dawley , Dióxido de Silício/química
18.
Int J Nanomedicine ; 15: 5333-5344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801692

RESUMO

Purpose: Cabazitaxel (CBZ) is a new taxane-based antitumor drug approved by the FDA for the treatment of prostate cancer, especially for patients with advanced prostate cancer for whom docetaxel is ineffective or causes aggravation. However, Tween 80 injection can cause serious allergic reactions, and CBZ itself has strong toxicity, adverse reactions, and poor tumor selectivity, which greatly limits its clinical applications. Therefore, the CBZ-loaded bovine serum albumin nanoparticles (CBZ-BSA-Gd-NPs) were developed to overcome the allergenic response of Tween 80 and realize the integration of diagnosis and treatment. Methods: CBZ-BSA-Gd-NPs were prepared by the biomineralization method. The characterization, magnetic resonance imaging (MRI), safety, and antitumor activity of the nanoparticles were evaluated in vitro and in vivo. Results: The prepared nanoparticles were uniform in size (166 nm), with good MRI performance and stability over 24 h. Compared with CBZ-Tween 80 injection, CBZ-BSA-Gd-NPs showed much lower hemolysis, similar tumor inhibition, and enhanced cellular uptake in vitro. The pharmacokinetic behavior of CBZ-BSA-Gd-NPs in rats showed that the retention time of the nanoparticles was prolonged, the clearance rate decreased, and the area under the drug-time curve increased. The distribution of CBZ-BSA-Gd-NPs in nude mice was characterized by UPLC-MS/MS and MRI, and the results showed that CBZ-BSA-Gd-NPs could effectively target tumor tissues with reduced distribution in the heart, liver, spleen, lungs, and kidneys compared with CBZ-Tween 80, which indicated that CBZ-BSA-Gd-NPs not only had a passive targeting effect on tumor tissue but also achieved the integration of diagnosis and treatment. In vivo, CBZ-BSA-Gd-NPs showed improved tumor inhibitory effect with a safer profile. Conclusion: In summary, CBZ-BSA-Gd-NPs can serve as an effective therapeutic drug carrier to deliver CBZ into prostate cancer, and realize the integration of diagnosis and therapy.


Assuntos
Antineoplásicos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Soroalbumina Bovina/administração & dosagem , Taxoides/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cromatografia Líquida , Meios de Contraste/administração & dosagem , Meios de Contraste/farmacocinética , Docetaxel , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Neoplasias da Próstata/diagnóstico por imagem , Ratos Sprague-Dawley , Soroalbumina Bovina/farmacocinética , Espectrometria de Massas em Tandem , Taxoides/farmacocinética , Distribuição Tecidual
19.
Int J Nanomedicine ; 15: 5361-5376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801694

RESUMO

Background and Aim: Polymeric nanoparticles (NPs) have received much attention as promising carrier systems in lung cancer and brain metastases. Methods: Here, for the first time, we investigated the feasibility of using inhaled cholesterol-PEG co-modified poly (n-butyl) cyanoacrylate NPs (CLS-PEG NPs) of docetaxel (DTX) for sustained pulmonary drug delivery in cancer metastasis. Results: Spray-dried or freeze-dried NPs yielded sustained drug release in vitro. In vitro inhalation evaluation data indicated that the inhalation formulation had better inhalability. Compared with intravenous (IV) administration, pharmacokinetic data suggested that the inhalation formulation prolonged plasma concentration of DTX for greater than 24 h and is more quickly and completely absorbed into the rat lung after intratracheal (IT) administration. Furthermore, freeze-dried powders were found to increase the t1/2 and area under curve (AUC) by 2.3 and 6.5 fold compared to the free drug after IT administration, and spray-dried powders were found to increase the t1/2 and AUC by 3.4 and 8.8 fold, respectively. After pulmonary administration of the inhalation formulation, DTX appeared to prolong the pulmonary absorption time. In addition, the inhalation formulation was distributed to the brain in a sustained release manner. Conclusion: These experimental results demonstrated that freeze- and spray-dried powders have the potential for pulmonary sustained release, and they also have the potential to be used as a novel treatment for the delivery of drugs that pass through the air-blood barrier and enter the brain and are efficient carriers for the treatment of brain metastasis.


Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/administração & dosagem , Células A549 , Administração por Inalação , Animais , Encéfalo/efeitos dos fármacos , Colesterol/química , Preparações de Ação Retardada , Docetaxel/farmacocinética , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Embucrilato/química , Feminino , Liofilização , Humanos , Pulmão/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Pós/química , Ratos Wistar , Distribuição Tecidual
20.
Int J Nanomedicine ; 15: 3965-3980, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606658

RESUMO

Aim: Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. Materials and Methods: PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P2h), 4h (P4h) and 12h (P12h). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit®-S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. Results: M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P2h, P4h and P12h were 10.1%, 28.60% and 65.45%. Significant (p < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in Tmax (from 2.5h to 6h), a prolongation in MRT0-∞ (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). Conclusion: E-M14C is a potential system for possible colon targeting of etoricoxib.


Assuntos
Colo/efeitos dos fármacos , Etoricoxib/farmacologia , Etoricoxib/farmacocinética , Voluntários Saudáveis , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ácidos Polimetacrílicos/química , Administração Oral , Adulto , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Colo/metabolismo , Liberação Controlada de Fármacos , Humanos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Adulto Jovem
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