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1.
Vaccine ; 37(42): 6208-6220, 2019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493950

RESUMO

Seasonal influenza vaccines represent a positive intervention to limit the spread of the virus and protect public health. Yet continual influenza evolution and its ability to evade immunity pose a constant threat. For these reasons, vaccines with improved potency and breadth of protection remain an important need. We previously developed a next-generation influenza vaccine that displays the trimeric influenza hemagglutinin (HA) on a ferritin nanoparticle (NP) to optimize its presentation. Similar to other vaccines, HA-nanoparticle vaccine efficacy is increased by the inclusion of adjuvants during immunization. To identify the optimal adjuvants to enhance influenza immunity, we systematically analyzed TLR agonists for their ability to elicit immune responses. HA-NPs were compatible with nearly all adjuvants tested, including TLR2, TLR4, TLR7/8, and TLR9 agonists, squalene oil-in-water mixtures, and STING agonists. In addition, we chemically conjugated TLR7/8 and TLR9 ligands directly to the HA-ferritin nanoparticle. These TLR agonist-conjugated nanoparticles induced stronger antibody responses than nanoparticles alone, which allowed the use of a 5000-fold-lower dose of adjuvant than traditional admixtures. One candidate, the oil-in-water adjuvant AF03, was also tested in non-human primates and showed strong induction of neutralizing responses against both matched and heterologous H1N1 viruses. These data suggest that AF03, along with certain TLR agonists, enhance strong neutralizing antibody responses following influenza vaccination and may improve the breadth, potency, and ultimately vaccine protection in humans.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Neutralizantes/imunologia , Vacinas contra Influenza/imunologia , Adjuvantes Imunológicos/química , Animais , Feminino , Células HEK293 , Testes de Inibição da Hemaglutinação , Hemaglutininas , Humanos , Macaca mulatta , Camundongos Endogâmicos BALB C , Nanopartículas , Receptores Toll-Like/agonistas
2.
Sci Rep ; 9(1): 11565, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399627

RESUMO

Preparation of sophisticated delivery systems for nanomedicine applications generally involve multi-step procedures using organic solvents. In this study, we have developed a simple self-assembling process to prepare docetaxel-loaded hyaluronic acid (HA) nanocapsules by using a self-emulsification process without the need of organic solvents, heat or high shear forces. These nanocapsules, which comprise an oily core and a shell consisting of an assembly of surfactants and hydrophobically modified HA, have a mean size of 130 nm, a zeta potential of -20 mV, and exhibit high docetaxel encapsulation efficiency. The nanocapsules exhibited an adequate stability in plasma. Furthermore, in vitro studies performed using A549 lung cancer cells, showed effective intracellular delivery of docetaxel. On the other hand, blank nanocapsules showed very low cytotoxicity. Overall, these results highlight the potential of self-emulsifying HA nanocapsules for intracellular drug delivery.


Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Ácido Hialurônico/química , Nanocápsulas/química , Células A549 , Antineoplásicos/farmacologia , Docetaxel/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Tensoativos/química
3.
Clin Cancer Res ; 25(15): 4846-4858, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31064780

RESUMO

PURPOSE: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. EXPERIMENTAL DESIGN: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo. RESULTS: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB. CONCLUSIONS: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Movimento Celular , Resistencia a Medicamentos Antineoplásicos , Proteínas de Neoplasias/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/farmacologia , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Espaço Intracelular , Camundongos , Nanocápsulas/química , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Org Chem ; 69(5): 1487-91, 2004 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-14987001

RESUMO

Cyclization of the N-dimethylphosphinoyl-2-methyl-3-aza-5-hexenyl radical has been studied at the UB3LYP/6-31+G(d)//UB3LYP/6-31G(d) hybrid density functional level. The corresponding radical precursor has been synthesized and found to give cis/trans ratios of up to 10/1 in reductive radical cyclizations. The relative energies of reactant and transition state conformers were determined. In discord with the Beckwith-Houk model, it has been found that chair-axial transition states, which lead to cis products, are lowest in energy, rationalizing the observed experimental diastereoselectivity.

5.
Org Lett ; 4(18): 3023-5, 2002 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-12201707

RESUMO

[reaction: see text] Organoselenium precursors of 3-aza-5-hexenyl radicals carrying a 1-hydroxyalkyl group in the 2-position were prepared by addition of organometallic reagents to N-allyl-2-aziridinecarbonitrile, reduction of the resulting aziridine ketone, and regioselective benzeneselenol ring opening of the aziridine. Reductive radical cyclization was highly selective, affording the corresponding trans-2,4-disubstituted pyrrolidine (cis/trans ca. 1/10) as the major diastereomer. Recrystallization afforded material that was substantially more enriched in the trans isomer (cis/trans < 1/25).


Assuntos
Pirrolidinas/síntese química , Aziridinas/química , Ciclização , Radicais Livres/química , Nitrilas/química , Estereoisomerismo
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