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1.
Int J Nanomedicine ; 15: 2841-2858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425521

RESUMO

Introduction: Osthole (Ost) is a coumarin compound that strengthens hippocampal neurons and neural stem cells against Aß oligomer-induced neurotoxicity in mice, and is a potential drug for the treatment of Alzheimer's disease (AD). However, the effectiveness of the drug is limited by its solubility and bioavailability, as well as by the low permeability of the blood-brain barrier (BBB). In this study, a kind of transferrin-modified Ost liposomes (Tf-Ost-Lip) was constructed, which could improve the bioavailability and enhance brain targeting. Methods: Tf-Ost-Lip was prepared by thin-film hydration method. The ability of liposomal formulations to translocate across BBB was investigated using in vitro BBB model. And the protective effect of Tf-Ost-Lip was evaluated in APP-SH-SY5Y cells. In addition, we performed pharmacokinetics study and brain tissue distribution analysis of liposomal formulations in vivo. We also observed the neuroprotective effect of the varying formulations in APP/PS-1 mice. Results: In vitro studies reveal that Tf-Ost-Lip could increase the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and increase the drug concentration across the BBB. Additionally, Tf-Ost-Lip was found to exert a protective effect on APP-SH-SY5Y cells. In vivo studies of pharmacokinetics and the Ost distribution in brain tissue indicate that Tf-Ost-Lip prolonged the cycle time in mice and increased the accumulation of Ost in the brain. Furthermore, Tf-Ost-Lip was also found to enhance the effect of Ost on the alleviation of Alzheimer's disease-related pathology. Conclusion: Transferrin-modified liposomes for delivery of Ost has great potential for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Cumarínicos/farmacologia , Lipossomos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/patologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular , Cumarínicos/química , Cumarínicos/farmacocinética , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Polietilenoglicóis/química , Presenilina-1/genética , Ratos Sprague-Dawley , Distribuição Tecidual , Transferrina/química
2.
Int J Nanomedicine ; 15: 1677-1691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214807

RESUMO

Background: Immune checkpoint blockades (ICBs) are a promising treatment for cancers such as melanoma by blocking important inhibitory pathways that enable tumor cells to evade immune attack. Programmed death ligand 1 monoclonal antibodies (aPDL1s) can be used as an ICB to significantly enhance the effectiveness of tumor immunotherapy by blocking the PD-1/PD-L1 inhibitory pathway. However, the effectiveness of aPDL1s may be limited by low selectivity in vivo and immunosuppressed tumor microenvironment including hypoxia. Purpose: To overcome the limitations, we develop a multifunctional immunoliposome, called CAT@aPDL1-SSL, with catalase (CAT) encapsulated inside to overcome tumor hypoxia and aPDL1s modified on the surface to enhance immunotherapeutic effects against melanoma. Methods: The multifunctional immunoliposomes (CAT@aPDL1-SSLs) are prepared using the film dispersion/post-insertion method. The efficacy of CAT@aPDL1-SSLs is verified by multiple experiments in vivo and in vitro. Results: The results of this study suggest that the multifunctional immunoliposomes preserve and protect the enzyme activity of CAT and ameliorate tumor hypoxia. Moreover, the enhanced cellular uptake of CAT@aPDL1-SSLs in vitro and their in vivo biodistribution suggest that CAT@aPDL1-SSLs have great targeting ability,resulting in improved delivery and accumulation of immunoliposomes in tumor tissue.Finally, by activating and increasing the infiltration of CD8+ T cells at the tumor site, CAT@aPDL1-SSLs inhibit the growth of tumor and prolong survival time of mice,with low systemic toxicity. Conclusion: In conclusion, the multifunctional immunoliposomes developed and proposed in this study are a promising candidate for melanoma immunotherapy, and could potentially be combined with other cancer therapies like radiotherapy and chemotherapy to produce positive outcomes.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Catalase/imunologia , Lipossomos/química , Melanoma/tratamento farmacológico , Hipóxia Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacocinética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Catalase/química , Linhagem Celular Tumoral , Feminino , Imunoterapia/métodos , Lipossomos/administração & dosagem , Lipossomos/farmacologia , Melanoma/patologia , Camundongos Endogâmicos C57BL , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos
3.
PLoS One ; 15(1): e0227891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978077

RESUMO

For the induction of antigen-specific T-cell responses by vaccination, an appropriate immune adjuvant is required. Vaccine adjuvants generally provide two functions, namely, immune potentiator and delivery, and many adjuvants that can efficiently induce T-cell responses are known to have the combination of these two functions. In this study, we explored a cationic lipid DOTAP-based adjuvant. We found that the microfluidic preparation of DOTAP nanoparticles induced stronger CD4+ and CD8+ T-cell responses than liposomal DOTAP. The further addition of Type-A CpG D35 in DOTAP nanoparticles increased the induction of T-cell responses, particularly in CD4+ T cells. Further investigations revealed that the size of DOTAP nanoparticles, prepared buffer conditions, and physicochemical interaction with vaccine antigen are important factors for the efficient induction of T-cell responses with a relatively small antigen dose. These results suggested that microfluidic-prepared DOTAP nanoparticles plus D35 are a promising adjuvant for a vaccine that induces therapeutic T-cell responses for treating cancer and infectious diseases.


Assuntos
Adjuvantes Imunológicos/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Imunidade Celular/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Vacinas/farmacologia , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Celular/imunologia , Lipossomos/farmacologia , Camundongos , Microfluídica , Nanopartículas/química , Vacinas/química
4.
Cancer Sci ; 111(4): 1344-1356, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31960547

RESUMO

5-Fluorouracil-based therapy remains the main approach in colorectal cancer, even though there are still some drawbacks, such as chemoresistance. In this study we combined 5-fluorouracil encapsulated in long-circulating liposomes with simvastatin, also encapsulated in long-circulating liposomes, that was previously proved to exert antitumor actions on the same tumor model. The production of angiogenic/inflammatory proteins was assessed by protein array and the production of markers for tumor aggressiveness (Bcl-2, Bax, and nuclear factor [NF]-κB) were determined by western blot analysis. Intratumor oxidative stress was evaluated through measurement of malondialdehyde level by HPLC, and through spectrophotometric analysis of catalytic activity of catalase and of total antioxidant capacity. Immunohistochemical analysis of tumors for CD31 expression was assessed. Intratumor activity of MMP-2 by gelatin zymography was also carried out. Our results revealed that combined therapies based on liposomal formulations exerted enhanced antitumor activities compared with combined treatment with free drugs. Sequential treatment with liposomal simvastatin and liposomal 5-fluorouracil showed the strongest antitumor activity in C26 colon carcinoma in vivo, mainly through inhibition of tumor angiogenesis. Important markers for cancer progression (Bcl-2, Bax, NF-κB, and intratumor antioxidants) showed that liposomal simvastatin might sensitize C26 cells to liposomal 5-fluorouracil treatment in both regimens tested. The outcome of simultaneous treatment with liposomal formulations was superior to sequential treatment with both liposomal types as the invasive capacity of C26 tumors was strongly increased after the latest treatment. The antitumor efficacy of combined therapy in C26 colon carcinoma might be linked to the restorative effects on proteins balance involved in tumor angiogenesis.


Assuntos
Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lipossomos/farmacologia , Camundongos , NF-kappa B/genética , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/genética
5.
Int J Nanomedicine ; 14: 8305-8320, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806959

RESUMO

Background: Phosphatidylcholine (PC) and Omega-3 fatty acid (Omega-3) are promising therapeutic molecules for treating inflammatory bowel disease (IBD). Purpose: Based on the IBD therapeutic potential of nanoparticles, we herein sought to develop Omega-3-incorporated PC nanoparticles (liposomes) as an orally administrable vehicle for treating IBD. Methods: Liposomes prepared with or without Omega-3 incorporation were compared in terms of colloidal stability and anitiinflammatory effects. Results: The incorporation of free Omega-3 (alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid) into liposomes induced time-dependent membrane fusion, resulting in particle size increase from nm to µm during storage. In contrast, krill oil incorporation into liposomes (KO liposomes) did not induce the fusion and the particle size maintained <250 nm during storage. KO liposomes also maintained colloidal stability in simulated gastrointestinal conditions and exhibited a high capacity to entrap the IBD drug, budesonide (BDS). KO liposomes greatly suppressed the lipopolysaccharide-induced production of pro-inflammatory cytokines in cultured macrophages and completely restored inflammation-impaired membrane barrier function in an intestinal barrier model. In mice subjected to dextran sulfate sodium-induced colitis, oral administration of BDS-entrapped KO liposomes suppressed tumor necrosis factor-α production (by 84.1%), interleukin-6 production (by 35.3%), and the systemic level of endotoxin (by 96.8%), and slightly reduced the macroscopic signs of the disease. Conclusion: Taken together, KO liposomes may have great potential as a nanovehicle for oral delivery of IBD drugs.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colite/tratamento farmacológico , Euphausiacea/química , Lipossomos/farmacologia , Óleos/química , Animais , Anti-Inflamatórios não Esteroides/química , Budesonida/química , Budesonida/farmacologia , Células CACO-2 , Colite/induzido quimicamente , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Ácidos Graxos Ômega-3/química , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Lipossomos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL
6.
Int J Nanomedicine ; 14: 8627-8645, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806961

RESUMO

Background and purpose: Systemic lupus erythematous (SLE) is an autoimmune disease caused by many factors. Lupus nephritis (LN) is a common complication of SLE and represents a major cause of morbidity and mortality. Previous studies have shown the advantages of multi-targeted therapy for LN and that TLR4 signaling is a target of anti-LN drugs. High-mobility group box 1 (HMGB1), a nuclear protein with a proinflammatory cytokine activity, binds specifically to TLR4 to induce inflammation. We aimed to develop PEGylated TAT peptide-cationic liposomes (TAT-CLs) to deliver anti-HMGB1 siRNA and dihydroartemisinin (DHA) to increase LN therapeutic efficiency and explore their treatment mechanism. Methods: We constructed the TAT-CLs-DHA/siRNA delivery system using the thin film hydration method. The uptake and localization of Cy3-labeled siRNA were detected by confocal microscopy and flow cytometry. MTT assays were used to detect glomerular mesangial cell proliferation. Real-time PCR, Western blot analysis, and ELISA evaluated the anti-inflammatory mechanism of TAT-CLs-DHA/siRNA. Results: We constructed the TAT-CLs-DHA/siRNA delivery system measuring approximately 140 nm with superior storage and serum stabilities. In vitro, it showed significantly greater uptake compared with unmodified liposomes and significant inhibition of glomerular mesangial cell proliferation. TAT-CLs-DHA/siRNA inhibited NF-κB activation in a concentration-dependent manner. Real-time PCR and Western blot analysis showed that TAT-CLs-DHA/siRNA downregulated expression of HMGB1 mRNA and protein. TAT-CLs-DHA/siRNA markedly diminished Toll-like receptor 4 (TLR4) expression and subsequent activation of MyD88, IRAK4, and NF-κB. Conclusion: TAT-CLs-DHA/siRNA may have the potential for treatment of inflammatory diseases such as LN mediated by the TLR4 signaling pathway.


Assuntos
Artemisininas/administração & dosagem , Produtos do Gene tat/genética , Proteína HMGB1/genética , Lipossomos/administração & dosagem , Nefrite Lúpica/terapia , RNA Interferente Pequeno/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipossomos/química , Lipossomos/farmacologia , Nefrite Lúpica/metabolismo , NF-kappa B/metabolismo , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
7.
Int J Nanomedicine ; 14: 9777-9792, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849468

RESUMO

Purpose: Staphylococcus aureus is the most common persistent pathogen in humans, so development of new formulations to combat pathogen invasion is quite necessary. Methods: In the current study, for the first time, the synergistic activity of recombinant lysostaphin and LL-37 peptide was studied against S. aureus. Moreover, different niosomal formulations of the peptide and protein were prepared and analyzed in terms of size, shape, zeta potential, and entrapment efficiency. Also, a long-term antibacterial activity of the best niosomal formulation and free forms was measured against S. aureus in vitro. Results: The optimal niosomal formulation was obtained by mixing the surfactants (span60 and tween60; 2:1 w/w), cholesterol, and dicetylphosphate at a ratio of 47:47:6, respectively. They showed uniform spherical shapes with the size of 565 and 325 nm for lysostaphin and LL-37, respectively. This formulation showed high entrapment efficiency for the peptide, protein, and a slow-release profile over time. Release kinetic was best fitted by Higuchi model indicating a diffusion-based release of the drugs. The lysostaphin/LL-37 niosomal formulation synergistically inhibited growth of S. aureus for up to 72 hours. However, the same amounts of free forms of both anti-microbial agents could not hold the anti-microbial effect and growth was seen in the following 72 hours. Cytotoxicity assay specified that lysostaphin/LL-37 niosomal combination had no deleterious effect on normal fibroblast cells at effective antimicrobial concentrations. Conclusion: This study indicated that the use of lysostaphin in combination with LL-37, either in niosomal or free forms, synergistically inhibited growth of S. aureus in vitro. In addition, niosomal preparation of antimicrobial agents could provide a long-term protection against bacterial infections.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Lisostafina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/farmacocinética , Peptídeos Catiônicos Antimicrobianos/farmacocinética , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Fibroblastos/efeitos dos fármacos , Lipossomos/química , Lipossomos/farmacologia , Lisostafina/genética , Lisostafina/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Infecções Estafilocócicas/tratamento farmacológico
8.
Ars pharm ; 60(4): 231-240, oct.-dic. 2019. graf, ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-188487

RESUMO

Antecedentes: durante varios años, se han realizado muchos intentos para mejorar la estabilidad liposomal. En 1986, Payne et al, introdujeron el concepto de pro-liposoma para la preparación de liposoma con el fin de evitar la inestabilidad fisicoquímica encontrada en algunas suspensiones de liposoma tales como agregación, fusión, hidrólisis, y/o oxidación. Objetivo: el objetivo de esta revisión es centrarse en diferentes aspectos relacionados con los Proliposomas, su método de preparación, técnicas de caracterización, asi como señalar su alcance en los sistemas de administración de fármacos. Métodos: los Proliposomas son una nueva forma de sistemas de administración de fármacos. Son productos granulares secos y de flujo libre compuestos por fármacos y fosfolípidos que, al añaderse el agua, se dispersan para formar una suspensión liposomal multilamelar. Resultados y discusión: estos Proliposomas son casi tan buenos o quizás mejores que los liposomas convencionales. En la presente revisión se explica brevemente el concepto de Proliposomas con un enfoque en sus componentes, preparación, caracterizaciones y su campo de aplicación. Conclusión: una extensa encuesta de literaturas y datos recogidos sugiere que los pro-liposomas son portadores de fármacos prometedores para el futuro


Background: For several years, many attempts have been made for the improvement of liposomal sta¬bility. In 1986, Payne et al, introduced the concept of Pro-liposome for liposome preparation in order to avoid physicochemical instability encountered in some liposome suspensions such as aggregation, fusion, hydrolysis, and/or oxidation. Objective: The objective of this review is to focus on different aspects related to Proliposomes, their method of preparation, characterization techniques and pointing out its scope in drug delivery systems. Methods: Proliposomes are a new form of drug delivery systems. They are dry, free-flowing granular products composed of drug and phospholipid which, upon addition of water, disperse to form a multi-lamellar liposomal suspension. Results and Discussion: These Proliposomes are nearly as good as or perhaps better than conventional liposomes. In the present review attempt has been made to briefly explain the concept of Proliposomes with a focus on its components, preparation, characterizations and their field of application. Conclusion: Extensive survey of literatures and collected data suggests that Pro-liposomes are promising drug carriers for the future


Assuntos
Lipossomos/farmacologia , Lipossomos/administração & dosagem , Fosfolipídeos/farmacologia , Disponibilidade Biológica , Lipossomos/farmacocinética , Solventes/farmacocinética , Esteroides
9.
Chem Commun (Camb) ; 55(93): 14081-14084, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31696872

RESUMO

Cholesterol (CHOL) is an indispensable component of liposomes. Incorporation of 7-dehydrocholesterol (7-DHC) instead of CHOL can efficiently enhance the anticancer activity of photosensitizer-encapsulated liposomes upon irradiation, yielding an IC50 value about half of that of CHOL-based controls. The photo-oxidation of 7-DHC into its endoperoxide form by singlet oxygen may account for the enhanced therapeutic effect, realizing an efficient combination of photodynamic therapy (PDT) and photoactivated chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Desidrocolesteróis/farmacologia , Lipossomos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desidrocolesteróis/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipossomos/química , Imagem Óptica , Tamanho da Partícula , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo
10.
Chem Commun (Camb) ; 55(95): 14359-14362, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31720593

RESUMO

Human islet amyloid polypeptide (hIAPP) oligomers are transient due to rapid aggregation rate in vitro, but play an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). Here we report an easy and robust method to generate toxic hIAPP oligomers, which are stable for at least 8 hours. The toxic hIAPP oligomers are quickly transformed from α-helix to ß-sheet by membrane phospholipid, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes, exhibiting distinct nanomechanical features from the hIAPP oligomers or pristine fibrils. DOPC liposomes significantly block the cytotoxicity induced by the hIAPP oligomers, which has the potential for new treatment.


Assuntos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/antagonistas & inibidores , Nanotecnologia , Fosfatidilcolinas/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Lipossomos/química , Lipossomos/farmacologia , Imagem Óptica , Fosfatidilcolinas/química
11.
ACS Appl Mater Interfaces ; 11(50): 46536-46547, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31751119

RESUMO

Local hypoxia in solid malignancies often results in resistance to radiotherapy (RT) and chemotherapy (CT), which may be one of the main reasons for their failure in clinical application. Especially, oxygen is an essential element for enhancing DNA damage caused by ionizing radiation in radiotherapy. Here, two biomimetic oxygen delivery systems were designed by encapsulating hemoglobin (Hb) alone into a liposome (Hb-Lipo) or co-encapsulating Hb and doxorubicin (DOX) into a liposome (DOX-Hb-Lipo). Our data indicated that both Hb-Lipo and DOX-Hb-Lipo could effectively alleviate hypoxia in tumors. We demonstrated that RT plus tumor-targeting delivery of oxygen mediated by Hb-Lipo could significantly overcome the tolerance of hypoxic cancer cells to RT, showing significantly enhanced cancer-cell killing and tumor growth inhibition ability, mainly attributing to hypoxia alleviation and increased reactive oxygen species production under RT in cancer cells. Furthermore, a melanoma model that was quite insensitive to both RT and CT was used to test the efficacy of chemoradiotherapy combined with hypoxia alleviation. RT plus Hb-Lipo only caused a limited increase in antitumor activity. However, extremely strong tumor inhibition could be obtained by RT combined with DOX-Hb-Lipo-mediated CT, attributed to radio-triggered DOX release and enhanced immunogenic cell death induced by RT under an oxygen supplement. Our study provided a valuable reference for overcoming hypoxia-induced radioresistance and a useful therapeutic strategy for cancers that are extremely insensitive to chemo- or radiotherapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Sistemas de Liberação de Medicamentos , Oxigênio/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Neoplasias da Mama/patologia , Quimiorradioterapia/métodos , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Doxorrubicina/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/efeitos da radiação , Feminino , Hemoglobinas/química , Hemoglobinas/farmacologia , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Morte Celular Imunogênica/efeitos da radiação , Lipossomos/química , Lipossomos/farmacologia , Células MCF-7 , Oxigênio/química , Radiação Ionizante , Espécies Reativas de Oxigênio/química , Hipóxia Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Nutr Sci Vitaminol (Tokyo) ; 65(Supplement): S109-S112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31619607

RESUMO

Astaxanthin (Asx) is known to be a potent quencher of singlet oxygen and an efficient scavenger of superoxide anion. However, the scavenging activity of Asx toward the hydroxyl radical was currently unclear because the high lipophilicity of Asx prevents analysis of such activity in water. Liposomes containing Asx (Asx-lipo) were previously shown to be dispersed in water. Analysis of the hydroxyl radical scavenging activity of Asx-lipo demonstrated a dose-dependence in water, with the effect of Asx being more potent than the vitamin E α-tocopherol (α-T). Furthermore, liposomes co-encapsulating Asx and vitamin E derivatives, namely tocotrienols (T3), showed a synergistic elimination effect on singlet oxygen and hydroxyl radical, although the antioxidative activity of liposomes co-encapsulating Asx and α-T was lower than the calculated additive value of each independent activity. A calculation of the most stable structure of Asx in the presence of α-T or T3, suggested that only T3 was able to hydrogen bond with Asx, and the Asx polyene chain partially interacting with the α-T3 triene chain, which could explain the synergistic effect between Asx and T3, but not Asx and α-T. This review introduces the hydroxyl radical scavenging activity of Asx, and its synergistic effect with T3.


Assuntos
Antioxidantes/farmacologia , Tocotrienóis/farmacologia , Vitamina E/farmacologia , Sinergismo Farmacológico , Lipossomos/farmacologia , Superóxidos/metabolismo , Xantofilas/farmacologia
13.
Oncol Rep ; 42(6): 2694-2705, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31578578

RESUMO

Several lines of evidence have clearly demonstrated the role of the tumor microenvironment in favoring the drug resistance of melanoma cells, as well as the progression of this cancer type. Since our previous studies proved that the accumulation of prednisolone disodium phosphate (PLP) in melanoma tissue inhibited tumor growth by exerting anti­angiogenic effects on the most abundant cells of the tumor microenvironment, tumor­associated macrophages (TAMs), the present study investigated whether PLP could enhance the cytotoxic effects of doxorubicin (DOX) on B16.F10 murine melanoma cells. To assess the antitumor efficacy of the combined therapeutic approach based on PLP and DOX, we used a co­culture system composed of bone marrow­derived macrophages (BMDMs) and B16.F10 murine melanoma cells at a cell density ratio that approximates the melanoma microenvironment in vivo, ensuring the polarization of the BMDMs into TAMs. Thus, we assessed the combined therapeutic effects of PLP and DOX on melanoma cell proliferation and apoptosis, as well as on supportive processes for tumor growth, such as oxidative stress as well as the angiogenic and inflammatory capacity of the cell co­culture. Our data demonstrated that the cytotoxicity of DOX was potentiated mainly via the anti­angiogenic activity of PLP in the melanoma microenvironment in vitro. Moreover, the amplitude of the cytotoxicity of the combined treatments may be linked to the degree of the suppression of the pro­angiogenic function of TAMs. Thus, the potent decrease in the expression of the majority of the angiogenic and inflammatory proteins in TAMs following the concomitant administration of PLP and DOX may be associated with their anti­proliferative, as well as pro­apoptotic effects on B16.F10 melanoma cells. However, the combination therapy tested did not affect the immunosuppressive phenotype of the TAMs, as the levels of two important markers of the M2­like phenotype of macrophages (IL­10 and Arg­1) were not reduced or even increased following these treatments. On the whole, the findings of this study indicated that PLP improved the therapeutic outcome of DOX in the melanoma microenvironment via the inhibition of the pro­angiogenic function of TAMs.


Assuntos
Doxorrubicina/farmacologia , Melanoma Experimental/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Prednisolona/análogos & derivados , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Humanos , Lipossomos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Melanoma Experimental/patologia , Camundongos , Neovascularização Patológica/patologia , Prednisolona/farmacologia , Microambiente Tumoral/efeitos dos fármacos
14.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505837

RESUMO

Cistanche tubulosa is a traditional Chinese herbal medicine that is widely used to regulate immunity, and phenylethanol glycosides (CPhGs) are among the primary components responsible for this activity. However, the application of CPhGs is negatively affected by their poor absorption and low oral utilization. Targeted drug delivery is an important development direction for pharmaceutics. Previous studies have indicated that CPhGs could block the conduction of the signaling pathways in TGF-ß1/smad and inhibit the activation of hepatic stellate cells (HSCs). The aim of this study was to evaluate the anti-hepatic fibrosis effect of CPhG liposomes by inhibiting HSC activation, promoting apoptosis, blocking the cell cycle, suppressing the conduction of signaling pathways in focal adhesion kinase(FAK)/phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt), and determining their in vitro hepatoprotective activity. In vitro release studies demonstrated that CPhG liposomes have a sustained release effect compared to drug CPhGs. HSC proliferation was inhibited after treatment with the CPhG liposomes (29.45, 14.72, 7.36 µg/mL), with IC50 values of 42.54 µg/mL in the MTT assay. Different concentrations of the CPhG liposomes could inhibit HSC proliferation, promote apoptosis, and block the cell cycle. The MTT method showed an obvious inhibition of HSC proliferation after CPhG liposome and Recombinant Rat Platelet-derived growth factor-BB(rrPDGF-BB) treatment. The levels of collagen-1, metallopeptidase inhibitor 1 (TIMP-1), α smooth muscle actin (α-SMA), and phosphorylated PI3K/Akt were downregulated, and matrix metalloproteinase-1 (MMP-1) was upregulated, by pretreatment with different concentrations of CPhG liposomes. Moreover, 29.45 µg/mL of CPhG liposomes could decrease the expression of the FAK protein and the phosphorylated PI3K and Akt protein downstream of FAK by overexpression of the FAK gene. This experiment suggests that CPhG liposomes may inhibit the activation of HSCs by inhibiting FAK and then reducing the expression of phosphorylated Akt/PI3K, thereby providing new insights into the application of CPhGs for liver fibrosis.


Assuntos
Cistanche/química , Sistemas de Liberação de Medicamentos , Glicosídeos/farmacologia , Álcool Feniletílico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Becaplermina/química , Becaplermina/genética , Becaplermina/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinase 1 de Adesão Focal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/química , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Imunidade/efeitos dos fármacos , Lipossomos/química , Lipossomos/farmacologia , Medicina Tradicional Chinesa , Álcool Feniletílico/química , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos
15.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505853

RESUMO

Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways.


Assuntos
Ativação do Complemento/efeitos dos fármacos , Síndrome de Hipersensibilidade a Medicamentos/tratamento farmacológico , Leucocitose/sangue , Lipossomos/farmacologia , Anfotericina B/química , Anfotericina B/farmacologia , Animais , Colesterol/química , Convertases de Complemento C3-C5/química , Convertases de Complemento C3-C5/farmacologia , Proteínas do Sistema Complemento/química , Proteínas do Sistema Complemento/metabolismo , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Síndrome de Hipersensibilidade a Medicamentos/patologia , Venenos Elapídicos/química , Venenos Elapídicos/farmacologia , Humanos , Hipotensão/sangue , Hipotensão/induzido quimicamente , Leucocitose/induzido quimicamente , Leucopenia/sangue , Leucopenia/induzido quimicamente , Lipossomos/química , Nanopartículas/química , Polietilenoglicóis/química , Ratos , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Zimosan/química , Zimosan/farmacologia
16.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509965

RESUMO

Collagen Tissue Disease-associated Interstitial Lung Fibrosis (CTD-ILDs) and Bronchiolitis Obliterans Syndrome (BOS) represent severe lung fibrogenic disorders, characterized by fibro-proliferation with uncontrolled extracellular matrix deposition. Hyaluronic acid (HA) plays a key role in fibrosis with its specific receptor, CD44, overexpressed by CTD-ILD and BOS cells. The aim is to use HA-liposomes to develop an inhalatory treatment for these diseases. Liposomes with HA of two molecular weights were prepared and characterized. Targeting efficiency was assessed toward CTD-ILD and BOS cells by flow cytometry and confocal microscopy and immune modulation by RT-PCR and ELISA techniques. HA-liposomes were internalized by CTD-ILD and BOS cells expressing CD44, and this effect increased with higher HA MW. In THP-1 cells, HA-liposomes decreased pro-inflammatory cytokines IL-1ß, IL-12, and anti-fibrotic VEGF transcripts but increased TGF-ß mRNA. However, upon analyzing TGF-ß release from healthy donors-derived monocytes, we found liposomes did not alter the release of active pro-fibrotic cytokine. All liposomes induced mild activation of neutrophils regardless of the presence of HA. HA liposomes could be also applied for lung fibrotic diseases, being endowed with low pro-inflammatory activity, and results confirmed that higher MW HA are associated to an increased targeting efficiency for CD44 expressing LFs-derived from BOS and CTD-ILD patients.


Assuntos
Bronquiolite Obliterante/tratamento farmacológico , Ácido Hialurônico/farmacologia , Lipossomos/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Células A549 , Adulto , Bronquiolite Obliterante/patologia , Sistemas de Liberação de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Receptores de Hialuronatos/efeitos dos fármacos , Ácido Hialurônico/química , Lipossomos/química , Microscopia Confocal , Monócitos/efeitos dos fármacos , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/genética , Fator A de Crescimento do Endotélio Vascular/genética
17.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502572

RESUMO

The goal of the current investigation was to prepare PEGylated Lipova E120 liposomes loaded with celecoxib for the effective treatment of rheumatoid arthritis (RA). PEGylated liposomes were prepared and were characterized using techniques such as particle size distribution, polydispersity index (PDI), zeta potential, encapsulation efficiency and in-vitro release, in-vivo and stability studies. The morphological study was characterized by scanning electron microscopy and transmission electron microscopy. To determine the interaction between drug and polymer Fourier transform infrared, Raman, thermogravimetric analysis and differential scanning calorimetry studies were performed. Results show that formulation F6 was optimized with a particle size of 92.12 +/- 1.7 nm, a PDI of 0.278 +/- 0.22, a zeta potential of - 40.8 +/- 1.7 mV with a maximum encapsulation of 96.6 +/- 0.05% of drug in the PEGylated liposomes. The optimized formulation shows a maximum release of drug i.e. 94.45 +/- 1.13% in 72 h. Tail immersion assay shows that the optimized formulation F6 significantly increases the reaction time and carrageenan-induced assay shows that the optimized formulation inhibits the increase in paw edema thus providing a pain relief treatment in RA. These results suggest that the PEGylated liposomes provide a sustained release of celecoxib and helps in effective treatment of RA.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Celecoxib/farmacologia , Lipossomos/farmacologia , Animais , Anti-Inflamatórios/química , Artrite Reumatoide/fisiopatologia , Celecoxib/química , Modelos Animais de Doenças , Humanos , Lipossomos/química , Masculino , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Ratos
19.
Nano Lett ; 19(9): 5844-5852, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424944

RESUMO

The majority of developed and approved anticancer nanomedicines have been designed to exploit the dogma of the enhanced permeability and retention (EPR) effect, which is based on the leakiness of the tumor's blood vessels accompanied by impeded lymphatic drainage. However, the EPR effect has been under scrutiny recently because of its variable manifestation across tumor types and animal species and its poor translation to human cancer therapy. To facilitate the EPR effect, systemically injected NPs should overcome the obstacle of rapid recognition and elimination by the mononuclear phagocyte system (MPS). We hypothesized that circulating monocytes, major cells of the MPS that infiltrate the tumor, may serve as an alternative method for achieving increased tumor accumulation of NPs, independent of the EPR effect. We describe here the accumulation of liposomal quantum dots (LipQDs) designed for active delivery via monocytes, in comparison to LipQDs designed for passive delivery (via the EPR effect), following IV administration in a mammary carcinoma model. Hydrophilic QDs were synthesized and entrapped in functionalized liposomes, conferring passive ("stealth" NPs; PEGylated, neutral charge) and active (monocyte-mediated delivery; positively charged) properties by differing in their lipid composition, membrane PEGylation, and charge (positively, negatively, and neutrally charged). The various physicochemical parameters affecting the entrapment yield and optical stability were examined in vitro and in vivo. Biodistribution in the blood, various organs, and in the tumor was determined by the fluorescence intensity and Cd analyses. Following the treatment of animals (intact and mammary-carcinoma-bearing mice) with disparate formulations of LipQDs (differing by their lipid composition, neutrally and positively charged surfaces, and hydrophilic membrane), we demonstrate comparable tumor uptake of QDs delivered by the passive and the active routes (mainly by Ly-6Chi monocytes). Our findings suggest that entrapping QDs in nanosized liposomal formulations, prepared by a new facile method, imparts superior structural and optical stability and a suitable biodistribution profile leading to increased tumor uptake of fluorescently stable QDs.


Assuntos
Lipossomos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Sistema Fagocitário Mononuclear/química , Pontos Quânticos/química , Animais , Vasos Sanguíneos/efeitos dos fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Lipídeos/química , Lipídeos/farmacologia , Lipossomos/química , Neoplasias Mamárias Animais/patologia , Camundongos , Nanomedicina , Células Neoplásicas Circulantes , Permeabilidade/efeitos dos fármacos
20.
Sci Adv ; 5(7): eaaw4197, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31355333

RESUMO

Surgical removal of the primary tumor is a common practice in breast cancer treatment. However, postsurgical metastasis poses an immense setback in cancer therapy. Considering that 90% of cancer-related deaths are due to metastasis, antimetastatic therapeutic strategies that can target disseminating tumor cells in the circulation before they can form secondary tumors hold preclinical and clinical potential for cancer patients. Our current work uses a liposomal formulation functionalized with the adhesion receptor E-selectin and the apoptosis-inducing ligand TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL) to reduce metastasis following tumor resection in an aggressive triple-negative breast cancer (TNBC) mouse model. We demonstrate that minimal administration of E-selectin-TRAIL liposomes can target metastasis in a TNBC model, with primary tumor resection to mimic clinical settings. Our study indicates that TRAIL liposomes, alone or in combination with existing clinically approved therapies, may neutralize distant metastasis of a broad range of tumor types systemically.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Experimentais/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Aspirina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Dioxolanos/farmacologia , Selectina E/química , Selectina E/genética , Feminino , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Lipossomos/química , Lipossomos/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/cirurgia , Camundongos , Metástase Neoplásica , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/cirurgia , Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgia
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