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1.
Adv Exp Med Biol ; 1159: 33-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502198

RESUMO

Are ceramide molecules capable of self-assembling in biological and phospholipid membranes to form ceramide channels: membrane channels capable to translocating proteins through said membranes? A number of papers have been published which support the conclusion that ceramide forms these large channels in membranes. The evidence is extensive and consisting of: flux studies using isolated mitochondria, liposomes and planar membranes; visualization by electron microscopy; elastic deformation studies; and regulation by Bcl-2 family proteins. The evidence supports a structural model of the channel shown to be stable by molecular dynamic simulations and having structural and mechanical properties consistent with multiple experiments. Yet the novelty of this claim raises legitimate questions. Indeed, a recent report questions the existence of ceramide channels based on liposome experiments. This review presents both a comprehensive description of the major observations supporting the case that ceramide channels do exist and addresses the issues raised in the skeptical report.


Assuntos
Membrana Celular/química , Ceramidas/química , Lipossomos/química , Mitocôndrias/química , Fosfolipídeos , Proteínas Proto-Oncogênicas c-bcl-2
3.
Int J Nanomedicine ; 14: 5159-5173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371954

RESUMO

Introduction: The use of liposomes as a drug delivery carrier (DDC) for the treatment of various diseases, especially cancer, is rapidly increasing, requiring more stringent synthesis, formulation, and preservation techniques to bolster safety and efficacy. Liposomes otherwise referred to as phospholipid vesicles are self-assembled colloidal particles. When formed in either the micrometer or nanometer size range, they are ideal candidates as DDC because of their biological availability, performance, activity, and compatibility. Defining and addressing the critical quality attributes (CQAs) along the pharmaceutical production scale will enable a higher level of quality control for reproducibility. More specifically, understanding the CQAs of nanoliposomes that dictate its homogeneity and stability has the potential to widen applications in biomedical science. Methods: To this end, we designed a study that aimed to define synthesis, characterization, formulation (encapsulation), preservation, and cargo delivery and trafficking as the major components within a target product profile for nanoliposomes. A series of synthetic schemes were employed to measure physicochemical properties relevant to nanomaterial drug product development, including concentration gradients, probe versus bath sonication, and storage temperature measured by microscopy (electron and light) and dynamic light scattering. Results: Concentration was found to be a vital CQA as reducing concentrations resulted in nanometer-sized liposomes of <350 nm. Liposomes were loaded with microRNA and fluorescence spectroscopy was used to determine loading efficacy and stability over time. Lyophilization was used to create a dry powder formulation that was then assessed for stability for 6 months. Lastly, breast cancer cell lines were used to ensure efficacy of microRNA delivery and localization. Conclusion: We conclude that microRNA can be loaded into nanometer-sized liposomes, preserved for months in a dried form, and maintain encapsulation after extended time periods in storage.


Assuntos
Neoplasias da Mama/terapia , Lipossomos/química , MicroRNAs/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Linhagem Celular Tumoral , Feminino , Humanos , Nanopartículas/ultraestrutura , Concentração Osmolar , Reprodutibilidade dos Testes
4.
Pharm Res ; 36(10): 144, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31392417

RESUMO

PURPOSE: Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation requires sufficient tumor boron delivery while minimizing nonspecific accumulation. METHODS: Thermal sensitive liposomes (TSLs) were designed to have a stable drug payload at physiological temperatures but engineered to have high permeability under mild hyperthermia. RESULTS: We found that TSLs improved the tumor-specific delivery of boronophenylalanine (BPA) and boronated 2-nitroimidazole derivative B-381 in D54 glioma cells. Uniquely, the 2-nitroimidazole moiety extended the tumor retention of boron content compared to BPA. CONCLUSION: This is the first study to show the delivery of boronated compounds using TSLs for BNCT, and these results will provide the basis of future clinical trials using TSLs for BNCT.


Assuntos
Compostos de Boro/química , Terapia por Captura de Nêutron de Boro , Lipossomos/química , Animais , Antineoplásicos/química , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacocinética , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/metabolismo , Doxorrubicina/química , Liberação Controlada de Fármacos , Feminino , Glioma/metabolismo , Humanos , Hipertermia Induzida , Camundongos Nus , Nitroimidazóis/administração & dosagem , Nitroimidazóis/química , Tamanho da Partícula , Fenilalanina/administração & dosagem , Fenilalanina/análogos & derivados , Fenilalanina/química , Fosfolipídeos/química , Temperatura Ambiente , Distribuição Tecidual
5.
Life Sci ; 234: 116787, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445028

RESUMO

Iron deficiency anemia (IDA) is a major worldwide public health problem. This is due to its prevalence among infants, children, adolescents, pregnant and reproductive age women. Ferrous sulfate (FeSO4) is the first line therapy for iron IDA. Unfortunately, it is reported that FeSO4 suffers from low absorption rate in the body and itself exhibits severe side effects. Herein, iron oxide magnetic nanoparticles-loaded liposomes (LMNPs) are prepared, characterized and evaluated as a treatment regimen for IDA in Wistar rats (as an animal model). Iron oxide magnetic nanoparticles (MNPs) are prepared and loaded into liposomes using the thin film hydration method. The size of the prepared formulations is in the range 10-100 nm, thus it can avoid the reticular endothelial system (RES), and increased their blood circulation time. For in vivo assessment, thirty-five Wistar rats are divided into 5 groups (n = 7): negative control group, positive control group, and three groups treated with different iron formulations (FeSO4, MNPs and LMNPs). Anemia is induced in the anemic groups by the bleeding method and then treatment started with different iron compounds administrated orally for 13 days. Hematological parameters are followed up during the treatment period. Results indicate that, in the LMNPs group, the hematological parameters turn to normal values and the histopathological structures of the liver, spleen and kidney remain normal. This proves that liposome increases the bioavailability of MNPs. In conclusion, LMNPs demonstrate superiority as a therapeutic regimen for the treatment of IDA among the tested iron formulations.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Compostos Ferrosos/administração & dosagem , Hematínicos/administração & dosagem , Lipossomos/química , Nanopartículas de Magnetita/química , Anemia Ferropriva/sangue , Animais , Disponibilidade Biológica , Feminino , Compostos Ferrosos/farmacocinética , Compostos Ferrosos/uso terapêutico , Hematínicos/farmacocinética , Hematínicos/uso terapêutico , Hemoglobinas/análise , Lipossomos/ultraestrutura , Nanopartículas de Magnetita/ultraestrutura , Ratos Wistar
6.
Chem Commun (Camb) ; 55(72): 10784-10787, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31432802

RESUMO

Medical magnetic resonance imaging (MRI) produces high-resolution anatomical images of the human body, but has limited capacity to provide useful molecular information. The light-responsive, liposomal MRI contrast agent described herein could be used to provide an intrinsic theranostic aspect to MRI and enable tracking the distribution and cargo release of drug delivery systems upon light-triggered activation.


Assuntos
Meios de Contraste/química , Sistemas de Liberação de Medicamentos , Gadolínio/química , Luz , Imagem por Ressonância Magnética , Humanos , Lipossomos/química , Estrutura Molecular
7.
Eur J Histochem ; 63(3)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31455073

RESUMO

RNA interference is a powerful approach to understand gene function both for therapeutic and experimental purposes. Since the lack of knowledge in the gene silencing of various hepatic cell lines, this work was aimed to compare two transfection agents, the liposome-based Lipofectamine™ RNAiMAX and the HepG2-specific, polymer-based GenMute™, in two cellular models of human hepatoma, HepG2 and Huh7.5. In the first part, we assessed transfection efficiency of a fluorescent Cy3-labeled negative control siRNA by cell imaging analysis; we found that cells treated with GenMute present a higher uptake of the fluorescent negative control siRNA when compared to Lipofectamine RNAiMAX-transfected cells, both in HepG2 and in Huh7.5 cells. In the second part, we evaluated GAPDH silencing with the two transfection reagents by RT-PCR similar GAPDH mRNA expression after each transfection treatment. Finally, we measured cell viability by the MTT assay, observing that cells transfected with GenMute have higher viability with respect to Lipofectamine RNAiMAX-administered cells. These results suggest that GenMute reagent might be considered the most suitable transfection agent for hepatic gene silencing.


Assuntos
Técnicas de Transferência de Genes , Lipídeos/química , Polímeros/química , RNA Interferente Pequeno/genética , Transfecção/métodos , Sequência de Bases , Carbocianinas/química , Carbocianinas/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Inativação Gênica , Gliceraldeído-3-Fosfato Desidrogenases/genética , Humanos , Metabolismo dos Lipídeos , Lipídeos/toxicidade , Lipossomos/química , Lipossomos/metabolismo , Lipossomos/toxicidade , Neoplasias Hepáticas/genética , Polímeros/metabolismo , Polímeros/toxicidade , Interferência de RNA
8.
DNA Cell Biol ; 38(10): 1048-1055, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433200

RESUMO

DNA condensed agents can improve the transfection efficiency of the cationic liposome delivery system. However, various condensed agents have distinct transfection efficiency and cellular cytotoxicity. The object of this study was to screen the optimal agents with the high transfection efficiency and low cytotoxicity from four polymer compressive materials, polyethylenimine (PEI), chitosan, poly-l-lysine (PLL), and spermidine. DNA was precompressed with these four agents and then combined to cationic liposomes. Subsequently, the entrapment and transfection efficiency of the obtained complexes were investigated. Finally, the particle sizes, cytotoxicity, and endocytosis fashion of these copolymers (Lipo-PEI, Lipo-chitosan, Lipo-PLL, and Lipo-spermidine) were examined. It was found that these four copolymers had significantly lower cytotoxicity and higher transfection efficiency (45.5%, 42.4%, 36.8%, and 47.4%, respectively) than those in the control groups. The transfection efficiency of Lipo-PEI and Lipo-spermidine copolymers were better than the other two copolymers. In 293T cells, nystatin significantly inhibited the transfection efficiency of Lipo-PEI-DNA and Lipo-spermidine-DNA (51.88% and 46.05%, respectively), which suggest that the endocytosis pathway of Lipo-spermidine and Lipo-PEI copolymers was probably caveolin dependent. Our study indicated that these dual-degradable copolymers especially liposome-spermidine copolymer could be used as the potential biocompatible gene delivery carriers.


Assuntos
Quitosana/química , Lipossomos/química , Polietilenoimina/química , Polilisina/química , Espermidina/química , Transfecção/métodos , Cátions , Caveolina 1/genética , Caveolina 1/metabolismo , Quitosana/metabolismo , Colesterol/química , Colesterol/metabolismo , Endocitose/efeitos dos fármacos , Endocitose/genética , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/metabolismo , Células HEK293 , Humanos , Lipossomos/metabolismo , Nistatina/farmacologia , Tamanho da Partícula , Plasmídeos/química , Plasmídeos/metabolismo , Polietilenoimina/metabolismo , Polilisina/metabolismo , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/metabolismo , Espermidina/metabolismo
9.
Chem Commun (Camb) ; 55(73): 10940-10943, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31441920

RESUMO

Different from traditional "always on" photothermal therapy (PTT) agents, tumor microenvironment responsive agents showed more tumor specificity and lower photo-toxicity to normal tissues. Herein, a photo-stable and reversible pH responsive phenazine dye (PIOH) was synthesized and assembled with liposomes forming nanoparticles (PIOH-NPs), which exhibited a strong NIR absorption in a weak acid environment and were successfully utilized for photoacoustic (PA) imaging-guided photothermal therapy in mice.


Assuntos
Antineoplásicos/uso terapêutico , Corantes Fluorescentes/uso terapêutico , Fenazinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Colesterol/química , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/toxicidade , Concentração de Íons de Hidrogênio , Hipertermia Induzida/métodos , Lecitinas/química , Lipossomos/química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho da Partícula , Fenazinas/síntese química , Fenazinas/química , Fenazinas/toxicidade , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Microambiente Tumoral/fisiologia
10.
Int J Nanomedicine ; 14: 4461-4474, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31296986

RESUMO

Background: Vincristine is a potent therapeutic agent with well-defined activity against hematologic malignancies and solid tumors. It is a cell-cycle specific drug with concentration and exposure duration dependent activity. When used by liposomal delivery, it exhibits enhanced anti-tumor activity. However, vincristine liposome formulation in the clinic is supplied as a 3-vial-kit due to lacking sufficient stability. So it has to be prepared in situ prior to use through a multi-step process. Purpose: The purpose here is to develop a more stable and ready-to-use liposomal formulation for vincritstine in one vial. Patients and methods: A series of preparations were investigated based on sphingomyelin/cholesterol/PEG2000-DSPE lipid composition, with different drug/lipid (D/L) ratios (1/10, 1/5, 1/2), using an active sucrose octasulfate triethylamine salt gradient loading method. In this work, compared to generic vincristine sulfate liposome injection (GVM), the stability both in vivo and in vitro and efficacy in vivo of novel vincristine liposomes were investigated. Results: It was shown that the degradation of vincristine during 2-8°C storage was significantly decreased from 8.2% in 1 month (GVM) to 2.9% in 12 months (D/L ratio 1/5). The half-time for sphingomyelin/cholesterol/PEG2000-DSPE liposomes in vivo could be adjusted from 17.4 h (D/L ratio 1/10) to 22.7 h (D/L ratio 1/2) in rats, while the half-time for GVM was only 11.1 h. The increase in drug retention contributed to the lower in vivo toxicity. The antitumor efficacy was evaluated using a human melanoma tumor model and showed remarkable improvement compared to GVM. Conclusion: The study demonstrates that the new formulation with the drug/lipid ratio of 1/5 owns a higher encapsulation efficiency, better stability, lower toxicity and superior antitumor efficacy, which is screened out for further development.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Vincristina/química , Vincristina/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Colesterol/química , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos Wistar , Esfingomielinas/química , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int J Nanomedicine ; 14: 4353-4366, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354265

RESUMO

Purpose: Gene therapy has become a promising remedy to treat disease by modifying the person's genes. The therapeutic potential of related tools such as CRISPR-Cas9 depends on the efficiency of delivery to the targeted cells. Numerous transfection reagents have been designed and lots of efforts have been devoted to develop carriers for this purpose. Therefore, the aim of the present study was to develop novel cholesterol-rich lipid-based nanoparticles to enhance transfection efficiency and serum stability. Materials and methods: We constructed two-, three- and four-component cationic liposomes (CLs) to evaluate the combined effect of cholesterol domain and DOPE (dioleoyl phosphatidylethanolamine), a fusogenic lipid, and the PEG (polyethylene glycol) moiety location inside or outside of the cholesterol domain on transfection efficiency and other properties of the particle. Lipoplex formation and pDNA (plasmid DNA) entrapment were assessed by gel retardation assay at different N/P ratios (3, 5, 7). Physicochemical characteristics, cytotoxicity, serum stability and endosomal escape capability of the lipoplexes were studied and transfection potential was measured by firefly luciferase assay. Next, HEK293 cell line stably expressing GFP was utilized to demonstrate the editing of a reporter through Cas9 and sgRNA plasmids delivery by the selected CL formula, which showed the highest transfection efficiency. Results: Among the designed CLs, the four-component formula [DOTAP (1,2-dioleoyl-3-trimethylammoniumpropane)/DOPE/cholesterol/Chol-PEG (cholesterol-polyethylene glycol)] showed the highest rate of transfection at N/P 3. Finally, transfection of Cas9/sgRNA by this formulation at N/P 3 resulted in 39% gene-editing efficiency to knockout GFP reporter. The results also show that this CL with no cytotoxicity effect can totally protect the plasmids from enzymatic degradation in serum. Conclusion: The novel PEGylated cholesterol domain lipoplex providing serum stability, higher transfection efficiency and endosomal release can be used for in vivo Cas9/sgRNA delivery and other future gene-therapy applications.


Assuntos
Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Colesterol/química , Edição de Genes , Nanopartículas/química , Transfecção/métodos , Cátions/química , Morte Celular , Colesterol/análogos & derivados , Ensaio de Desvio de Mobilidade Eletroforética , Endossomos/metabolismo , Ácidos Graxos Monoinsaturados/química , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Lipossomos/química , Tamanho da Partícula , Fosfatidiletanolaminas/química , Plasmídeos/metabolismo , Polietilenoglicóis/química , Compostos de Amônio Quaternário/química , RNA Guia/metabolismo , Eletricidade Estática
12.
J Photochem Photobiol B ; 197: 111544, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31295716

RESUMO

Photodynamic therapy (PDT) induced by protoporphyrin IX (PpIX) has been widely used in dermatological practices such as treatment of skin cancers. Clearance rate depends on different factors such as light irradiation, skin oxygenation and drug penetration. The poor penetration of 5-aminolevulinic acid (5-ALA) with topical application is limited and restrains the production of PpIX which could restrict PDT outcomes. This review will focus on techniques already used to enhance drug penetration in human skin, and will present their results, advantages, and drawbacks. Chemical and physical pretreatments will be discussed. Chemical pre-treatments comprise of drug formulation modification, use of agents that modify the heme cycle, enhance PpIX formation, and the combination of differentiation-promoting agent prior to PDT. On the other hand, physical pretreatments affect the skin barrier by creating holes in the skin or by removing stratum corneum. To promote drug penetration, iontophoresis and temperature modulation are interesting alternative methods. Cellular mechanisms enrolled during chemical or physical pretreatments have been investigated in order to understand how 5-ALA penetrates the skin, why it is preferentially metabolized in PpIX in tumour cells, and how it could be accumulated in deeper skin layers. The objective of this review is to compare clinical trials that use innovative technology to conventional PDT treatment. Most of these pretreatments present good or even better clinical outcomes than usual PDT.


Assuntos
Fármacos Fotossensibilizantes/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Ácido Aminolevulínico/química , Ácido Aminolevulínico/metabolismo , Ácido Aminolevulínico/uso terapêutico , Composição de Medicamentos , Humanos , Lipossomos/química , Micelas , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/química , Protoporfirinas/metabolismo , Protoporfirinas/uso terapêutico , Neoplasias Cutâneas/patologia
13.
Chem Soc Rev ; 48(16): 4347-4360, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31263808

RESUMO

To exert its role of a functional polymer, DNA relies on a molecular self-assembly process that is driven by the interactions of only four units placed in a defined order. Extending the structural diversity of recognition motifs in DNA, to and beyond analogues of the nucleobases, will open doors to self-assembled materials with advanced programmable properties. DNA-inspired systems are becoming useful for numerous applications unachievable by the nucleic acids in their native composition. Potential applications of rationally designed oligo- and polyphosphodiesters reside in the areas of drug delivery, diagnostic signalling and imaging, in systems for efficient energy transfer or the precise ordering on the nanoscale. The field of DNA-inspired phosphodiesters highlights the general value and utility of precision in the composition of oligomers and polymers. In this tutorial review, we will summarize the approaches of directing the self-assembly of DNA-inspired, sequence-specific polyphosphodiesters into soft materials with unique properties. These data expose the so far underexploited potential of DNA-derived systems in solving some of the key issues in various technological areas, such as advanced biomaterials, morphologically defined soft matter or the controlled polymer folding and assembly. Moreover, precise positioning of structurally diverse molecules within a polymer chain creates unmatched opportunities for encoding information on the molecular level and transmitting it further to the microscopic and even macroscopic level via noncovalent interactions.


Assuntos
DNA/química , Polímeros/química , Azidas/química , Lipossomos/química , Compostos Organofosforados/química , Polímeros/síntese química
14.
Int J Nanomedicine ; 14: 4755-4765, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308656

RESUMO

Background: Many techniques and methods have been used clinically to relieve pain from cartilage repair, but the long-term effect is still unsatisfactory. Purpose: The objective of this study was to form an artificial chondroid tissue gene enhanced tissue engineering system to repair cartilage defects via nanosized liposomes. Methods: Cationic nanosized liposomes were prepared and characterized using transmission electron microscope (TEM) and dynamic laser light scattering (DLS). The rat mesenchymal stem cells (rMSCs) were isolated, cultivated, and induced by SRY (Sex-Determining Region Y)-Box 9 (Sox9) via cationic nanosized liposomes. The induced rMSCs were mixed with a thermo-sensitive chitosan hydrogel and subcutaneously injected into the nude mice. Finally, the newly-formed chondroid tissue obtained in the injection parts, and the transparent parts were detected by HE, collagen II, and safranin O. Results: It was found that the presently prepared cationic nanosized liposomes had the diameter of 85.76±3.48 nm and the zeta potential of 15.76±2.1 mV. The isolated rMSCs proliferation was fibroblast-like, with a cultivated confluence of 90% confluence in 5-8 days, and stained positive for CD29 and CD44 while negative for CD34 and CD45. After transfection with cationic nanosized liposomes, we observed changes of cellular morphology and a higher expression of SOX9 compared with control groups, which indicated that rMSCs could differentiate into chondrocyte in vitro. By mixing transfected rMSCs with the thermo-sensitive hydrogel of chitosan in nude mice, chondroid tissue was successfully obtained, demonstrating that rMSCs can differentiate into chondrogenic cells in vivo. Conclusion: This study explored new ways to improve the quality of tissue engineered cartilage, thus accelerating clinical transformation and reducing patient pain.


Assuntos
Condrogênese , Técnicas de Transferência de Genes , Nanopartículas/química , Engenharia Tecidual/métodos , Animais , Cátions , Diferenciação Celular , Forma Celular , Células Cultivadas , Condrogênese/efeitos dos fármacos , Géis , Lipossomos/química , Lipossomos/ultraestrutura , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos Nus , Ratos Sprague-Dawley , Fatores de Transcrição SOX9/metabolismo , Temperatura Ambiente
15.
Biomater Sci ; 7(9): 3866-3875, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31309204

RESUMO

Photothermal therapy (PTT) is emerging as a promising treatment for skin cancer. Plasmon-resonant gold-coated liposome nanoparticles (Au Lipos NPs) specifically absorb Near Infra-Red (NIR) light resulting in localized hyperthermia (PTT). In the current study, curcumin (a hydrophobic anticancer agent) was entrapped in Au Lipos NPs as nanocrystals to act as an adjuvant for the PTT of melanoma. NIR light irradiation on Au Lipos Cur NPs triggered the release of curcumin nanocrystals which coalesce to form curcumin microcrystals (CMCs). An in situ"nano to micro" transition in the crystal state of curcumin was observed. This in situ transition leads to the formation of CMCs. These CMCs exhibited sustained release of curcumin for a prolonged duration (>10 days). The localized availability of curcumin aids in enhancing PTT by inhibiting the growth and mobility of cancer cells that escape PTT. In the in vitro modified scratch assay, the Au Lipos Cur NP + Laser group showed >1.5 fold enhanced therapeutic coverage when compared with the Au Lipos NP + Laser group. In vivo PTT studies performed in a B16 tumor model using Au Lipos Cur NPs showed a significant reduction of the tumor volume along with the localized release of curcumin in the tumor environment. It was observed that the localized release of curcumin enables an immediate adjuvant effect resulting in the enhancement of PTT.


Assuntos
Adjuvantes Farmacêuticos/química , Antineoplásicos/química , Curcumina/química , Ouro/química , Lipossomos/química , Nanopartículas Metálicas/química , Adjuvantes Farmacêuticos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular , Quimioterapia Adjuvante , Cristalização , Curcumina/administração & dosagem , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Hipertermia Induzida , Raios Infravermelhos , Melanoma/terapia , Nanopartículas Metálicas/administração & dosagem , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Fototerapia/métodos , Neoplasias Cutâneas/terapia , Microambiente Tumoral
16.
Chem Commun (Camb) ; 55(58): 8434-8437, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31259350

RESUMO

Phosphatidylcholine is the main component of liposomes and other phospholipid-based nanocarriers in drug delivery. However, the functions and applications of these nanocarriers are extremely limited by conventional phospholipids. Here we report novel disulfide phosphatidylcholines (SS-PCs) and SS-PC based liposomes (SS-LPs) used as alternatives to traditional phospholipids and liposomes.


Assuntos
Dissulfetos/química , Portadores de Fármacos/química , Lipossomos/química , Fosfatidilcolinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dissulfetos/síntese química , Dissulfetos/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Humanos , Lipossomos/síntese química , Lipossomos/metabolismo , Camundongos , Oxirredução , Fosfatidilcolinas/síntese química , Fosfatidilcolinas/metabolismo
17.
Nat Commun ; 10(1): 2905, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266953

RESUMO

Delivery into mammalian cells remains a significant challenge for many applications of proteins as research tools and therapeutics. We recently reported that the fusion of cargo proteins to a supernegatively charged (-30)GFP enhances encapsulation by cationic lipids and delivery into mammalian cells. To discover polyanionic proteins with optimal delivery properties, we evaluate negatively charged natural human proteins for their ability to deliver proteins into cultured mammalian cells and human primary fibroblasts. Here we discover that ProTα, a small, widely expressed, intrinsically disordered human protein, enables up to ~10-fold more efficient cationic lipid-mediated protein delivery compared to (-30)GFP. ProTα enables efficient delivery at low- to mid-nM concentrations of two unrelated genome editing proteins, Cre recombinase and zinc-finger nucleases, under conditions in which (-30)GFP fusion or cationic lipid alone does not result in substantial activity. ProTα may enable mammalian cell protein delivery applications when delivery potency is limiting.


Assuntos
Edição de Genes/métodos , Lipossomos/química , Proteínas/química , Edição de Genes/instrumentação , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Integrases/química , Integrases/genética , Integrases/metabolismo , Lipossomos/metabolismo , Transporte Proteico , Proteínas/genética , Proteínas/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Nucleases de Dedos de Zinco/química , Nucleases de Dedos de Zinco/genética , Nucleases de Dedos de Zinco/metabolismo
18.
Chem Biol Interact ; 310: 108753, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319075

RESUMO

Multitarget ligands (MTL) based on sterically hindered phenol and containing a quaternary ammonium moiety (SHP-n-Q) were synthesized. These compounds are inhibitors of cholinesterases with antioxidant properties. The inhibitory selectivity is 10-fold potent for BChE than for AChE. IC50 of SHP-n-Q for BChE is 20 µM. SHP-n-Q and their nanosystems exhibit more pronounced antioxidant properties than the synthetic antioxidant (hindered phenol, butylated hydroxytoluene). These compounds display a low hemolytic activity against human red blood cells. The nanotechnological approach was used to increase the bioavailability of SHP-n-Q derivatives. For water soluble SHP-n-Q derivative, the self-assembled structures have a size close to 100 nm at critical association concentration (0.01 M). Mixed cationic liposomes based on l-α-phosphatidylcholine and SHP-n-Q of 100 nm diameter were prepared. The stability, encapsulation efficacy and release from liposomes of a model drug, Rhodamine B, depend on the structure of SHP-n-Q. Cationic liposomes based on l-α-phosphatidylcholine and SHP-3-Q show a good stability in time (1year) and a sustained release (>65 h). They are promising templates for the development of anti-Alzheimer MT-drug delivery systems.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Fenóis/química , Acetilcolinesterase/química , Compostos de Amônio , Antioxidantes/farmacologia , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Lipossomos/química , Nanoestruturas , Fenóis/síntese química , Relação Estrutura-Atividade
19.
Chemphyschem ; 20(16): 2110-2121, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31265754

RESUMO

The physicochemical properties and transfection efficacies of two samples of a cationic lipid have been investigated and compared in 2D (monolayers at the air/liquid interface) and 3D (aqueous bulk dispersions) model systems using different techniques. The samples differ only in their chain composition due to the purity of the oleylamine (chain precursor). Lipid 8 (using the oleylamine of technical grade for cost-efficient synthesis) shows lateral phase separation in the Langmuir layers. However, the amount of attached DNA, determined by IRRAS, is for both samples the same. In 3D systems, lipid 8 p forms cubic phases, which disappear after addition of DNA. At physiological temperatures, both lipids (alone and in mixture with cholesterol) assemble to lamellar aggregates and exhibit comparable DNA delivery efficiency. This study demonstrates that non-lamellar structures are not compulsory for high transfection rates. The results legitimate the utilization of oleyl chains of technical grade in the synthesis of cationic transfection lipids.


Assuntos
Aminas/química , DNA/química , Lipídeos/química , Lipossomos/química , Aminas/síntese química , Aminas/normas , Aminas/toxicidade , Animais , Bovinos , Linhagem Celular Tumoral , Colesterol/química , Técnicas de Transferência de Genes/normas , Humanos , Lipídeos/síntese química , Lipídeos/normas , Lipídeos/toxicidade , Lipossomos/normas , Lipossomos/toxicidade , Estrutura Molecular , Transição de Fase , Suínos , Transfecção/normas , Temperatura de Transição
20.
Chem Pharm Bull (Tokyo) ; 67(10): 1131-1138, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31316036

RESUMO

Membrane curvature formation is important for various biological processes such as cell motility, intracellular signal transmission, and cellular uptake of foreign substances. However, it remains still a challenging topic to visualize the membrane curvature formation on the cell membranes in real-time imaging. To develop and design membrane curvature-sensors, we focused on amphipathic helical peptides of proteins belonging to the Bin/Amphiphysin/Rvs (BAR) family as the starting point. BAR proteins individually have various characteristic structures that recognize different curvatures, and the derived peptides possess the potential to function as curvature sensors with a variety of recognition abilities. Peptide-based curvature sensors can have wide applications in biological research fields due to their small size, easy modification, and large production capability in comparison to protein-based sensors. In the present study, we found that an amphipathic peptide derived from sorting nexin1 (SNX1) has a curvature-recognition ability. The mutation studies of the initial peptide revealed a close correlation between the α-helicity and lipid binding ability of the peptides. In particular, the amino acids located on the hydrophobic face played a vital role in curvature recognition. The α-helix formation of the peptides was thought to serve to accommodate lipid-packing defects on the membrane surface and to maintain their binding to lipid vesicles. The structure-activity correlation found in this study have the potential to contribute to the design of peptide-based curvature sensors that will enable the capture of various life phenomena in cells.


Assuntos
Membrana Celular/química , Correlação de Dados , Peptídeos/química , Peptídeos/síntese química , Humanos , Bicamadas Lipídicas/química , Lipossomos/síntese química , Lipossomos/química , Relação Estrutura-Atividade
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