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1.
Eur J Pharm Biopharm ; 195: 114177, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38185193

RESUMO

BACKGROUND: Small interfering RNA (siRNA) holds great promise for treating various lung diseases, but the lack of safe and efficient pulmonary siRNA delivery systems has hindered its advance into the clinics. The epidermal growth factor receptor (EGFR) which promotes cell proliferation, and the programmed cell death ligand 1 (PD-L1) which plays a crucial role in suppressing cytotoxic T cells activity, are two important targets for treating non-small cell lung cancer (NSCLC). Here, we explored the potential of PEG12-KL4, a synthetic peptide, to deliver siRNA to various NSCLC cells and to lung tissues in mice. METHODS: PEG12-KL4 was used to transfect siRNAs targeted at both EGFR and PD-L1 into NSCLC cells. Immunoblotting was used to evaluate the siRNA silencing effects in HCC827 and NCI-H1975 NSCLC cells. CD8+ T cell-mediated NSCLC cell killing was employed to demonstrate the functional effects of PD-L1 siRNA knock-down. Fluorescent siRNAs were used to visualise siRNA uptake in cells as well as to enable biodistribution studies in BALB/c mice. RESULTS: Our results showed that PEG12-KL4 was efficient in mediating siRNA knock-down of EGFR and PD-L1 in various NSCLC cells. Importantly, the PEG12-KL4 peptide enabled significantly better siRNA delivery than the commercial Lipofectamine 2000 reagent. We hypothesised that PEG12-KL4 peptide enabled siRNA to either escape from or bypass endosomal degradation as indicated by confocal fluorescence imaging. Notably, combined knock-down of EGFR and PD-L1 in NCI-H1975 cells resulted in better effector T cell-mediated cancer cell killing than knock-down of PD-L1 alone. Moreover, biodistribution of PEG12-KL4/siRNA complexes following intravenous administration revealed poor lung delivery with the fluorescent siRNA accumulating in the liver. In contrast, intratracheal delivery of PEG12-KL4/siRNA complexes resulted in the fluorescent siRNA to be detected in the lung with retarded renal excretion. CONCLUSION: In conclusion, we demonstrated that the co-delivery of siRNAs targeting EGFR and PD-L1 using PEG12-KL4 is feasible and represents a promising future strategy to treat NSCLC, whereby pulmonary siRNA delivery is favourable to intravenous administration.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , RNA Interferente Pequeno/metabolismo , Distribuição Tecidual , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Pulmão/metabolismo , Peptídeos/metabolismo
2.
Curr Res Food Sci ; 7: 100624, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37954914

RESUMO

Bangia fusco-purpurea is an economically important seaweed with Fujian characteristics. Given that its harvest is seasonal, drying is often used to remove moisture, extend storage time, and facilitate further processing. Hence, the current study sought to explore the impact of different drying processes on the quality and volatile fingerprints of Bangia fusco-purpurea. To this end, the effects of hot air drying (HAD) and vacuum freeze drying (VFD) on the drying characteristics, microstructure, rehydration, and volatile components of dried B. fusco-purpurea were investigated. The results showed that the water removal efficiency of HAD was significantly higher than that of VFD. However, VFD better preserved the skeletal structure of B. fusco-purpurea than HAD, with a faster rehydration rate and a more uniform cell structure after rehydration. Using electronic nose and comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOF MS), significant differences in the volatile profiles of fresh, HAD, and VFD B. fusco-purpurea were assessed. E-nose analysis revealed that both HAD and VFD treatments significantly reduced sulfides, aromatic compounds, and nitrogen oxides in fresh B. fusco-purpurea. However, the alcohol, aldehyde, and ketone contents were lower in the VFD samples compared with HAD and fresh samples, whereas the content of methyl flavor substances was significantly higher. GC × GC-TOF MS analysis revealed that the most abundant volatile categories in HAD and VFD were hydrocarbons, alcohols, and esters. The number of volatile components in the HAD samples was significantly lower than in the VFD and fresh samples. As drying progressed, hydrocarbons and alcohols were formed in dried B. fusco-purpurea due to the thermal degradation of carbohydrates, lipids, amino acids, and the Maillard reaction. There were also significant flavor differences between HAD and VFD B. fusco-purpurea. Thus, although HAD exhibits better drying efficiency, VFD has more significant advantages in terms of product quality.

3.
Pharmaceutics ; 13(12)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34959328

RESUMO

Multi-drug-resistant tuberculosis (MDR-TB) is a huge public health problem. The treatment regimen of MDR-TB requires prolonged chemotherapy with multiple drugs including second-line anti-TB agents associated with severe adverse effects. Capreomycin, a polypeptide antibiotic, is the first choice of second-line anti-TB drugs in MDR-TB therapy. It requires repeated intramuscular or intravenous administration five times per week. Pulmonary drug delivery is non-invasive with the advantages of local targeting and reduced risk of systemic toxicity. In this study, inhaled dry powder formulation of capreomycin targeting the lung was developed using spray drying technique. Among the 16 formulations designed, the one containing 25% capreomycin (w/w) and spray-dried at an inlet temperature of 90 °C showed the best overall performance with the mass median aerodynamic diameter (MMAD) of 3.38 µm and a fine particle fraction (FPF) of around 65%. In the pharmacokinetic study in mice, drug concentration in the lungs was approximately 8-fold higher than the minimum inhibitory concentration (MIC) (1.25 to 2.5 µg/mL) for at least 24 h following intratracheal administration (20 mg/kg). Compared to intravenous injection, inhaled capreomycin showed significantly higher area under the curve, slower clearance and longer mean residence time in both the lungs and plasma.

4.
Mol Pharm ; 18(6): 2218-2232, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34014665

RESUMO

Pulmonary delivery of small interfering RNA (siRNA) is a promising therapeutic strategy for treating various respiratory diseases but an effective carrier for the delivery of siRNA into the cells of the lungs and a robust gene-silencing effect is still lacking. Previously, we reported that the KL4 peptide, a synthetic cationic peptide with a repeating KLLLL sequence, can mediate effective siRNA transfection in lung epithelial cells but its high hydrophobic leucine content, and hence poor water solubility, limits its application as a delivery vector. Here, we show that the covalent attachment of monodisperse poly(ethylene glycol) (PEG) improves the solubility of KL4 and the uptake of its complex with siRNA into lung epithelial cells, such that very robust silencing is produced. All PEGylated KL4 peptides, with PEG length varying between 6 and 24 monomers, could bind and form nanosized complexes with siRNA, but the interaction between siRNA and peptides became weaker as the PEG chain length increased. All PEGylated KL4 peptides exhibited satisfactory siRNA transfection efficiency on three human lung epithelial cell lines, including A549 cells, Calu-3 cells, and BEAS-2B cells. The PEG12KL4 peptide, which contains 12 monomers of PEG, was optimal for siRNA delivery and also demonstrated a low risk of inflammatory response and toxicity in vivo following pulmonary administration.


Assuntos
Portadores de Fármacos/química , Pulmão/metabolismo , Peptídeos/química , RNA Interferente Pequeno/administração & dosagem , Doenças Respiratórias/terapia , Células A549 , Inativação Gênica , Humanos , Interações Hidrofóbicas e Hidrofílicas , Polietilenoglicóis/química , RNA Interferente Pequeno/genética , Doenças Respiratórias/genética , Solubilidade , Transfecção/métodos
5.
Nucleic Acid Ther ; 31(3): 220-228, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32352853

RESUMO

A safe and effective delivery system is considered a key to the success of nucleic acid therapeutics. It has been reported that pulmonary surfactants or their components could facilitate the uptake of small interfering RNA (siRNA) into the lung epithelial cells. Previously, our group investigated the use of KL4 peptide, a synthetic cationic peptide that simulates the structural properties of surfactant protein B (SP-B), as siRNA delivery vector. Although KL4 peptide exhibits good in vitro siRNA transfection efficiency on lung epithelial cells, its therapeutic potential is limited by its poor aqueous solubility due to the presence of a high proportion of hydrophobic leucine residues. In this study, we aim to address the solubility issue, designing five different modified peptides by replacing the hydrophobic leucine with alanine or valine, and assess their potential as siRNA delivery vectors. While the modified peptides retain the overall cationic property, their siRNA binding is also affected and their transfection efficiency is inferior to the parent KL4 peptide. A closer examination of the conformation of these peptides by circular dichroism shows that substitution of leucine residues leads to the change of the secondary structure from α-helical content to either ß-sheet or more disordered, ß-turn conformations. Relatively conservative amino acid substitutions, in terms of hydrophobicity bulk, lead to substantial conformational alteration, heavily impacting siRNA binding and release, cellular uptake, and transfection efficiency. Although the peptide modification strategy employed in this study was unsuccessful in developing an improved version of KL4 peptide for siRNA delivery, it highlights the importance of the α-helical conformation for efficient siRNA transfection, providing useful insights for future development of peptide-based RNA delivery system.


Assuntos
Peptídeos , Dicroísmo Circular , Peptídeos/genética , Conformação Proteica em alfa-Hélice , Estrutura Secundária de Proteína , RNA Interferente Pequeno/genética
6.
Trends Pharmacol Sci ; 41(10): 715-729, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32893004

RESUMO

RNA-based medicine is receiving growing attention for its diverse roles and potential therapeutic capacity. The largest obstacle in its clinical translation remains identifying a safe and effective delivery system. Studies investigating RNA therapeutics in pulmonary diseases have rapidly expanded and drug administration by inhalation allows the direct delivery of RNA therapeutics to the target site of action while minimizing systemic exposure. In this review, we highlight recent developments in pulmonary RNA delivery systems with the use of nonviral vectors. We also discuss the major knowledge gaps that require thorough investigation and provide insights that will help advance this exciting field towards the bedside.


Assuntos
RNA , Administração por Inalação , Humanos , Interferência de RNA , RNA Interferente Pequeno
7.
J Vis Exp ; (161)2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32773763

RESUMO

In the development of inhalable dry powder formulations, it is essential to evaluate their biological activities in preclinical animal models. This paper introduces a noninvasive method of intratracheal delivery of dry powder formulation in mice. A dry powder loading device that consists of a 200 µL gel loading pipette tip connected to an 1 mL syringe via a three-way stopcock is presented. A small amount of dry powder (1-2 mg) is loaded into the pipette tip and dispersed by 0.6 mL of air in the syringe. Because pipette tips are disposable and inexpensive, different dry powder formulations can be loaded into different tips in advance. Various formulations can be evaluated in the same animal experiment without device cleaning and dose refilling, thereby saving time and eliminating the risk of cross-contamination from residual powder. The extent of powder dispersion can be inspected by the amount of powder remaining in the pipette tip. A protocol of intubation in mouse with a custom-made light source and a guiding cannula is included. Proper intubation is one of the key factors that influences the intratracheal delivery of dry powder formulation to the deep lung region of the mouse.


Assuntos
Composição de Medicamentos , Inaladores de Pó Seco , Administração por Inalação , Animais , Cateterismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Pós , RNA Mensageiro/administração & dosagem
8.
Int J Pharm ; 572: 118818, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678379

RESUMO

The development of small interfering RNA (siRNA) formulation for pulmonary delivery is a key to the clinical translation of siRNA therapeutics for the treatment of respiratory diseases. Most inhalable siRNA powder formulations published to date were limited by the siRNA content which was often too low to be clinically relevant. This study aimed to prepare inhalable siRNA powder formulations that contained high siRNA loading of over 6% w/w by spray drying, with human serum albumin (HSA) investigated as a dispersion enhancer to improve the aerosol performance. The effect of siRNA, HSA and solute concentrations in the formulations were evaluated systemically using factorial analyses. All the spray dried siRNA powders exhibited excellent aerosol performance with fine particle fraction (FPF) consistently over 50% in all the formulations. An enrichment of HSA on the particle surface was observed. Surface corrugation was more prominent as HSA composition increased. Importantly, the bioactivity of siRNA was successfully preserved upon spray drying as demonstrated in the in vitro transfection study, and up to 78% of intact siRNA retained in the spray dried powder. Overall, HSA is an effective dispersion enhancer and spray drying is an appropriate technique to produce inhalable dry powder with high siRNA loading for further investigation.


Assuntos
RNA Interferente Pequeno/administração & dosagem , Albumina Sérica Humana/química , Administração por Inalação , Aerossóis , Humanos , Tamanho da Partícula , Pós
9.
J Control Release ; 314: 102-115, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31629037

RESUMO

Pulmonary delivery of messenger RNA (mRNA) has considerable potential as therapy or vaccine for a range of lung diseases. Inhaled dry powder formulation of mRNA is particularly attractive as it has superior stability and dry powder inhaler is relatively easy to use. A safe and effective mRNA delivery vector as well as a suitable particle engineering method are required to produce a dry powder formulation that is respirable and mediates robust transfection in the lung. Here, we introduce a novel RNA delivery vector, PEG12KL4, in which the synthetic cationic KL4 peptide is attached to a monodisperse linear PEG of 12-mers. The PEG12KL4 formed nano-sized complexes with mRNA at 10:1 ratio (w/w) and mediated effective transfection on human lung epithelial cells. PEG12KL4/mRNA complexes were successfully formulated into dry powder by spray drying (SD) and spray freeze drying (SFD) techniques. Both SD and SFD powder exhibited satisfactory aerosol properties for inhalation. More importantly, the biological activity of the PEG12KL4 /mRNA complexes were successfully preserved after drying. Using luciferase mRNA, the intratracheal administration of the liquid or powder aerosol of PEG12KL4 /mRNA complexes at a dose of 5µg mRNA resulted in luciferase expression in the deep lung region of mice 24h post-transfection. The transfection efficiency was superior to naked mRNA or lipoplexes (Lipofectamine 2000), in which luciferase expression was weaker and restricted to the tracheal region only. There was no sign of inflammatory response or toxicity of the PEG12KL4 /mRNA complexes after single intratracheal administration. Overall, PEG12KL4 is an excellent mRNA transfection agent for pulmonary delivery. This is also the first study that successfully demonstrates the preparation of inhalable dry powder mRNA formulations with in vivo transfection efficiency, showing the great promise of PEG12KL4 peptide as a mRNA delivery vector candidate for clinical applications.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Pulmão/metabolismo , Polietilenoglicóis/química , RNA Mensageiro/administração & dosagem , Células A549 , Administração por Inalação , Aerossóis , Animais , Inaladores de Pó Seco , Células Epiteliais/metabolismo , Feminino , Liofilização , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Transfecção
10.
Asian J Pharm Sci ; 13(2): 163-172, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32104389

RESUMO

The therapeutic potential of small nucleic acids such as small interfering RNA (siRNA) to treat lung diseases has been successfully demonstrated in many in vivo studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation. In this study, spray freeze drying was employed to prepare dry powder of small nucleic acids. Mannitol and herring sperm DNA were used as bulking agent and model of small nucleic acid therapeutics, respectively. Formulations containing different solute concentration and DNA concentration were produced. The scanning electron microscope (SEM) images showed that the porosity of the particles increased as the solute concentration decreased. Powders prepared with solute concentration of 5% w/v were found to maintain a balance between porosity and robustness. Increasing concentration of DNA improved the aerosol performance of the formulation. The dry powder formulation containing 2% w/w DNA had a median diameter of 12.5 µm, and the aerosol performance study using next generation impactor (NGI) showed an emitted fraction (EF) and fine particle fraction (FPF) of 91% and 28% respectively. This formulation (5% w/v solute concentration and 2% w/w nucleic acid) was adopted subsequently to produce siRNA powder. The gel retardation and liquid chromatography assays showed that the siRNA remained intact after spray freeze drying even in the absence of delivery vector. The siRNA powder formulation exhibited a high EF of 92.4% and a modest FPF of around 20%. Further exploration of this technology to optimise inhaled siRNA powder formulation is warranted.

11.
Mol Pharm ; 14(12): 4606-4617, 2017 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-29121767

RESUMO

Pulmonary delivery of small interfering RNA (siRNA) has huge potential for the treatment of a wide range of respiratory diseases. The ability of naked siRNA to transfect cells in the lungs without a delivery vector has prompted the investigation of whether an endogenous component is at least partially responsible for the cellular uptake of siRNA, and whether a safe and efficient delivery system could be developed from this component to further improve the transfection efficiency. Surfactant protein B (SP-B), a positively charged protein molecule found in lung surfactant, is one of the possible candidates. While the role of SP-B in siRNA transfection remains to be determined, the SP-B mimic, synthetic KL4 peptide, was investigated in this study as a potential siRNA carrier. KL4 is a 21-residue cationic peptide that was able to bind to siRNA to form nanosized complexes. It mediated siRNA transfection effectively in vitro on human lung epithelial cells, A549 cells, and BEAS-2B cells, which was comparable to Lipofectamine 2000. When commercial pulmonary surfactant (Infasurf) was added in the transfection medium, the gene silencing effect of siRNA in cells transfected with Lipofectamine 2000 was completely abolished, whereas those transfected with KL4 remained unaffected. At 4 °C, KL4 failed to deliver siRNA into the cells, indicating that an energy-dependent process was involved in the uptake of the complexes. Chlorpromazine (inhibitor of chathrin-mediated endocytosis), but not nystatin (inhibitor of caveolae-mediated endocytosis), inhibited the uptake of KL4/siRNA complexes, suggesting that they entered cells through clathrin-mediated endocytosis. There was no sign of cytotoxicity or immune response caused by KL4 and KL4/siRNA complexes. Overall, this study demonstrated that synthetic KL4 peptide is a promising candidate for siRNA carrier for pulmonary delivery and could be a potential platform for delivering other types of nucleic acid therapeutics.


Assuntos
Portadores de Fármacos/química , Peptídeos/química , Proteína B Associada a Surfactante Pulmonar/química , RNA Interferente Pequeno/uso terapêutico , Transfecção/métodos , Células A549 , Produtos Biológicos/química , Cátions/química , Clorpromazina/farmacologia , Endocitose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Inativação Gênica , Humanos , Lipídeos/química , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Nistatina/farmacologia
12.
Int J Pharm ; 530(1-2): 40-52, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28720537

RESUMO

Pulmonary delivery of short interfering RNA (siRNA) has been widely studied in both animal and clinical studies to treat various respiratory diseases by gene silencing through RNA interference. Some of these studies showed that the administration of naked siRNA (without the use of any delivery vectors) could achieve satisfactory gene silencing effect, a unique feature to pulmonary delivery. Liquid aerosols were mostly used with very limited studies on the use of powder aerosols for siRNA. In this study, siRNA was co-spray dried with mannitol and l-leucine, the latter being a dispersion enhancer. To the best of our knowledge, this is the first time that siRNA in its naked form was formulated into an inhalable dry powder using spray drying technology. The aerosol performance of the powder was evaluated by Next Generation Impactor (NGI). The presence of l-leucine in the formulation could improve the aerosolization of siRNA-containing powders. Results from the X-ray photoelectron spectroscopy (XPS) suggested that l-leucine was enriched on the particle surface and promote powder dispersion. Among the different siRNA formulations being examined, the one that contained 50% w/w of l-leucine exhibited the best aerodynamic performance, with a high emitted fraction (EF) of around 80% and a modest fine particle fraction (FPF) of 45%. Importantly, the integrity of siRNA was successfully retained as evaluated by gel retardation assay and high performance liquid chromatography (HPLC).


Assuntos
Leucina/química , Pós , RNA Interferente Pequeno/administração & dosagem , Administração por Inalação , Aerossóis , Química Farmacêutica , Inaladores de Pó Seco , Inativação Gênica , Tamanho da Partícula
13.
Molecules ; 21(9)2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27657028

RESUMO

RNA interference (RNAi) is a potent and specific post-transcriptional gene silencing process. Since its discovery, tremendous efforts have been made to translate RNAi technology into therapeutic applications for the treatment of different human diseases including respiratory diseases, by manipulating the expression of disease-associated gene(s). Similar to other nucleic acid-based therapeutics, the major hurdle of RNAi therapy is delivery. Pulmonary delivery is a promising approach of delivering RNAi therapeutics directly to the airways for treating local conditions and minimizing systemic side effects. It is a non-invasive route of administration that is generally well accepted by patients. However, pulmonary drug delivery is a challenge as the lungs pose a series of anatomical, physiological and immunological barriers to drug delivery. Understanding these barriers is essential for the development an effective RNA delivery system. In this review, the different barriers to pulmonary drug delivery are introduced. The potential of RNAi molecules as new class of therapeutics, and the latest preclinical and clinical studies of using RNAi therapeutics in different respiratory conditions are discussed in details. We hope this review can provide some useful insights for moving inhaled RNAi therapeutics from bench to bedside.

14.
Mol Pharm ; 13(9): 3141-52, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27458925

RESUMO

The major intracellular barriers associated with DNA delivery using nonviral vectors are inefficient endosomal/lysosomal escape and poor nuclear uptake. LAH4-L1, a pH responsive cationic amphipathic peptide, is an efficient DNA delivery vector that promotes the release of nucleic acid into cytoplasm through endosomal escape. Here we further enhance the DNA transfection efficiency of LAH4-L1 by incorporating nuclear localizing signal (NLS) to promote nuclear importation. Four NLSs were investigated: Simian virus 40 (SV40) large T-antigen derived NLS, nucleoplasmin targeting signal, M9 sequence, and the reverse SV40 derived NLS. All peptides tested were able to form positively charged nanosized complexes with DNA. Significant improvement in DNA transfection was observed in slow-dividing epithelial cancer cells (Calu-3), macrophages (RAW264.7), dendritic cells (JAWSII), and thymidine-induced growth-arrested cells, but not in rapidly dividing cells (A549). Among the four NLS-modified peptides, PK1 (modified with SV40 derived NLS) and PK2 (modified with reverse SV40 derived NLS) were the most consistent in improving DNA transfection; up to a 10-fold increase in gene expression was observed for PK1 and PK2 over the unmodified LAH4-L1. Additionally PK1 and PK2 were shown to enhance cellular uptake as well as nuclear entry of DNA. Overall, we show that the incorporation of SV40 derived NLS, in particular, to LAH4-L1 is a promising strategy to improve DNA delivery efficiency in slow-dividing cells and dendritic cells, with development potential for in vivo applications and as a DNA vaccine carrier.


Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Núcleo Celular/metabolismo , Peptídeos/farmacologia , Plasmídeos/metabolismo , Células A549 , Transporte Ativo do Núcleo Celular/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Vetores Genéticos , Humanos , Concentração de Íons de Hidrogênio , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Sinais de Localização Nuclear/efeitos dos fármacos , Peptídeos/metabolismo , Plasmídeos/genética , Células RAW 264.7 , Vírus 40 dos Símios/genética , Transfecção
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