RESUMO
Although liposomal doxorubicin (LPD) is widely used for cancer treatment, knowledge concerning the toxicity induced by this drug in healthy organs and tissues is limited. LPD-induced toxicity studies relative to free doxorubicin (DOX) have focused on cardiotoxicity in tumor-bearing animals. On the other hand, the results on DOX-induced cardiotoxicity depending on gender are controversial. One of the manifestations of toxicity is tissue inflammation. 67Ga-citrate has been used for decades to assess inflammation in various pathologies. In this work, the ex vivo biodistribution of 67Ga-citrate is used to evaluate induced multi-organ toxicity in healthy 10-week-old male and female CD1 mice treated for 5 weeks with LPD. Toxicity in males, determined by 67Ga-citrate, was evident only in the target organs of liposomes (spleen, liver, kidneys, and lungs); the average weight loss was 11% and mortality was 14%. In female mice, 67Ga-citrate revealed a cytotoxic effect in practically all organs, the average weight loss was 37%, and the mortality after the last dose of LPD was 66%. These results confirm the usefulness of 67Ga-citrate and the importance of stratifying by sex in the toxicological evaluation of drugs.
Assuntos
Antibióticos Antineoplásicos , Cardiotoxicidade , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/tratamento farmacológico , Ácido Cítrico/toxicidade , Doxorrubicina/análogos & derivados , Doxorrubicina/toxicidade , Feminino , Inflamação , Lipossomos/farmacologia , Masculino , Camundongos , Polietilenoglicóis , Distribuição Tecidual , Redução de PesoRESUMO
INTRODUCTION: Praziquantel (PZQ) is the only commercially available drug for schistosomiasis. The current shortage of alternative effective drugs and the lack of successful preventive measures enhance its value. The increase in the prevalence of PZQ resistance under sustained drug pressure is, therefore, an upcoming issue. OBJECTIVE: To overcome the tolerance to PZQ using nanotechnology after laboratory induction of a Schistosoma mansoni isolate with reduced sensitivity to the drug during the intramolluscan phase. MATERIALS AND METHODS: Shedding snails were treated with PZQ doses of 200 mg/kg twice/ week followed by an interval of one week and then repeated twice in the same manner. The success of inducing reduced sensitivity was confirmed in vitro via the reduction of cercarial response to PZQ regarding their swimming activity and death percentage at different examination times. RESULTS: Oral treatment with a single PZQ dose of 500 mg/kg in mice infected with cercariae with reduced sensitivity to PZQ revealed a non-significant reduction (35.1%) of total worm burden compared to non-treated control mice. Orally inoculated PZQ-encapsulated niosomes against S. mansoni with reduced sensitivity to PZQ successfully regained the pathogen's sensitivity to PZQ as evidenced by measuring different parameters in comparison to the non-treated infected animals with parasites with reduced sensitivity to PZQ. The mean total worm load was 1.33 ± 0.52 with a statistically significant reduction of 94.09% and complete eradication of male worms. We obtained a remarkable increase in the percentage reduction of tissue egg counts in the liver and intestine (97.68% and 98.56%, respectively) associated with a massive increase in dead eggs and the complete absence of immature stages. CONCLUSION: PZQ-encapsulated niosomes restored the drug sensitivity against laboratory-induced S. mansoni adult worms with reduced sensitivity to PZQ.
Introducción. El prazicuantel es el único fármaco disponible comercialmente para la esquistosomiasis. La escasez actual de medicamentos alternativos y la falta de medidas preventivas eficaces aumentan su valor. La creciente prevalencia de la resistencia al prazicuantel bajo una presión prolongada del fármaco es, por tanto, un tema emergente. Objetivos. Superar la tolerancia al prazicuantel mediante nanotecnología después de la inducción en laboratorio de un aislamiento de Schistosoma mansoni con sensibilidad reducida al fármaco durante la fase intramolusco. Materiales y métodos. Los caracoles que liberaban cercarias se trataron con prazicuantel en dosis de 200 mg/kg dos veces por semana, seguidas de un intervalo de una semana, y luego se repitieron dos veces de la misma manera. La inducción exitosa de la sensibilidad reducida se confirmó in vitro mediante la reducción de la reacción de las cercarias al prazicuantel con respecto a su actividad de natación y el porcentaje de muerte en diferentes momentos de examen. El éxito en inducir una menor sensibilidad se confirmó in vitro mediante la reducción de la reacción de las cercarias al prazicuantel. Resultados. El tratamiento oral con una dosis única de prazicuantel de 500 mg/kg en ratones infectados con cercarias con sensibilidad reducida al prazicuantel, reveló una reducción no significativa (35,1 %) de la carga total de gusanos en comparación con los ratones de control no tratados. Los niosomas encapsulados en prazicuantel inoculados por vía oral contra S. mansoni con sensibilidad reducida al prazicuantel, permitieron reestablecer con éxito la sensibilidad del patógeno al medicamento, como lo demostró la medición de diferentes parámetros en comparación con los animales infectados no tratados con parásitos con sensibilidad reducida a prazicuantel. La carga media total de gusanos fue de 1,33 ± 0,52, con una reducción estadísticamente significativa del 94,09 %, y la erradicación completa de los gusanos machos adultos. Se obtuvo un aumento notable en el porcentaje de reducción del recuento de huevos en el tejido del hígado y el intestino (97,68 % y 98,56 %, respectivamente), asociado con un aumento masivo de huevos muertos y ausencia total de estadios inmaduros. Conclusión. Los niosomas encapsulados en prazicuantel restauraron la sensibilidad al fármaco contra gusanos adultos de S. mansoni con sensibilidad reducida al prazicuantel inducida en el laboratorio.
Assuntos
Praziquantel , Schistosoma mansoni , Animais , Resistência a Medicamentos , Lipossomos/farmacologia , Masculino , Camundongos , Praziquantel/farmacologia , Praziquantel/uso terapêutico , CaramujosRESUMO
Currently, there are over 230 different COVID-19 vaccines under development around the world. At least three decades of scientific development in RNA biology, immunology, structural biology, genetic engineering, chemical modification, and nanoparticle technologies allowed the accelerated development of fully synthetic messenger RNA (mRNA)-based vaccines within less than a year since the first report of a SARS-CoV-2 infection. mRNA-based vaccines have been shown to elicit broadly protective immune responses, with the added advantage of being amenable to rapid and flexible manufacturing processes. This review recapitulates current advances in engineering the first two SARS-CoV-2-spike-encoding nucleoside-modified mRNA vaccines, highlighting the strategies followed to potentiate their effectiveness and safety, thus facilitating an agile response to the current COVID-19 pandemic.
Assuntos
Engenharia Biomédica , Vacinas contra COVID-19 , COVID-19 , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , SARS-CoV-2 , Vacina de mRNA-1273 contra 2019-nCoV , Engenharia Biomédica/métodos , Engenharia Biomédica/tendências , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/classificação , Vacinas contra COVID-19/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Humanos , Imunogenicidade da Vacina , Lipossomos/farmacologia , Nanopartículas , Nucleosídeos/farmacologia , Nucleosídeos/fisiologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas/farmacologiaRESUMO
The purpose of this study was to encapsulate carvacrol into liposomes in order to promote its application in active food packaging. Response surface methodology was used to evaluate the effect of the concentration of the liposomal components on its characteristics. The optimum formulation for the preparation of liposomes with the highest encapsulation efficiency (59.0 ± 1.99%) was found to be 3000 µg mL-1 of cholesterol and 4000 µg mL-1 of carvacrol. Carvacrol reduced the polydispersity index and increased the zeta potential and the thermal stability of liposomes. Fourier-transform infrared spectroscopy indicated that the interaction of carvacrol with liposomes occurred probably through hydrogen-bonding. The incorporation into liposomes maintained the antibacterial effect of carvacrol, but when in the film, carvacrol liposomes were not effective against the microorganisms tested. Liposomes may offer a viable option for stabilizing carvacrol, however, more studies are necessary to enable its application in food packaging.
Assuntos
Antibacterianos/química , Cimenos/química , Embalagem de Alimentos/métodos , Lipossomos/química , Álcool de Polivinil/química , Antibacterianos/farmacologia , Plásticos Biodegradáveis/química , Cimenos/farmacologia , Escherichia coli/efeitos dos fármacos , Lipossomos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Staphylococcus aureus/efeitos dos fármacosRESUMO
BACKGROUND AND AIM: Extensively drug-resistant (XDR) Klebsiella pneumoniae represent a major threat in intensive care units. The aim of the current study was to formulate a niosomal form of azithromycin (AZM) and to evaluate its in vitro effect on XDR K. pneumoniae as a single agent or in combination with levofloxacin. MATERIAL AND METHODS: Forty XDR K. pneumoniae isolates (23 colistin-sensitive and 17 colistin-resistant) were included in the study. Formulation and characterization of AZM niosomes were performed. The in vitro effect of AZM solution/niosomes alone and in combination (with levofloxacin) was investigated using the checkerboard assay, confirmed with time-kill assay and post-antibiotic effect (PAE). RESULTS: The AZM niosome mean minimal inhibitory concentration (MIC) (187.4 ± 209.1 µg/mL) was significantly lower than that of the AZM solution (342.5 ± 343.4 µg/mL). AZM niosomes/levofloxacin revealed a 40% synergistic effect compared to 20% with AZM solution/levofloxacin. No antagonistic effect was detected. The mean MIC values of both AZM niosomes and AZM solution were lower in the colistin-resistant group than in the colistin-sensitive group. The mean PAE time of AZM niosomes (2.3 ± 1.09 h) was statistically significantly longer than that of the AZM solution (1.37 ± 0.5 h) (p = 0.023). CONCLUSION: AZM niosomes were proved to be more effective than AZM solution against XDR K. pneumoniae, even colistin-resistant isolates.
Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Levofloxacino/farmacologia , Antibacterianos/química , Azitromicina/química , Composição de Medicamentos , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Klebsiella pneumoniae/crescimento & desenvolvimento , Lipossomos/química , Lipossomos/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
Candida infections represent a threat to human health. Candida albicans is the main causative agent of invasive candidiasis, especially in immunosuppressed patients. The emergence of resistant strains has required the development of new therapeutic strategies. In this context, the use of liposomes as drug carrier systems is a promising alternative in drug development. Thus, considering the evidence demonstrating that sesquiterpene farnesol is a bioactive compound with antifungal properties, this study evaluated the activity farnesol-containing liposomes against different Candida strains. The IC50 of farnesol and its liposomal formulation was assessed in vitro using cultures of Candida albicans, Candida tropicalis, and Candida krusei. The Minimum Fungicidal Concentration (MFC) was established by subculture in solid medium. The occurrence of fungal dimorphism was analyzed using optical microscopy. The effects on antifungal resistance to fluconazole were assessed by evaluating the impact of combined therapy on the growth of Candida strains. The characterization of liposomes was carried out considering their vesicular size, polydispersion index, and zeta medium potential, in addition to electron microscopy analysis. Farnesol exerted an antifungal activity that might be associated with the inhibition of fungal dimorphism, especially in Candida albicans. The incorporation of farnesol into liposomes significantly increased its antifungal activity against C. albicans, C. tropicalis, and C. krusei. In addition, liposomal farnesol potentiated the action of fluconazole against C. albicans and C. tropicalis. On the other hand, the association of unconjugated farnesol with fluconazole resulted in antagonistic effects. In conclusion, farnesol-containing liposomes have the potential to be used in antifungal drug development. However, further research is required to investigate how the antifungal properties of farnesol are affected by the interaction with liposomes, contributing to the modulation of antifungal resistance to conventional drugs.
Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Farneseno Álcool/farmacologia , Fluconazol/farmacologia , Antifúngicos/química , Farmacorresistência Fúngica/efeitos dos fármacos , Farneseno Álcool/química , Fluconazol/química , Lipossomos/química , Lipossomos/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
In order to make more efficient chitosan-based nanoparticles for transfection in physiological condition, chitosomes composed of chitosan modified with arginine and complexed with DOTAP/DOPE lipids are synthesized (named chitosomes) by reverse phase evaporation technique. Structure analyses of chitosomes with or without plasmid DNA (pDNA) are performed by electrophoresis, zeta potential, dynamic light scattering, small angle X-ray scattering and isothermal titration calorimetry, and transfection efficiency and cytotoxicity are performed in HEK293 T cells. Chitosomes have a positive surface charge (X¯= 52â¯mV) with an average size of 116â¯nm, and interaction with pDNA are favored thermodynamically and do not suffer aggregation significantly. In our experimental conditions, the transfection efficiency average reaches 86%⯱â¯3, while the Lipofectamine® reaches 87%⯱â¯5 in vitro. Cytotoxicity of chitosomes are tolerable. Structural analyses show that that chitosomes-pDNA complexes appear to have multilamellar vesicle structures hosting pDNA in-between bilayers which favor interaction with cell membrane and delivery of pDNA. Results show that synthesized chitosomes are promising carriers for gene delivery.
Assuntos
Arginina/química , Quitosana/química , DNA/química , Técnicas de Transferência de Genes , Arginina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quitosana/farmacologia , DNA/genética , Células HEK293 , Humanos , Lipossomos/química , Lipossomos/farmacologia , Estrutura Molecular , Tamanho da Partícula , Plasmídeos , Propriedades de SuperfícieRESUMO
The adrenal cortical carcinoma (ACC) treatment, for which mitotane (o,p'-DDD) is the drug of choice, still remains a challenge both because of the well-known solubility problems of the drug, and its serious side effects. Mitotane is currently administered as oral tablets. The loading of mitotane into nanocarriers has been suggested as a way to circumvent the low solubility of the drug and its limited oral bioavailability. In this work, we have developed liposomes containing mitotane to enhance its intestinal absorption and oral bioavailability. Liposomes were produced by spray-drying of a mixture of phospholipids and the developed formulation was optimized by studying the degree of crystallinity, spray-drying conditions, phospholipid/mitotane ratio, and influence of mannitol in the hydrating ethanolic solution. An optimal liposomal formulation was produced with a phospholipid:mitotane combination (3.34:1), exhibiting a mean hydrodynamic diameter around 1 µm and spherical shape. The produced mitotane liposomes were re-suspended by hydrating the spray-dried powders in a stirred tank, and tested their intestinal permeability (ex vivo) and relative bioavailability (in vivo), against a free drug solution (with or without Trigliceril®CM). Our results support the conclusion that the loading of mitotane in liposomes enhanced its intestinal absorption and relative bioavailability.
Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Lipossomos/farmacologia , Mitotano/metabolismo , Mitotano/farmacologia , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Absorção Intestinal/efeitos dos fármacos , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Fosfolipídeos/metabolismo , Fosfolipídeos/farmacologia , Pós/farmacologia , Ratos , Ratos Wistar , Solubilidade/efeitos dos fármacos , Comprimidos/metabolismo , Comprimidos/farmacologiaRESUMO
Bovine mastitis caused by Staphylococcus aureus is a serious problem in dairy production and effective immunoprophylaxis is an unmet goal so far. The objective of this work was to assess the humoral immune response of heifer calves against two recombinant S. aureus antigens: Clumping factor A (ClfA) and Fibronectin Binding Protein A (FnBPA), formulated with a novel adjuvant based on cationic liposomes (Lip) and CpG oligodeoxynucleotides (CpG-ODN). Six groups of 6-8 months old heifer calves received three doses biweekly of antigens, formulated with Al(OH)3, liposomes, CpG-ODN or Lip + CpG-ODN. Animals also received a fourth dose after a year (day 410) and a booster before calving. The administration of Al(OH)3+FnBPA/ClfA and Lip + FnBPA/ClfA + CpG-ODN induced the highest specific IgG levels, after the first 3 doses and induced a fast increase of antibodies after the fourth dose. All the formulations stimulated the production of specific IgG1, after the third and fourth dose. Specific IgG2 for both proteins was only stimulated after the fourth dose by Lip + FnBPA/ClfA + CpG-ODN. Pre-calving immunisation with Lip + FnBPA/ClfA + CpG-ODN led to the highest IgG levels during the calving period and to the production of the IgG2 subclass. The formulation was also able to stimulate the highest antibody levels in milk, 30 and 45 days after pre-calving booster. The combination of liposomes and CpG-ODN as adjuvant for a subunit vaccine, together with the immunisation schedule described, induced a strong humoral immune response with production of specific IgG2. The formulation demonstrated to induce immune memory allowing the application of a single pre-calving booster to maintain high antibody levels throughout the period of increased susceptibility to intramammary infections.
Assuntos
Antígenos de Bactérias/imunologia , Imunidade Humoral , Mastite Bovina/prevenção & controle , Oligodesoxirribonucleotídeos/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Fatores Etários , Animais , Anticorpos Antibacterianos/sangue , Bovinos , Imunoglobulina G/sangue , Memória Imunológica , Lipossomos/farmacologia , Mastite Bovina/imunologia , Mastite Bovina/microbiologia , Staphylococcus aureus , Vacinação , Soro do Leite/imunologiaRESUMO
With the aim improving drug delivery, liposomes have been employed as carriers for chemotherapeutics achieving promising results; their co-encapsulation with magnetic nanoparticles is evaluated in this work. The objective of this study was to examine the physicochemical characteristics, the pharmacokinetic behaviour, and the efficacy of pegylated liposomes loaded with cisplatin and magnetic nanoparticles (magnetite) (Cis-MLs). Cis-MLs were prepared by a modified reverse-phase evaporation method. To characterize their physicochemical properties, an evaluation was made of particle size, ζ-potential, phospholipid and cholesterol concentration, phase transition temperature (Tm), the encapsulation efficiency of cisplatin and magnetite, and drug release profiles. Additionally, pharmacokinetic studies were conducted on normal Wistar rats, while apoptosis and the cytotoxic effect were assessed with HeLa cells. We present a method for simultaneously encapsulating cisplatin at the core and also embedding magnetite nanoparticles on the membrane of liposomes with a mean vesicular size of 104.4 ± 11.5 nm and a ζ-potential of -40.5 ± 0.8 mV, affording a stable formulation with a safe pharmacokinetic profile. These liposomes elicited a significant effect on cell viability and triggered apoptosis in HeLa cells.