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Pregnant women are still considered as drug orphans. Developing new medications for pregnancy complications is an urgent need. Nanomedicines seem to be a promising approach to control the biodistribution of drugs to ensure both the mother's and the fetus' safety. Understanding the interaction between nanoparticles and the placental barrier is a key factor to the success of the development of nanomedicines for pregnant women. In this study, we evaluated the behavior of fluorescent PEGylated liposomes and lipoplexes in human placental tissue using in vitro and ex vivo models, BeWo cell culture and suspended villous placental explants, respectively. Fluorescent based analytical tools such as Fluorescence activated cells sorting (FACS), confocal microscopy and HPLC coupled to fluorescence detection were used to assess liposomes penetration and their endocytosis mechanisms in the placenta. First, no influence of the PEGylation density was observed on the cellular internalization of liposomal formulations using both models. The comparison between neutral and cationic liposomes exhibits a significant higher internalization of the cationic formulation compared to the neutral ones. In addition, the HPLC quantification of the fluorescent liposomes in human villous explants demonstrated an increase of cationic liposomes uptake with increasing incubation concentrations. Similar uptake of cationic liposomes and lipoplexes, containing the same cationic lipid, the DMAPAP but with an overall neutral surface charge, was observed and evidenced the higher effect of composition than charge surface on trophoblast penetration. Moreover, both cationic liposomes and lipoplexes exhibited an endocytosis mechanism of internalization via pathways implicating dynamin. These data highlight the key role of the liposome's lipid composition and the possibility to modulate their internalization in the placenta by adjusting their design.
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Lipossomos , Placenta , Cátions/metabolismo , Feminino , Humanos , Lipídeos/química , Lipossomos/química , Placenta/metabolismo , Gravidez , Distribuição TecidualRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-ß peptide (Aß) and especially the Aß peptide 1-42 (Aß1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aß1-42 in the blood and promote its elimination through the "sink effect" and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aß1-42. Treatment of AD-like transgenic mice with anti-Aß1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aß soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aß levels in plasma. This study represents the first example of Aß1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.
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Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais/química , Modelos Animais de Doenças , Transtornos da Memória/terapia , Nanopartículas/administração & dosagem , Polímeros/administração & dosagem , Animais , Anticorpos Monoclonais/imunologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Nanopartículas/metabolismo , Polímeros/química , Polímeros/metabolismo , Recuperação de Função FisiológicaRESUMO
Nanomedicine as a therapeutic approach for pregnancy-related diseases could offer improved treatments for the mother while avoiding side effects for the fetus. In this study, we evaluated the potential of liposomes as carriers for small interfering RNAs to placental cells. Three neutral formulations carrying rhodamine-labelled siRNAs were evaluated on an in vitro model, i.e., human primary villous cytotrophoblasts. siRNA internalization rate from lipoplexes were compared to the one in the presence of the lipofectamine reagent and assessed by confocal microscopy. Results showed cellular internalization of nucleic acid with all three formulations, based on two cationic lipids, either DMAPAP or CSL-3. Moreover, incubation with DMAPAP+AA provided a rate of labelled cells as high as with lipofectamine (53 ± 15% and 44 ± 12%, respectively) while being more biocompatible. The proportion of cells which internalized siRNA were similar when using DMAPAP/DDSTU (16 ± 5%) and CSL-3 (22 ± 5%). This work highlights that liposomes could be a promising approach for gene therapy dedicated to pregnant patients.
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Técnicas de Transferência de Genes , Lipossomos/uso terapêutico , Complicações na Gravidez/terapia , Feminino , Vetores Genéticos/uso terapêutico , Humanos , Nanomedicina/métodos , Gravidez , Complicações na Gravidez/genética , RNA Interferente Pequeno/uso terapêutico , Trofoblastos/metabolismo , Trofoblastos/patologiaRESUMO
Lung cancer is a highly vascularized tumor for which a combination between an antitumor agent, cisplatin, and an antiangiogenic molecule, fisetin, appears a promising therapeutic approach. In order to deliver both chemotherapies within the tumor, to enhance fisetin solubility and decrease cisplatin toxicity, an encapsulation of both drugs into liposomes was developed. Purification and freeze-drying protocols were optimized to improve both the encapsulation and liposome storage. The cytotoxicity of the encapsulated chemotherapies was evaluated on Lewis lung carcinoma (3LL) cell lines. The antitumor effect of the combination was evaluated in vivo on an ectopic mouse model of Lewis Lung carcinoma. The results showed that fisetin and cisplatin co-loaded liposomes were successfully prepared. Freeze-drying allowed a 30 days storage limiting the release of both drugs. The combination index between liposomal fisetin and liposomal cisplatin on 3LL cell line after 24 h of exposure showed a clear synergism: CI = 0.7 for the co loaded liposomes and CI = 0.9 for the mixture of cisplatin loaded and fisetin loaded liposomes. The co-encapsulating formulation showed in vivo efficacy against an ectopic murine model of Lewis Lung carcinoma with a probable reduction in the toxicity of cisplatin through co-encapsulation with fisetin.
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Antineoplásicos , Carcinoma Pulmonar de Lewis , Flavonóis , Neoplasias Pulmonares , Camundongos , Animais , Cisplatino/farmacologia , Lipossomos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Fosfolipídeos/uso terapêutico , Modelos Animais , Linhagem Celular TumoralRESUMO
Nanomedicine offers the possibility of modifying the distribution of encapsulated drugs and biomolecules. Nanomedicine could limit the transplacental passage and/or enhance the concentration of drugs in placental tissue; this approach could be exploited for the treatment of pregnancy disorders. In the context of pregnancy, tackling the biological fate of both the nanocarrier and the drug has high importance in ensuring both the mother's and the fetus' safety.In this study, we propose a method for quantifying the uptake of liposomes inside placental tissue using covalently labeled liposomes and adapting a high-performance liquid chromatography (HPLC) method using a fluorescent detector. An optimized protocol for liquid-liquid extraction of fluorescent lipids from placental tissue extracts, followed by HPLC analysis, is detailed in this chapter. The HPLC method allows the quantification of fluorescent lipids using a calibration curve, including the biological matrix and extraction procedures. The internalization rate of fluorescent liposomes within human villous placental explants was quantitatively assessed, thanks to the HPLC developed method and suitable analytical tools.
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Lipossomos , Placenta , Gravidez , Humanos , Feminino , Placenta/metabolismo , Lipossomos/metabolismo , Cromatografia Líquida de Alta Pressão , Transporte Biológico , Corantes/metabolismo , Lipídeos/químicaRESUMO
Pregnancy-associated disorders affect around 20% of pregnancies each year around the world. The risk associated with pregnancy therapeutic management categorizes pregnant women as "drug orphan" patients. In the last few decades, nanocarriers have demonstrated relevant properties for controlled drug delivery, which have been studied for pregnancy-associated disorders. To develop new drug dosage forms it is mandatory to have access to the right evaluation models to ensure their usage safety and efficacy. This review exposes the various placental-based models suitable for nanocarrier evaluation for pregnancy-associated therapies. We first review the current knowledge about nanocarriers as drug delivery systems and how placenta can be used as an evaluation model. Models are divided into three categories: in vivo, in vitro, and ex vivo placental models. We then examine the recent studies using those models to evaluate nanocarriers behavior towards the placental barrier and which information can be gathered from these results. Finally, we propose a flow chart on the usage and the combination of models regarding the nanocarriers and nanoparticles studied and the intended therapeutic strategy.
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Flavonoids have been considered as promising molecules for cancer treatment due to their pleiotropic properties such as anti-carcinogenic, anti-angiogenic or efflux proteins inhibition. However, due to their lipophilic properties and their chemical instability, vectorization seems compulsory to administer flavonoids. Flavonoids have been co-encapsulated with other anti-cancer agents in a broad range of nanocarriers aiming to i) achieve a synergistic/additive effect at the tumor site, ii) delay drug resistance apparition by combining agents with different action mechanisms or iii) administer a lower dose of the anti-cancer drug, reducing its toxicity. However, co-encapsulation could lead to a change in the nanoparticles' diameter and drug-loading, as well as a decrease in their stability during storage. The preparation process should also take into accounts the physico-chemical properties of both the flavonoid and the anti-cancer agent. Moreover, the co-encapsulation could affect the release and activity of each drug. This review aims to study the formulation, preparation and characterization strategies of these co-loaded nanomedicines, as well as their stability. The in vitro assays to predict the nanomedicines' behavior in biological fluids, as well as their in vivo efficacy, are also discussed. A special focus concerns the evaluation of their synergistic effect on tumor treatment.
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Antineoplásicos , Nanopartículas , Antineoplásicos/química , Flavonoides/farmacologia , Nanomedicina , Nanopartículas/químicaRESUMO
Liposomes constitute the most exploited drug-nanocarrier with several liposomal drugs on the market. Microfluidic-based preparation methods stand up as a promising approach with high reproducibility and the ability to scale up. In this study, liposomes composed of DOPC, cholesterol, and DSPE-PEG 2000 with different molar ratios were fabricated using a microfluidic system. Process and conditions were optimized by applying design of experiments (DoE) principles. Furthermore, data were used to build an artificial neural network (ANN) model, to predict size and polydispersity index (PDI). Sets of runs were designed by DoE and performed on a micromixer microfluidic chip. Lipids' molar ratio and the process parameters, i.e. total flow rate (TFR) and flow rate ratio (FRR), were found to be the most influential factors on the formation of vesicles with target size and PDI under 100 nm and lower than 0.2, respectively. Size and PDI were predicted by the ANN model for 3 preparations with defined experimental conditions. The results showed no significant difference in size and PDI between the preparations and their values calculated with the ANN. In conclusion, production of optimized liposomes with high reproducibility was achieved by the application of microfluidic manufacturing processes, DoE, and Artificial Intelligence (AI). Microfluidic-based preparation methods assisted by computational tools would enable a faster development and clinical transfer of nanobased medications.
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Lipossomos , Microfluídica , Inteligência Artificial , Aprendizado de Máquina , Microfluídica/métodos , Tamanho da Partícula , Reprodutibilidade dos TestesRESUMO
Facial angiofibromas (FA) are one of the most obvious cutaneous manifestations of tuberous sclerosis complex. Topical rapamycin for angiofibromas has been reported as a promising treatment. Several types of vehicles have been used hitherto, but polymeric micelles and especially those made of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) seem to have shown better skin bioavailability of rapamycin than the so far commonly used ointments. To better understand the influence of polymeric micelles on the behavior of rapamycin, we explored it through mixed polymeric micelles combining TPGS and poloxamer, evaluating stability and skin bioavailability to define an optimized formulation to effectively treat FA. Our studies have shown that TPGS improves the physicochemical behavior of rapamycin, i.e., its solubility and stability, due to a strong inclusion in micelles, while poloxamer P123 has a more significant influence on skin bioavailability. Accordingly, we formulated mixed-micelle hydrogels containing 0.1% rapamycin, and the optimized formulation was found to be stable for up to 3 months at 2-8 °C. In addition, compared to hydroalcoholic gel formulations, the studied system allows for better biodistribution on human skin.
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Alzheimer's disease (AD) represents the most common form of dementia worldwide, affecting more than 35 million people. Advances in nanotechnology are beginning to exert a significant impact in neurology. These approaches, which are often based on the design and engineering of a plethora of nanoparticulate entities with high specificity for brain capillary endothelial cells, are currently being applied to early AD diagnosis and treatment. In addition, nanoparticles (NPs) with high affinity for the circulating amyloid-ß (Aß) forms may induce "sink effect" and improve the AD condition. There are also developments in relation to in vitro diagnostics for AD, including ultrasensitive NP-based bio-barcodes, immunosensors, as well as scanning tunneling microscopy procedures capable of detecting Aß(1-40) and Aß(1-42). However, there are concerns regarding the initiation of possible NP-mediated adverse events in AD, thus demanding the use of precisely assembled nanoconstructs from biocompatible materials. Key advances and safety issues are reviewed and discussed.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Nanopartículas/uso terapêutico , Acridinas/uso terapêutico , Doença de Alzheimer/metabolismo , Benzotiazóis , Materiais Biocompatíveis/uso terapêutico , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Cromonas/uso terapêutico , Sistemas de Liberação de Medicamentos , Compostos Férricos/química , Compostos Férricos/uso terapêutico , Ouro/uso terapêutico , Humanos , Nanopartículas de Magnetita/uso terapêutico , Nanopartículas/efeitos adversos , Tiazóis/uso terapêuticoRESUMO
Dermatillomania or skin picking disorder (SPD) is a chronic, recurrent, and treatment resistant neuropsychiatric disorder with an underestimated prevalence that has a concerning negative impact on an individual's health and quality of life. The current treatment strategies focus on behavioral and pharmacological therapies that are not very effective. Thus, the primary objective of this review is to provide an introduction to SPD and discuss its current treatment strategies as well as to propose biomaterial-based physical barrier strategies as a supporting or alternative treatment. To this end, searches were conducted within the PubMed database and Google Scholar, and the results obtained were organized and presented as per the following categories: prevalence, etiology, consequences, diagnostic criteria, and treatment strategies. Furthermore, special attention was provided to alternative treatment strategies and biomaterial-based physical treatment strategies. A total of six products with the potential to be applied as physical barrier strategies in supporting SPD treatment were shortlisted and discussed. The results indicated that SPD is a complex, underestimated, and underemphasized neuropsychiatric disorder that needs heightened attention, especially with regard to its treatment and care. Moreover, the high synergistic potential of biomaterials and nanosystems in this area remains to be explored. Certain strategies that are already being utilized for wound healing can also be further exploited, particularly as far as the prevention of infections is concerned.
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Microfluidization has been investigated as a new, scalable, and basic component saving method to produce cationic lipid nanoparticles, in particular for the delivery of short interfering RNAs (siRNAs). The design of experiment (DoE) allowed to reach optimized characteristics in terms of nanocarrier size reduction and low polydispersity. The structure of cationic liposomes and siRNA-lipoplexes was characterized. The optimized preparation parameters were identified as three microfluidization passages at a pressure of 10,000 psi, with a thin film hydration volume of 4 ml. Microfluidized liposomes mean size was 160 nm, with a polydispersity index of 0.2-0.3 and a zeta potential of +40 mV to +60 mV. Positive versus negative charge ratio between the charges of the cationic lipid and the phosphate charges of the siRNAs is a key factor determining the structure and silencing efficacy of siRNA lipoplexes. At a (+/-) charge ratio of 8, a proportion of 88% of the siRNA was associated to microfluidized lipoplexes, which remained stable for one month. These lipoplexes exhibited moderate cytotoxicity and gene silencing efficacy, which should be further optimized.
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Lipídeos , Nanopartículas , Cátions , Lipossomos , RNA Interferente Pequeno , TransfecçãoRESUMO
(1) Background: Glioblastoma (GBM) is the most frequent cerebral tumor. It almost always relapses and there is no validated treatment for second-line GBM. We proposed the coencapsulation of fisetin and cisplatin into liposomes, aiming to (i) obtain a synergistic effect by combining the anti-angiogenic effect of fisetin with the cytotoxic effect of cisplatin, and (ii) administrate fisetin, highly insoluble in water. The design of a liposomal formulation able to encapsulate, retain and deliver both drugs appeared a challenge. (2) Methods: Liposomes with increasing ratios of cholesterol/DOPC were prepared and characterized in term of size, PDI and stability. The incorporation of fisetin was explored using DSC. The antiangiogneic and cytotoxic activities of the selected formulation were assayed in vitro. (3) Results: We successfully developed an optimized liposomal formulation incorporating both drugs, composed by DOPC/cholesterol/DODA-GLY-PEG2000 at a molar ratio of 75.3/20.8/3.9, with a diameter of 173 ± 8 nm (PDI = 0.12 ± 0.01) and a fisetin and cisplatin drug loading of 1.7 ± 0.3% and 0.8 ± 0.1%, respectively, with a relative stability over time. The maximum incorporation of fisetin into the bilayer was determined at 3.2% w/w. Then, the antiangiogenic activity of fisetin was maintained after encapsulation. The formulation showed an additive effect of cisplatin and fisetin on GBM cells; (4) Conclusions: The developed co-loaded formulation was able to retain the activity of fisetin, was effective against GBM cells and is promising for further in vivo experimentations.
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Caspases play an important role as mediators of cell death in acute and chronic neurological disorders. Although peptide inhibitors of caspases provide neuroprotection, they have to be administered intracerebroventricularly because they cannot cross the blood-brain barrier (BBB). Herein, we present a nanocarrier system that can transfer chitosan nanospheres loaded with N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK), a relatively specific caspase-3 inhibitor, across BBB. Caspase-3 was chosen as a pharmacological target because of its central role in cell death. Polyethylene glycol-coated nanospheres were conjugated to an anti-mouse transferrin receptor monoclonal antibody (TfRMAb) that selectively recognizes the TfR type 1 on the cerebral vasculature. We demonstrate with intravital microscopy that this nanomedicine is rapidly transported across the BBB without being measurably taken up by liver and spleen. Pre- or post-treatment (2 h) with intravenously injected Z-DEVD-FMK-loaded nanospheres dose dependently decreased the infarct volume, neurological deficit, and ischemia-induced caspase-3 activity in mice subjected to 2 h of MCA occlusion and 24 h of reperfusion, suggesting that they released an amount of peptide sufficient to inhibit caspase activity. Similarly, nanospheres inhibited physiological caspase-3 activity during development in the neonatal mouse cerebellum on postnatal day 17 after closure of the BBB. Neither nanospheres functionalized with TfRMAb but not loaded with Z-DEVD-FMK nor nanospheres lacking TfRMAb but loaded with Z-DEVD-FMK had any effect on either paradigm, suggesting that inhibition of caspase activity and subsequent neuroprotection were due to efficient penetration of the peptide into brain. Thus, chitosan nanospheres open new and exciting opportunities for brain delivery of biologically active peptides that are useful for the treatment of CNS disorders.
Assuntos
Barreira Hematoencefálica/metabolismo , Inibidores de Caspase , Inibidores de Cisteína Proteinase/metabolismo , Nanomedicina/métodos , Fármacos Neuroprotetores/metabolismo , Peptídeos/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/patologia , Isquemia Encefálica/prevenção & controle , Caspase 3/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/uso terapêutico , Camundongos , Nanosferas , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Transporte Proteico/fisiologia , RatosRESUMO
A novel application of capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) was proposed to efficiently detect and monitor the interaction between polymeric nanoparticles and the ß-Amyloid peptide (Aß(1-42)), a biomarker for Alzheimer's Disease (AD), at concentrations close to physiological conditions. The CE-LIF method allowed the interaction between PEGylated poly(alkyl cyanoacrylate) nanoparticles (NPs) and the soluble Aß(1-42) peptide monomers to be highlighted. These results were confirmed by surface plasmon resonance (SPR) and confocal laser scanning microscopy (CLSM). Whereas SPR showed an interaction between the NPs and the Aß(1-42) peptide, CLSM allowed the formation of large aggregates/assemblies at high NP and peptide concentrations to be visualized. All these results suggested that these nanoparticles could bind the Aß(1-42) peptide and influence its aggregation kinetics. Interestingly, the non-PEGylated poly(alkyl cyanoacrylate) NPs did not alter the aggregation kinetics of the Aß(1-42) peptide, thus emphasizing the high level of discrimination of the CE-LIF method with respect to NPs.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Eletroforese Capilar/métodos , Fluorometria/métodos , Nanopartículas/química , Cinética , Lasers , Métodos , Polímeros/química , Ligação Proteica , Multimerização ProteicaRESUMO
Rapamycin has been used topically to treat facial angiofibromas associated with tuberous sclerosis for more than a decade. In the absence of a commercial form, a large number of formulations have been clinically tested. However, given the great heterogeneity of these studies, particularly with regard to the response criteria, it was difficult to know the impact and thus to compare the relevance of the formulations used. The objective of this work was therefore to evaluate the link between the diffusion of rapamycin and the physico-chemical characteristics of these different formulations on Strat-M® membranes as well as on human skin using Franz cells. Our results underline the importance of the type of vehicle used (hydrogel > cream > lipophilic ointment), the soluble state of rapamycin and its concentration close to saturation to ensure maximum thermodynamic activity. Thus, this is the first time that a comparative study of the different rapamycin formulations identified in the literature for the management of facial angiofibromas has been carried out using a pharmaceutical and biopharmaceutical approach. It highlights the important parameters to be considered in the development and optimization of topical rapamycin formulations with regard to cutaneous absorption for clinical efficacy.
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Objectives: In recent years, various formulations containing rapamycin, mainly petrolatum-based, have been tested on facial angiofibromas in tuberous sclerosis. They are often poorly tolerated due to irritation and bleeding. In addition, their effectiveness was insufficient in young adults. The objective of this study was to develop and characterise a hydro-alcoholic gel containing solubilised rapamycin. The stability of the product stored at 4°C was evaluated over 1 year. Methods: Two different 0.1% rapamycin gels were formulated with or without α-tocopherol and urea. Different methods were used to characterise the gels: HPLC, gas chromatography, pH, visual observation and optical microscopy. A physico-chemical and microbiological stability study was also conducted for 1 year at 4°C. Results: Gels were physically and microbiologically stable after 1 year at 4°C: organoleptic characteristics and pH unchanged, no significant decrease in rapamycin was observed, tocopherol droplet size was constant and rheological behaviour was not altered. Conclusions: This study describes a new gel formulation to improve skin penetration using various excipients to promote skin tolerance. This study provides, for the first time, detailed stability data for a hydro-alcoholic rapamycin gel.
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Angiofibroma/tratamento farmacológico , Antibióticos Antineoplásicos/química , Composição de Medicamentos/tendências , Neoplasias Faciais/tratamento farmacológico , Sirolimo/química , Administração Tópica , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/análise , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/tendências , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Géis , Humanos , Interações Hidrofóbicas e Hidrofílicas , Sirolimo/administração & dosagem , Sirolimo/análise , Resultado do TratamentoRESUMO
Nucleoside analogs are first line chemotherapy in various severe diseases: AIDS (acquired immunodeficiency disease syndrome), cytomegalovirus infections, cancer etc. However, most of these compounds suffer from poor bioavailability via oral route. In order to get around this drawback, researchers have imagined many strategies including drug metabolism inhibitors, bio adhesive nanoparticles, amino ester prodrugs, as well as enhancing absorption by increasing drug lipophilicity. This paper illustrated these approaches by developing their application to some nucleoside analogs. Moreover, some of these strategies were very successful and some resulting compounds are now approved by FDA (Food and Drug Administration).
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Sistemas de Liberação de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Proteínas de Membrana Transportadoras , Nanopartículas , Nucleosídeos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Inibidores Enzimáticos/metabolismo , Humanos , Lipídeos/química , Proteínas de Membrana Transportadoras/metabolismo , Nanopartículas/química , Nucleosídeos/química , Nucleosídeos/metabolismoRESUMO
Controlled distribution of a drug by its association to a nanocarrier is a promising approach for the treatment of pregnancy disorders such as preeclampsia. For this application, tracking both the nanocarrier and the drug is necessary to ensure the safety of both the mother and the foetus. This study reports a method to visualize and quantify the uptake of liposomal formulations in placental tissue using florescent labelling and appropriate analytical tools. Lipoplexes were labelled with a fluorescent lipid, DOPE-NBD while the encapsulated siRNA was fluorescently labelled with rhodamine. Lipoplexes were incubated with villous placenta explants, explants were imaged with confocal microscopy, then DOPE-NBD was extracted from the explant and quantified by HPLC. Qualitative evaluation by confocal microscopy showed the presence of lipoplexes and siRNA into the outer layer of the placental explants, the syncytiotrophoblast. For quantitative evaluation, an HPLC method for the quantification of fluorescent lipid DOPE-NBD in placental tissue was developed and validated. The developed method was applied to quantify the DOPE-NBD uptake in the placental tissue. Increased amounts of DOPE-NBD were detected in placental explants when increasing the incubation concentration of lipoplexes. This study provides a method to evaluate the interactions between liposomal formulation and the placental barrier.
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Lipossomos/administração & dosagem , Placenta/metabolismo , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Microscopia Confocal , Gravidez , RNA Interferente Pequeno/administração & dosagemRESUMO
Preeclampsia is a serious pregnancy disorder characterized by the onset of high blood pressure and proteinuria. Although the understanding of the disease is increasing, it remains without treatment, other than the delivery of the baby and the placenta. This review sets out to discuss some new developments and strategies in the treatment of preeclampsia. We briefly review the current knowledge on the preeclamptic pathophysiology. We then examine the recent trends in preeclampsia treatment and, in particular, the tracks of potential therapeutic targets. Finally, we focus on the possibilities nanocarriers could offer in the management of preeclampsia. Indeed, nanocarriers could help to prevent transplacental passage and promote placental-specific drug delivery, thereby enhancing efficacy and improving safety. Tendencies are then drawn from the available studies on the optimal characteristics of a nanocarrier to deliver drugs to the placenta.