RESUMO
The spleen emerges as a pivotal target for mRNA delivery, prompting a continual quest for specialized and efficient lipid nanoparticles (LNPs) designed to enhance spleen-selective transfection efficiency. Here we report imidazole-containing ionizable lipids (IMILs) that demonstrate a pronounced preference for mRNA delivery into the spleen with exceptional transfection efficiency. We optimized IMIL structures by constructing and screening a multidimensional IMIL library containing multiple heads, tails, and linkers to perform a structure-activity correlation analysis. Following high-throughput in vivo screening, we identified A3B7C2 as a top-performing IMIL in spleen-specific mRNA delivery via the formulated LNPs, achieving a remarkable 98% proportion of splenic transfection. Moreover, A3B7C2-based LNPs are particularly potent in splenic dendritic cell transfection. Comparative analyses revealed that A3B7C2-based LNPs achieved a notable 2.8-fold and 12.9-fold increase in splenic mRNA transfection compared to SM102 and DLin-MC3-DMA lipid formulations, respectively. Additionally, our approach yielded an 18.3-fold enhancement in splenic mRNA expression compared to the SORT method without introducing additional anionic lipids. Collectively, these IMILs highlight promising avenues for further research in spleen-selective mRNA delivery. This work offers valuable insights for the swift discovery and rational design of ionizable lipid candidates tailored for spleen-selective transfection, thereby facilitating the application of mRNA therapeutics in spleen-related interventions.
Assuntos
Imidazóis , Lipídeos , RNA Mensageiro , Baço , Baço/metabolismo , Imidazóis/química , Lipídeos/química , Lipídeos/síntese química , RNA Mensageiro/administração & dosagem , RNA Mensageiro/genética , Animais , Camundongos , Transfecção/métodos , Nanopartículas/química , Estrutura MolecularRESUMO
Lipid nanoparticles (LNPs) are the most clinically successful drug delivery systems that have accelerated the development of mRNA drugs and vaccines. Among various structural components of LNPs, more recent attention has been paid in ionizable lipids (ILs) that was supposed as the key component in determining the effectiveness of LNPs for inâ vivo mRNA delivery. ILs are typically comprised of three moieties including ionizable heads, linkers, and hydrophobic tails, which suggested that the combination of different functional groups in three moieties could produce ILs with diverse chemical structures and biological identities. In this concept article, we provide a summary of chemical design strategy for high-performing IL candidates and discuss their structure-activity relationships for shifting tissue-selective mRNA delivery. We also propose an outlook for the development of next-generation ILs, enabling the broader translation of mRNA formulated with LNPs.
Assuntos
Lipídeos , Nanopartículas , RNA Mensageiro , RNA Mensageiro/metabolismo , RNA Mensageiro/química , Lipídeos/química , Lipídeos/síntese química , Humanos , Nanopartículas/química , Estrutura Molecular , Relação Estrutura-Atividade , Animais , Sistemas de Liberação de MedicamentosRESUMO
Lipid-porphyrin conjugates are considered nowadays as promising building blocks for the conception of drug delivery systems with multifunctional properties such as photothermal therapy (PTT), photodynamic therapy (PDT), phototriggerable release, photoacoustic and fluorescence imaging. For this aim, we have recently synthesized a new lipid-porphyrin conjugate named PhLSM. This was obtained by coupling pheophorbide-a (Pheo-a), a photosensitizer derived from chlorophyll-a, to egg lyso-sphingomyelin. The pure PhLSMs were able to self-assemble into vesicle-like structures that were however not stable and formed aggregates with undefined structures due to the mismatch between the length of the alkyl chain in sn-1 position and the adjacent porphyrin. Herein, stable PhLSMs lipid bilayers were achieved by mixing PhLSMs with cholesterol which exhibits a complementary packing parameter. The interfacial behavior as well as the fine structures of their equimolar mixture was studied at the air/buffer interface by the mean of Langmuir balance and x-ray reflectomerty (XRR) respectively. Our XRR analysis unraveled the monolayer thickening and the increase in the lateral ordering of PhLSM molecules. Interestingly, we could prepare stable vesicles with this mixture that encapsulate hydrophilic fluorescent probe. The light-triggered release kinetics and the photothermal conversion were studied. Moreover, the obtained vesicles were photo-triggerable and allowed the release of an encapsulated cargo in an ON-OFF fashion.
Assuntos
Sistemas de Liberação de Medicamentos , Lipídeos/química , Fosfolipídeos/química , Porfirinas/química , Clorofila/análogos & derivados , Clorofila/síntese química , Clorofila/química , Colesterol/química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos da radiação , Cinética , Luz , Bicamadas Lipídicas/química , Bicamadas Lipídicas/efeitos da radiação , Lipídeos/síntese química , Lipídeos/efeitos da radiação , Lipídeos/uso terapêutico , Lipossomos/química , Lipossomos/efeitos da radiação , Lipossomos/uso terapêutico , Fosfolipídeos/síntese química , Fosfolipídeos/farmacologia , Fosfolipídeos/efeitos da radiação , Fotoquimioterapia/tendências , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Terapia Fototérmica/tendências , Porfirinas/síntese química , Porfirinas/efeitos da radiação , Porfirinas/uso terapêuticoRESUMO
Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are available nowadays, with well-defined therapeutic protocols. The poor bioavailability, non-selective action, high systemic toxicity, and lack of effectiveness of most AAs have stimulated the search for novel chemotherapy protocols, including technological approaches that provide drug delivery systems (DDS) for gold standard medicines. Nanostructured lipid carriers (NLC) are DDS that contain a core of solid and lipid liquids stabilised by surfactants. NLC have high upload capacity for lipophilic drugs, such as the majority of AAs. These nanoparticles can be prepared with a diversity of biocompatible (synthetic or natural) lipid blends, administered by different routes and functionalised for targeting purposes. This review focused on the research carried out from 2000 to now, regarding NLC formulations for AAs (antimetabolites, antimitotics, alkylating agents, and antibiotics) encapsulation, with special emphasis on studies carried out in vivo. NLC systems for codelivery of AAs were also considered, as well as those for non-classical drugs and therapies (natural products and photosensitisers). NLC have emerged as powerful DDS to improve the bioavailability, targeting and efficacy of antineoplastics, while decreasing their toxic effect in the treatment of different types of cancer.
Assuntos
Antineoplásicos , Portadores de Fármacos , Composição de Medicamentos , Lipídeos , Nanopartículas , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapêutico , Humanos , Lipídeos/síntese química , Lipídeos/química , Lipídeos/farmacocinética , Lipídeos/uso terapêutico , Nanopartículas/química , Nanopartículas/uso terapêutico , Tamanho da Partícula , Tensoativos/químicaRESUMO
Herbal antioxidant like curcumin holds great potential to treat neurodegenerative disease like Alzheimer's disease. However, its therapeutic potency is obstructed due to rapid metabolism, poor solubility, GI susceptibility, enzymatic degradation and lower bioavailability. Thus, the present work aimed to design and optimize curcumin-loaded NLC (CNL) with higher drug entrapment, prolonged release and better stability. CNL was prepared by modified melt emulsification method followed by ultrasonication. The formulation was optimized by 3 factor 3 level Box-Behnken design using solid: liquid lipid, surfactant concentration and ultrasonication time as independent variable while particle size, entrapment efficiency and % drug release as dependant variable. The design suggested 3.092 solid:liquid lipid, 2.131% surfactant and 4.757 min ultrasonication fit best to get the optimized formulation. The size of the optimized CNL was noted 124.37 ± 55.81 nm, which is in the acceptable range for brain delivery. SEM results also comply with this size range (near 150 nm) and demonstrated almost spherical and uniform particles with porous and uneven surface structures. PDI, zeta potential, entrapment efficiency and % drug release were observed as 0.201 ± 0.00, - 17.2 ± 2.35 mV, 93.62 ± 0.68% and 92.73 ± 0.06%, respectively. The NLC demonstrated initial burst release with subsequent prolonged release of drug for 48 h. Weibull kinetic equation with 0.9958 R2, minimum AIC and maximum MSC value was found best fit to explain the release behavior. The ß exponent and diffusional coefficient (n) indicated combined release mechanism with Fickian diffusion as drug release mechanism. Formulation was also found stable at different storage condition.
Assuntos
Curcumina/síntese química , Portadores de Fármacos/síntese química , Desenho de Fármacos/métodos , Lipídeos/síntese química , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Curcumina/administração & dosagem , Curcumina/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Lipídeos/administração & dosagem , Lipídeos/farmacocinética , Nanopartículas , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Tensoativos/administração & dosagem , Tensoativos/síntese química , Tensoativos/farmacocinética , Difração de Raios X/métodosRESUMO
Macrophages act as a cellular reservoir in HIV infection. Elimination of HIV from macrophages has been an unfulfilled dream due to the failure of drugs to reach them. To address this, we developed CD44 receptor-targeted, novel hyaluronic acid (HA)-coated nanostructured lipid carriers (NLCs) of efavirenz via washless layer-by-layer (LbL) assembly of HA and polyallylamine hydrochloride (PAH). NLCs were subjected to TEM analysis, size and zeta potential, in vitro release and encapsulation efficiency studies. The uptake of NLCs in THP-1 cells was studied using fluorescence microscopy and flow cytometry. The anti-HIV efficacy was evaluated using p24 antigen inhibition assay. NLCs were found to be spherical in shape with anionic zeta potential (-23.66 ± 0.87 mV) and 241.83 ± 5.38 nm particle size. NLCs exhibited prolonged release of efavirenz during in vitro drug release studies. Flow cytometry revealed 1.73-fold higher uptake of HA-coated NLCs in THP-1 cells. Cytotoxicity studies showed no significant change in cell viability in presence of NLCs as compared with the control. HA-coated NLCs distributed throughout the cell including cytoplasm, plasma membrane and nucleus, as observed during fluorescence microscopy. HA-coated NLCs demonstrated consistent and significantly higher inhibition (81.26 ± 1.70%) of p24 antigen which was 2.08-fold higher than plain NLCs. The obtained results suggested preferential uptake of HA-coated NLCs via CD44-mediated uptake. The present finding demonstrates that HA-based CD44 receptor targeting in HIV infection is an attractive strategy for maximising the drug delivery to macrophages and achieve effective viral inhibition.
Assuntos
Portadores de Fármacos/administração & dosagem , HIV-1/efeitos dos fármacos , Receptores de Hialuronatos , Macrófagos/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Alcinos/administração & dosagem , Alcinos/síntese química , Alcinos/metabolismo , Benzoxazinas/administração & dosagem , Benzoxazinas/síntese química , Benzoxazinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ciclopropanos/administração & dosagem , Ciclopropanos/síntese química , Ciclopropanos/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1/fisiologia , Humanos , Receptores de Hialuronatos/metabolismo , Lipídeos/administração & dosagem , Lipídeos/síntese química , Macrófagos/metabolismo , Nanoestruturas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Células THP-1RESUMO
The suitability as FRET probes of two bichromophoric 1-deoxydihydroceramides containing a labelled spisulosine derivative as a sphingoid base and two differently ω-labelled fluorescent palmitic acids has been evaluated. The ceramide synthase (CerS) catalyzed metabolic incorporation of ω-azido palmitic acid into the above labeled spisulosine to render the corresponding ω-azido 1-deoxyceramide has been studied in several cell lines. In addition, the strain-promoted click reaction between this ω-azido 1-deoxyceramide and suitable fluorophores has been optimized to render the target bichromophoric 1-deoxydihydroceramides. These results pave the way for the development of FRET-based assays as a new tool to study sphingolipid metabolism.
Assuntos
Ceramidas/metabolismo , Corantes Fluorescentes/síntese química , Lipídeos/síntese química , Oxirredutases/metabolismo , Ácidos Palmíticos/química , Animais , Linhagem Celular , Química Click , Transferência Ressonante de Energia de Fluorescência , Humanos , Camundongos , Espectrometria de Fluorescência , Espectrometria de Massas em TandemRESUMO
The present study deals with intensified synthesis of designer lipids with application of ultrasound based on biocatalyzed reaction between long chain triglyceride and medium chain fatty acid. The effects of various reaction conditions like molar ratio of reactant, reaction temperature, and enzyme loading along with the effect of ultrasound parameters such as duty cycle and irradiation time on the rate of formation of designer lipids has been investigated. The ultrasound assisted process was also compared with the traditional process so as to clearly bring out the intensification effects. During the study, it was clearly demonstrated that the optimum reaction conditions for maximum yield of designer lipids as 92% was molar ratio of medium chain fatty acid to long chain triglyceride as 4:1, reaction temperature of 40 °C, enzyme loading of 3%, duty cycle of 70%, 240 W as power dissipation and 360 min as reaction time. The recyclability study of enzyme showed its effectiveness up to 10 cycles. The synthesized designer lipid showed higher oxidative stability for 35 days and also showed Newtonian behaviour with eye appealing colour. The current study demonstrates development of an eco-friendly technique for intensified synthesis of designer lipids having numerous nutraceutical benefits.
Assuntos
Lipídeos/síntese química , Sonicação/métodos , Biocatálise , Ácidos Graxos/análise , Oxirredução , Temperatura , Triglicerídeos/análiseRESUMO
Elastic liposomes consist of phospholipids and of surfactants, could be considered as promising nanotechnological platforms for skin drug delivery. The aim of the present study was the formation of elastic liposomes by thin film hydration method, using different phospholipids and surfactants, in order to determine the effect of the components on their physical characteristics and on their physical stability. Physical properties of elastic liposomes were evaluated using dynamic light scattering (DLS)method. The particle size at the day of their preparation, was ranged between small and large unilamellar vesicles (SUVs and LUVs), dependent on the hydrophilicity of the surfactant used, while their PDI (Poly Dispersity Index) value was close to zero, indicating monodispersed systems. Physical stability study involved the measure of particle size, as a quantifiable physical property, at selected times over a 30-days period, at storage conditions: (i) 4 °C, (ii) 25 °C, iii) 45 °C, suggested that refrigerated conditions promote physical stability, while high temperatures induce aggregation. According to the physical stability study elastic liposomes composed ofTween80 were found to bemore stable than those composed of Span80, at ambient conditions. The goal of our investigation was centred to the development and evaluation of a well know liposomal category i.e. elastic liposomes, by modified their composition with common surfactants (i.e. Span and/or Tween), creating, a new liposomal class namely, elastic lipo-niosomes. To the best of knowledge this the first time that these hybrid vesicles appeared in the literature exhibiting the aforementioned category lipid/surfactants and molar ratios.
Assuntos
Lipídeos/química , Físico-Química , Lipídeos/síntese química , Lipossomos/síntese química , Lipossomos/química , Tamanho da PartículaRESUMO
Ser/Thr protein phosphatases (PPs) regulate a substantial range of cellular processes with protein phosphatases 1 (PP1) and 2â A (PP2A) accounting for over 90 % of the activity within cells. Nevertheless, tools to study PPs are limited as PPs inhibitors, particularly those selective for PP1 inhibition, are relatively scarce. Two examples of PP1-selective inhibitors, which share structural similarities, are tautomycin (TTM) and tautomycetin (TTN). This work describes the development of PP1/PP2A inhibitors that incorporate key structural features of TTM and TTN and are designed to conserve regions known to bind the active site of PP1/PP2A but vary regions that differentially contact the hydrophobic groove of PP1/PP2A. In all 28 TTN analogues were synthetically generated that inhibit PP1/PP2A activity at <250â mM; seven possessed inhibition activity at 100â nM. The IC50 values were determined for the seven most active analogues, which ranged from 34 to 1500â nM (PP1) and 70 to 6800â nM (PP2A). Four of the seven analogues possessed PP1 selectivity, and one demonstrated eightfold selectivity in the nanomolar range (PP1 IC50 =34â nM, PP2A IC50 =270â nM). A rationale is given for the observed differences in selectivity.
Assuntos
Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Lipídeos/farmacologia , Proteína Fosfatase 2/antagonistas & inibidores , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Furanos/síntese química , Furanos/química , Humanos , Lipídeos/síntese química , Lipídeos/química , Estrutura Molecular , Proteína Fosfatase 2/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-AtividadeRESUMO
Structured lipids (SLs) refer to a new type of functional lipids obtained by chemically, enzymatically, or genetically modifying the composition and/or distribution of fatty acids in the glycerol backbone. Due to the unique physicochemical characteristics and health benefits of SLs (for example, calorie reduction, immune function improvement, and reduction in serum triacylglycerols), there is increasing interest in the research and application of novel SLs in the food industry. The chemical structures and molecular architectures of SLs define mainly their physicochemical properties and nutritional values, which are also affected by the processing conditions. In this regard, this holistic review provides coverage of the latest developments and applications of SLs in terms of synthesis strategies, physicochemical properties, health aspects, and potential food applications. Enzymatic synthesis of SLs particularly with immobilized lipases is presented with a short introduction to the genetic engineering approach. Some physical features such as solid fat content, crystallization and melting behavior, rheology and interfacial properties, as well as oxidative stability are discussed as influenced by chemical structures and processing conditions. Health-related considerations of SLs including their metabolic characteristics, biopolymer-based lipid digestion modulation, and oleogelation of liquid oils are also explored. Finally, potential food applications of SLs are shortly introduced. Major challenges and future trends in the industrial production of SLs, physicochemical properties, and digestion behavior of SLs in complex food systems, as well as further exploration of SL-based oleogels and their food application are also discussed.
Assuntos
Lipídeos/biossíntese , Lipídeos/síntese química , Digestão , Ácidos Graxos/química , Humanos , Metabolismo dos Lipídeos , Lipídeos/química , Estrutura Molecular , Valor Nutritivo , Compostos OrgânicosRESUMO
Omega-3 polyunsaturated fatty acids (PUFAs) have been known to have beneficial effects in the prevention of various diseases. Recently, it was identified that the bioactivities of omega-3 are related to lipid mediators, called pro-resolving lipid mediators (SPMs), converted from PUFAs, so they have attracted much attention as potential pharmaceutical targets. Here, we aimed to build an efficient production system composed of enzymatic and chemical catalysis that converts docosahexaenoic acid (DHA) into lipid mediators. The cyanobacterial lipoxygenase, named Osc-LOX, was identified and characterized, and the binding poses of enzyme and substrates were predicted by ligand docking simulation. DHA was converted into three lipid mediators, a 17S-hydroxy-DHA, a 7S,17S-dihydroxy-DHA (RvD5), and a 7S,15R-dihydroxy-16S,17S-epoxy-DPA (new type), by an enzymatic reaction and deoxygenation. Also, two lipid mediators, 7S,15R,16S,17S-tetrahydroxy-DPA (new type) and 7S,16R,17S-trihydroxy-DHA (RvD2), were generated from 7S,15R-dihydroxy-16S,17S-epoxy-DPA by a chemical reaction. Our study suggests that discovering new enzymes that have not been functionally characterized would be a powerful strategy for producing various lipid mediators. Also, this combination catalysis approach including biological and chemical reactions could be an effective production system for the manufacturing lipid mediators.
Assuntos
Ácidos Docosa-Hexaenoicos/síntese química , Mediadores da Inflamação/síntese química , Inflamação/tratamento farmacológico , Lipídeos/síntese química , Catálise , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/síntese química , Ácidos Graxos Ômega-3/química , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Humanos , Inflamação/patologia , Mediadores da Inflamação/química , Mediadores da Inflamação/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/química , Lipídeos/farmacologia , Lipoxigenase/químicaRESUMO
Ionizable cationic lipids are critical components involved in nanoparticle formulations, which are utilized in delivery platforms for RNA therapeutics. While general criteria regarding lipophilicity and measured pKa in formulation are understood to have impacts on utility in vivo, greater granularity with respect to the impacts of the structure on calculated and measured physicochemical parameters and the subsequent performance of those ionizable cationic lipids in in vivo studies would be beneficial. Herein, we describe structural alterations made within a lipid class exemplified by 4, which allow us to tune calculated and measured physicochemical parameters for improved performance, resulting in substantial improvements versus the state of the art at the outset of these studies, resulting in good in vivo activity within a range of measured basicity (pKa = 6.0-6.6) and lipophilicity (cLogD = 10-14).
Assuntos
Lipídeos/química , RNA Interferente Pequeno/metabolismo , Transfecção/métodos , Animais , Cátions/química , Fator VII/antagonistas & inibidores , Fator VII/genética , Fator VII/metabolismo , Feminino , Humanos , Cinética , Lipídeos/síntese química , Camundongos , Nanopartículas/química , Tamanho da Partícula , Interferência de RNA , Estabilidade de RNA , RNA Interferente Pequeno/sangue , Relação Estrutura-AtividadeRESUMO
2,3,5-Trisubstituted tetrahydrofuran moiety is ubiquitous in natural products. These have served as appealing candidates for total synthesis due to their varied bio- and pharmaceutical activities. This tutorial review delineates the ingenious efforts by many researchers in the total synthesis of selected natural products based on a common 2,3,5-trisubstituted tetrahydrofuran core structure. Many of the syntheses display nuanced interplay between new methods and the ingenuity of planned strategies achieved through catalysis or cascade chemistry. In some cases, the chiron approach has come quite handy, wherein the structural features and the stereochemistry in select molecules could map well with naturally available starting materials. This compilation also aims to enhance the diversity space based on these natural products and further interest in sustainable total synthesis.
Assuntos
Produtos Biológicos/síntese química , Furanos/química , Produtos Biológicos/química , Ácidos Graxos/síntese química , Ácidos Graxos/química , Furanos/síntese química , Lactonas/síntese química , Lactonas/química , Lipídeos/síntese química , Lipídeos/química , Sesquiterpenos/síntese química , Sesquiterpenos/química , EstereoisomerismoRESUMO
Structured lipids (SL) represent a new generation of lipids, considered bioactive compounds. Medium-chain, oleic (18:1n-9), and medium-chain fatty acid (MCFA) structured lipids (MOM-SL) were produced by acidolysis reaction in solvent-free medium with capric (10:0) and lauric (12:0) free fatty acids (FFAs) and triolein or olive oil, using Yarrowia lipolytica lipase as biocatalyst. MCFAs were rapidly incorporated into sn-1,3 SL in acidolysis reactions with triolein and olive oil, up until 30% of incorporation efficiency of capric and lauric acids in SLs. The kinetics of MCFA incorporation in MOM-SL was influenced by the FFA:TAG molar ratio, and for reactions between triolein and lauric acid, increasing FFA:TAG from 2:1 to 4:1 enhanced MCFA incorporation in SL. Y. lipolytica lipase showed a strictly 1,3-regioselective profile in acidolysis reaction, confirmed by nuclear magnetic resonance spectroscopy. Immobilization of this lipase by microencapsulation in chitosan-alginate beads resulted in similar incorporation efficiency for lauric acid with olive oil TAG and this reaction could be performed for 5 cycles without catalytic activity loss. This lipase showed promising properties as a potential biocatalyst that may be effectively used in production of bioactive structured lipids, which might be applied for prevention of metabolic and inflammatory disorders related to obesity.
Assuntos
Alginatos/química , Quitosana/química , Enzimas Imobilizadas , Lipase/química , Lipídeos/síntese química , Lipídeos/farmacologia , Yarrowia/enzimologia , Biocatálise , Técnicas de Química Sintética , Suplementos Nutricionais , Composição de Medicamentos , Ativação Enzimática , Esterificação , Ácidos Graxos/química , Concentração de Íons de Hidrogênio , Lipídeos/química , Lipólise , Microesferas , Azeite de Oliva/químicaRESUMO
Sustained release lipid microparticles for a potential veterinary application were produced by the means of spray congealing using saturated triglycerides with respective surfactants. The spray congealing process was optimized using unloaded and loaded microparticles, revealing the highest impact of the spray flow on material loss. Yield could be optimized by increasing the spray flow as well as a reduction of the melt temperature from 90 to 75 °C. For the delivery system developed in this study, a release of around 15 days was targeted. The release profile was in first hand determined with the use of model substances (aspartame and tryptophan), before incorporating the decapeptide Gonadorelin [6-D-Phe]. Release could be controlled between 2 and 28 d, which was dependent on stability of microparticles upon incubation, type and concentration of emulsifier, as well as the used triglyceride. Differential scanning calorimetry and X-ray powder diffraction confirmed the crystallization behavior of C14 and C16-triglycerides in combination with various emulsifiers in different modification without impact on release.
Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Hormônio Liberador de Gonadotropina/síntese química , Lipídeos/síntese química , Microesferas , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/farmacocinética , Lipídeos/administração & dosagem , Lipídeos/farmacocinética , Tamanho da Partícula , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacocinética , Difração de Raios X/métodosRESUMO
A series of boron-containing lipids were prepared by reactions of cyclic oxonium derivatives of polyhedron boranes and metallacarboranes (closo-dodecaborate anion, cobalt and iron bis(dicarbollides)) with amine and carboxylic acids which are derived from cholesterol. Stable liposomal formulations, on the basis of synthesized boron-containing lipids, hydrogenated soybean l-α-phosphatidylcholine and (HSPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) as excipients, were prepared and then characterized by dynamic light scattering (DLS) that revealed the formation of particles to be smaller than 200â nm in diameter. The resulting liposomal formulations showed moderate to excellent loading and entrapment efficiency, thus justifying the design of the compounds to fit in the lipid bilayer and ensuring ease of in vivo use for future application. The liposomal formulations based on cobalt and iron bis(dicarbollide)-based lipids were found to be nontoxic against both human breast normal epithelial cells MCF-10A and human breast cancer cells MCF-7.
Assuntos
Compostos de Boro , Boro , Colesterol , Lipídeos , Lipossomos , Boranos/química , Boro/química , Compostos de Boro/síntese química , Compostos de Boro/química , Colesterol/química , Humanos , Lipídeos/síntese química , Lipídeos/química , Lipídeos/farmacologia , Lipossomos/síntese química , Lipossomos/química , Lipossomos/farmacologia , Células MCF-7 , Compostos Organometálicos/química , Compostos Organometálicos/farmacologiaRESUMO
Novel vitamin E chelate derivatives and their VIV/V complexes have been synthesized and characterized, and their anticancer properties have been evaluated. The new complexes have been designed to exhibit enhanced cytotoxicity by combining high lipophilicity with the properties of vanadium to induce the formation of reactive oxygen species (ROS). In particular, the ß-tocopherol derivatives with iminodiethanol (ß-tocDEA) and dipicolylamine (ß-tocDPA) as well their VV and VIV complexes, [VVO(ß-tocDEA] and [VIVO(ß-tocDPA] have been synthesized and characterized by Nuclear Magnetic Resonance (NMR), Ultra Violet-Visible (UV-Vis) and Electron Paramagnetic Resonance (EPR) spectroscopies. Although the ß-tocopherol compounds exhibit antioxidant activity their complexes induce formation of radicals. In addition, two vanadium amphiphilic complexes of 2,2'-((2-hydroxyoctadecyl)azanediyl)bis(ethan-1-ol) (C18DEA) and 1-(bis(pyridin-2-ylmethyl)amino)octadecan-2-ol (C18DPA) known to activate O2 and produce ROS were synthesized and characterized (C. Drouza, A. Dieronitou, I. Hadjiadamou, M. Stylianou, J. Agric. Food. Chem., vol. 65, 2017, pp. 4942-4951). The four amphiphilic vanadium complexes exhibit enhanced hydrolytic stability. All compounds found to be cytotoxic for cancer cells exhibiting activity similar or higher to cis-platin.
Assuntos
Complexos de Coordenação , Citotoxinas , Lipídeos , Neoplasias , Vanádio , Vitamina E , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacocinética , Citotoxinas/farmacologia , Células HEK293 , Células HeLa , Humanos , Lipídeos/síntese química , Lipídeos/química , Lipídeos/farmacocinética , Lipídeos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Vanádio/química , Vanádio/farmacocinética , Vanádio/farmacologia , Vitamina E/síntese química , Vitamina E/química , Vitamina E/farmacocinética , Vitamina E/farmacologiaRESUMO
Sunlight is important to health, but higher exposure to radiation causes early aging of the skin and skin damage that can lead to skin cancers. This study aimed at producing a stable octyl p-methoxycinnamate (OMC)-loaded nanostructured lipid carrier (NLC) sunscreen, which can help in the photoprotective effect. NLC was produced by emulsification-sonication method and these systems were composed of myristyl myristate (MM), caprylic capric triglyceride (CCT), Tween® 80 (TW), and soybean phosphatidylcholine (SP) and characterized by dynamic light scattering (DLS), zeta potential (ZP) measurement, atomic force microscopy (AFM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and in vitro release studies. Pre-formulation studies were performed changing TW concentrations and no differences were found at concentrations of 1.0 and 2.0%. Two selected formulations were designed and showed an average size of 91.5-131.7, polydispersity index > 0.2, and a negative value of ZP. AFM presented a sphere-like morphology and SEM showed ability to form a thin film. DSC exhibited that the incorporation of OMC promoted reduction of enthalpy due to formation of a more amorphous structure. Drug release shows up to 55.74% and 30.57%, and this difference could be related to the presence of SP in this formulation that promoted a more amorphous structure; the release mechanism study indicated Fickian diffusion and relaxation. Sun protection factor (SPF) evaluation was performed using NLC and presented values around 40, considerably higher than those observed in the literature. The developed formulations provide a beneficial alternative to conventional sunscreen formulations.
Assuntos
Cinamatos/síntese química , Portadores de Fármacos/síntese química , Lipídeos/síntese química , Nanoestruturas/química , Fator de Proteção Solar/métodos , Protetores Solares/síntese química , Varredura Diferencial de Calorimetria/métodos , Cinamatos/farmacocinética , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Lipídeos/farmacocinética , Microscopia de Força Atômica/métodos , Microscopia Eletrônica de Varredura/métodos , Tamanho da Partícula , Protetores Solares/farmacocinéticaRESUMO
RNA interference induced by small interfering RNA (siRNA) is a promising strategy for the treatment of various intractable diseases including cancer. Lipid nanoparticles (LNP) composed of ionizable lipids and siRNA are known as a leading siRNA delivery system. However, LNPs composed of conventional ionizable lipids will be aggregated in the physiological environment because of loss of ionization. Therefore, the inclusion of hydrophilic polymer-conjugated lipids such as polyethylene glycol (PEG)-conjugated lipid is required to improve the LNP stability. Herein, we synthesized a novel charge-reversible lipid derivative, dioleoylglycerophosphate-diethylenediamine conjugate (DOP-DEDA). The surface of LNP composed of DOP-DEDA (DOP-DEDA LNP) was constantly ionized and positively charged at pH 6.0, almost neutral at pH 7.4, and negatively charged at pH 8.0. Importantly, DOP-DEDA LNP were stable in the physiological milieu without PEG-conjugated lipid. DOP-DEDA LNP disrupted the red blood cells only under the low-pH condition in a hemolysis assay, suggesting that the interaction between DOP-DEDA LNP and biological membranes is pH-dependent. DOP-DEDA LNP encapsulating siRNA against polo-like kinase 1 (siPLK1) highly suppressed the expression of PLK1 mRNA and its protein. The cellular uptake of DOP-DEDA LNP was increased in an apolipoprotein E3 (apoE3) dose-dependent manner. In addition, DOP-DEDA LNP was taken up into cancer cells via both clathrin- and caveola-mediated endocytosis pathways. These findings indicate that LNP composed of this charge-reversible lipid should be a highly stable and potent siRNA delivery vector.