RESUMO
BACKGROUND: Glioblastoma is a lethal neoplasm with few effective therapy options. As a mainstay in the current treatment of glioma at present, chemotherapeutic agents usually show inadequate therapeutic efficiency due to their low blood brain barrier traversal and brain targeting, together with tumor multidrug resistance. Novel treatment strategies are thus urgently needed to improve chemotherapy outcomes. RESULTS: Here, we report that nanomedicines developed by functionalizing the neurotropic rabies virus-derived polypeptide, RVG, and loading reduction-sensitive nanomicelles (polymer and doxorubicin) enable a highly specific and efficacious drug accumulation in the brain. Interestingly, curcumin serves as the hydrophobic core of the polymer, while suppressing the major efflux proteins in doxorubicin-resistant glioma cells. Studies on doxorubicin-resistant rat glioma cells demonstrate that the RVG-modified micelles exhibit superior cell entry and antitumor activity. In vivo research further showed that RVG modified nanomicelles significantly enhanced brain accumulation and tumor inhibition rate in mice, leading to a higher survival rate with negligible systemic toxicity. Moreover, effective suppression of recurrence and pulmonary metastatic nodules were also determined after the RVG-modified nanomicelles treatment. CONCLUSIONS: The potential of RVG-modified nanomicelles for glioma was demonstrated. Brain accumulation was markedly enhanced after intravenous administration. This unique drug delivery nanoplatform to the brain provides a novel and powerful therapeutic strategy for the treatment of central nervous system disorders including glioma.
Assuntos
Encéfalo/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/metabolismo , Micelas , Animais , Antineoplásicos , Materiais Biocompatíveis , Neoplasias Encefálicas/tratamento farmacológico , Sobrevivência Celular , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Glioblastoma , Glioma/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Peptídeos/metabolismo , RatosRESUMO
Molybdenum oxide (MoOx) nanosheets have drawn increasing attention for minimally invasive cancer treatments but still face great challenges, including complex modifications and the lack of efficient accumulation in tumor. In this work, a novel multifunctional degradable FA-BSA-PEG/MoOx nanosheet was fabricated (LA-PEG and FA-BSA dual modified MoOx): the synergistic effect of PEG and BSA endows the nanosheet with excellent stability and compatibility; the FA, a targeting ligand, facilitates the accumulation of nanosheets in the tumor. In addition, DTX, a model drug for breast cancer treatment, was loaded (76.49%, 1.5 times the carrier weight) in the nanosheets for in vitro and in vivo antitumor evaluation. The results revealed that the FA-BSA-PEG/MoOx@DTX nanosheets combined photothermal and chemotherapy could not only inhibit the primary tumor growth but also suppress the distant tumor growth (inhibition rate: 51.7%) and lung metastasis (inhibition rate: 93.6%), which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, which co-contributes towards effective suppression of tumor and lung metastasis. Our experiments demonstrated that this novel multifunctional nanosheet is a promising platform for combined chemo-photothermal therapy.
Assuntos
Materiais Biocompatíveis/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Molibdênio/química , Nanoestruturas/uso terapêutico , Óxidos/química , Animais , Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Ácido Fólico/química , Humanos , Hipertermia Induzida , Raios Infravermelhos , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Nanoestruturas/toxicidade , Polietilenoglicóis/química , Soroalbumina Bovina/química , Ácido Tióctico/química , Distribuição TecidualRESUMO
Mitochondrial respiration is mediated by a set of multisubunit assemblies of proteins that are embedded in the mitochondrial inner membranes. Respiratory complexes do not only contain central catalytic subunits essential for the bioenergetic transformation, but also many short trans-membrane subunits (sTMs) that are implicated in the proper assembly of complexes. Defects in sTMs have been discovered in some human neurodegenerative diseases. Here we identify a new subunit that we named Stmp1 and have characterized its function using both computational and experimental approaches. Stmp1 is a short trans-membrane protein, and sequence/structure analysis revealed that it shares common features like the small size, presence of a single or two TM region, and a COOH-terminal charged region, as many typical sTMs of respiratory complexes. In situ hybridization and RT-PCR assays showed that the Stmp1 expression is ubiquitous throughout zebrafish embryogenesis. In adults, Stmp1 expression was highest in the brain compared with muscle and liver. In zebrafish larvae (3-5 days postfertilization), antisense morpholino oligonucleotide-mediated knockdown of the Stmp1 gene (Stmp1-MO) resulted in a series of mild morphological defects, including abnormal shape of head and jaw and cardiac edema. Larvae injected with the Stmp1-MO had negligible responses to touch stimuli. By ventilation frequency analysis we found that Stmp1-MO-injected zebrafish displayed a severe dysfunction of ventilatory activities when exposed to hypoxic conditions, suggesting a defective mitochondrial activity induced by the loss of Stmp1. Phylogenetic profiling of known respiratory sTMs compared with Stmp1 revealed that all defined sTMs from four respiratory complexes have restricted or variable phyletic distribution, indicating that they are products of evolutionary innovations to fulfill lineage-related functional requirements for respiratory complexes. Thus, being present in animals, filasterea, choanoflagellida, amoebozoa, and plants, Stmp1 may have evolved to confer a new or complementary regulation of respiratory activities.
Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Complexo de Proteínas da Cadeia de Transporte de Elétrons/classificação , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Humanos , Hibridização In Situ , Larva/genética , Larva/crescimento & desenvolvimento , Proteínas Mitocondriais/classificação , Dados de Sequência Molecular , Filogenia , Subunidades Proteicas/classificação , Subunidades Proteicas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Fatores de Tempo , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/classificaçãoRESUMO
Currently, colon-specific drug delivery systems have been investigated for drugs that can exert their bioactivities in the colon. In this study, Eudragit® S100 coated calcium pectinate microsphere, a pH-dependent and enzyme-dependent system, as colon-specific delivery carrier for curcumin was investigated. Curcumin-loaded calcium pectinate microspheres were prepared by emulsification-linkage method, and the preparation technology was optimised by uniform experimental design. The morphology of microspheres was observed under scanning electron microscopy. Interactions between drug and polymers were investigated with differential scanning calorimetry (DSC) and X-ray diffraction. In vitro drug release studies were performed in simulated colonic fluid in the presence of Pectinex Ultra SP-L or 1% (w/v) rat caecal content, and the results indicated that the release of curcumin was significantly increased in the presence of 1% (w/v) rat caecal contents. It could be concluded that Eudragit® S100 coated calcium pectinate microsphere was a potential carrier for colon delivery of curcumin.
Assuntos
Colo/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Curcumina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Pectinas/administração & dosagem , Ácidos Polimetacrílicos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Varredura Diferencial de Calorimetria , Ceco/efeitos dos fármacos , Ceco/metabolismo , Materiais Revestidos Biocompatíveis/administração & dosagem , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Colo/metabolismo , Neoplasias do Colo/metabolismo , Curcumina/química , Curcumina/farmacologia , Microscopia Eletrônica de Varredura , Microesferas , Pectinas/química , Pectinas/farmacologia , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacologia , Ratos , Difração de Raios XRESUMO
BACKGROUND: CUR is a promising drug candidate based on its good bioactivity, but use of CUR is potentially restricted because of its poor solubility and bioavailability. AIM: The aim of this study was to prepare an aqueous formulation of curcumin nanosuspension (CUR-NS) to improve its solubility and change its in vivo behavior. METHODS: CUR-NS was prepared by high-pressure homogenization method. Drug state in CUR-NS was evaluated by powder X-ray diffraction. Pharmacokinetics and biodistribution of CUR-NS after intravenous administration in rabbits and mice were studied. RESULTS: The solubility and dissolution of CUR in the form of CUR-NS were significantly higher than those of crude CUR. X-ray crystallography diffraction indicated that the crystalline state of CUR in nanosuspension was preserved. Pharmacokinetics and biodistribution results of CUR-NS after intravenous administration in rabbits and mice showed that CUR-NS presented a markedly different pharmacokinetic property as compared to the CUR solution. AUC(0-infinity) of CUR-NS (700.43 +/- 281.53 microg/mL, min) in plasma was approximately 3.8-fold greater than CUR solution (145.42 +/- 9.29 microg/mL min), and the mean residence time (194.57 +/- 32.18 versus 15.88 +/- 3.56 minutes) was 11.2-fold longer. CONCLUSION: Nanosuspension could serve as a promising intravenous drug-delivery system for curcumin.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Curcumina/química , Curcumina/farmacocinética , Excipientes , Nanopartículas , Nanosferas/análise , Vitamina E/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Disponibilidade Biológica , Fenômenos Químicos , Química Farmacêutica , Curcumina/administração & dosagem , Portadores de Fármacos , Estabilidade de Medicamentos , Infusões Intravenosas , Camundongos , Nanosferas/química , Tamanho da Partícula , Polietilenoglicóis , Pós , Coelhos , Solubilidade , Suspensões , Distribuição TecidualRESUMO
Sugar-containing monomer vinylbenzylglycosylallyamide (VBG) was synthesized by vinylbenzyl amine and delta-gluconolactone in dimethylformamide(DMF) solution. The sugar-based hydrogel was prepared by free radical crosslinking copolymerization of VBG, itaconic acid (IA) and acrylamide (AM). The release properties of Aspirin from xerogels matrices and from hydrogel in different pH solutions and different concentration NaCl solutions were studied respectively. The release mechanism of Aspirin was further confirmed by evaluating the n value in Peppas equation. The results indicated that the drug release increased with the increase of pH values and with the decrease of NaCl concentration.
Assuntos
Resinas Acrílicas/química , Aspirina/administração & dosagem , Hidrogel de Polietilenoglicol-Dimetacrilato/síntese química , Succinatos/química , Compostos de Vinila/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Aspirina/química , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Concentração de Íons de HidrogênioRESUMO
To remedy the problems riddled in cancer chemotherapy, such as poor solubility, low selectivity, and insufficient intra-cellular release of drugs, novel heparin-based redox-sensitive polymeric nanoparticles were developed. The amphiphilic polymer, heparin-alpha-tocopherol succinate (Hep-cys-TOS) was synthesized by grafting hydrophobic TOS to heparin using cystamine as the redox-sensitive linker, which could self-assemble into nanoparticles in phosphate buffer saline (PBS) with low critical aggregation concentration (CAC) values ranging from 0.026 to 0.093mg/mL. Paclitaxel (PTX)-loaded Hep-cys-TOS nanoparticles were prepared via a dialysis method, exhibiting a high drug-loading efficiency of 18.99%. Physicochemical properties of the optimized formulation were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM) and differential scanning calorimetry (DSC). Subsequently, the redox-sensitivity of Hep-cys-TOS nanoparticles was confirmed by the changes in size distribution, morphology and appearance after dithiothreitol (DTT) treatment. Besides, the in vitro release of PTX from Hep-cys-TOS nanoparticles also exhibited a redox-triggered profile. Also, the uptake behavior and pathways of coumarin 6-loaded Hep-cys-TOS nanoparticles were investigated, suggesting the nanoparticles could be taken into MCF-7 cells in energy-dependent, caveolae-mediated and cholesterol-dependent endocytosis manners. Later, MTT assays of different PTX-free and PTX-loaded formulations revealed the desirable safety of PTX-free nanoparticles and the enhanced anti-cancer activity of PTX-loaded Hep-cys-TOS nanoparticles (IC50=0.79µg/mL). Apoptosis study indicated the redox-sensitive formulation could induce more apoptosis of MCF-7 cells than insensitive one (55.2% vs. 41.7%), showing the importance of intracellular burst release of PTX. Subsequently, the hemolytic toxicity confirmed the safety of the nanoparticles for intravenous administration. The results indicated the developed redox-sensitive nanoparticles were promising as intracellular drug delivery vehicles for cancer treatment.
Assuntos
Antineoplásicos/química , Heparina/química , Nanopartículas/química , Paclitaxel/química , alfa-Tocoferol/química , Adipatos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Oxirredução , Paclitaxel/farmacologia , Tamanho da Partícula , Polímeros/químicaRESUMO
Curcumin (Cur), a hydrophobic polyphenolic compound, possesses a wide range of biological activities. However, its prominent application in cancer treatment is limited due to low aqueous solubility and rapid metabolism. Recently, micelle-based drug delivery system has been proven to be an attractive alternative for poorly soluble drugs. In order to improve the application of Cur as an anti-cancer agent, in this study, we synthesized the αvß3 integrin-targeted peptide (RGD) functionalized polymer (RGD-PEG-PLA). The RGD conjugated Cur loaded micelles (Cur-RPP) were prepared using the thin-film hydration method with modification and the preparation process was optimized with a central composite design. The obtained Cur-RPP presented spherical shape with a particle size of 20 nm and high drug loading (4.70%). Compared with the Cur propylene glycol solution, the in vitro release of Cur from the prepared micelles showed the sustained-release property. Cellular uptake of Cur-RPP was found to be higher than that of non-RGD modified micelles due to the binding effect between αvß3 integrin and RGD in human umbilical vein endothelial cells (HUVEC) and mouse melanoma cell lines (B16). In B16 tumor-bearing mice, Cur-RPP showed the stronger inhibiting effect on growth of tumor compared with non-RGD modified micelles. It could be concluded from these results that the RGD modified micelles might be a potential carrier for Cur.
Assuntos
Curcumina/administração & dosagem , Nanocápsulas/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Oligopeptídeos/farmacocinética , Polietilenoglicóis/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Difusão , Masculino , Camundongos , Micelas , Nanocápsulas/química , Nanocompostos/química , Nanocompostos/ultraestrutura , Neoplasias Experimentais/patologia , Oligopeptídeos/química , Resultado do TratamentoRESUMO
Amoitone B is a newly synthesized derivative of antitumor drug cytosporone B, which exhibits excellent anticancer activity in vivo. Nevertheless, the water-insolubility and short biological half-life limit its further development. In the present study, polyethylene glycol-modified, Amoitone B-loaded long circulating nanostructured lipid carriers (AmB-PEG-NLC) were prepared by the emulsion-evaporation and low temperature-solidification method. The in vitro antitumor activity and intracellular uptake of AmB-PEG-NLC in the human colon cancer SW620 cells and liver cancer HepG2 cells were evaluated in detail. MTT assay was employed to investigate the inhibition effect on cellular viability. Propidium iodide and DAPI staining were performed to visually examine the fluorescent morphology changes of the cells incubated with AmB-PEG-NLC. Flow cytometry was utilized to determine the influence of AmB-PEG-NLC on apoptosis of SW620. The intracellular uptake was observed by rhodamine B, a fluorescent maker. Cytotoxicity assay, observation of morphological changes and apoptosis examination revealed that AmB-PEG-NLC could markedly enhance the cytotoxicity of AmB against cancer cell compared to AmB solution and AmB-NLC. An increased uptake of PEG-NLC was obtained compared with NLC in SW620 cells, which might attribute to the effect of PEG. Based on these results, AmB-PEG-NLC could be a promising delivery system for AmB with effective cancer therapy.
Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/química , Fenilacetatos/administração & dosagem , Polietilenoglicóis/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Tamanho da Partícula , Fenilacetatos/farmacocinética , Fenilacetatos/farmacologiaRESUMO
Targeted drug delivery system for tumor cells is an appealing platform on enhancing the therapeutic effects and reducing the side effects of the drug. In this study, we developed folate-modified curcumin (Cur) loaded micelles (Cur-FPPs) for cancer chemotherapy. The targeting material, Folate-PEG3000-PLA2000, was synthesized by the amide bond formation reaction. And the Cur loaded micelles were prepared by thin-film hydration method with mPEG2000-PLA2000 (Cur-PPs) or mPEG2000-PLA2000 and Folate-PEG3000-PLA2000 (Cur-FPPs) as carrier. A central composite design (CCD) was used to optimize the formulation, and the optimized Cur-FPPs was prepared with the weight ratio of Folate-PEG3000-PLA2000 and mPEG2000-PLA2000 at 1:9. The average size of the mixed micelles was 70nm, the encapsulating efficiency and drug-loading were 80.73±0.16% and 4.84±0.01%, respectively. Compared with the Cur propylene glycol solution, the in vitro release of Cur from Cur-FPPs showed a sustained manner. Furthermore, the in vitro cytotoxicity and cellular uptake of Cur-FPPs were significantly enhanced towards MCF-7 and HepG2 cells. The pharmacokinetic studies in rats indicated that a 3-fold increase in the half-life was achieved for Cur loaded micelle formulations relative to solubilized Cur. All the results demonstrated that folate-modified Cur micelles could serve as a potential nanocarrier to improve the solubility and anti-cancer activity of Cur.
Assuntos
Curcumina/uso terapêutico , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Micelas , Neoplasias/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/administração & dosagem , Curcumina/farmacocinética , Curcumina/farmacologia , Endocitose/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Células Hep G2 , Humanos , Irritantes/farmacologia , Ácido Láctico/síntese química , Ácido Láctico/química , Células MCF-7 , Masculino , Microscopia de Fluorescência , Tamanho da Partícula , Poliésteres , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polímeros/síntese química , Polímeros/química , Coelhos , Ratos , Eletricidade Estática , Tensoativos/síntese química , Tensoativos/químicaRESUMO
The aim of the present study is to synthesize Pluronic F127-polyethylenimine-folate (PF127-PEI-FA) copolymer, construct a mixed micelle system with PF127-PEI-FA copolymer and Pluronic P123 (PP123) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel (PTX). The results of intestinal absorption revealed that the PTX-loaded micelles displayed superior permeability across intestinal barrier than free drug and PF127-PEI-FA/PP123 mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cytotoxicity and cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-glycoprotein (P-gp) and enhancement of the electrostatic interaction of positive micelles with the negative intestinal epithelial cells, thereby promoting the permeation across the intestinal wall. The presence of verapamil and Pluronic both improved the intestinal absorption of PTX, which further certified the effect of Pluronic on P-gp inhibition. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC(0â36 h)) of PTX-loaded micelles was three times greater than the PTX solution (dissolved in a 50/50 (vol/vol) mixture of Cremophore EL/dehydrated ethanol) (p < 0.05). In general PF127-PEI-FA/PP123 mixed micelles were proved to be potential oral drug delivery system for PTX.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Portadores de Fármacos/síntese química , Ácido Fólico/análogos & derivados , Paclitaxel/administração & dosagem , Poloxâmero/síntese química , Polietilenoimina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Varredura Diferencial de Calorimetria , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Composição de Medicamentos , Ácido Fólico/síntese química , Ácido Fólico/química , Humanos , Absorção Intestinal , Masculino , Micelas , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Tamanho da Partícula , Poloxâmero/química , Polietilenoimina/síntese química , Polietilenoimina/química , Ratos , Ratos Wistar , Solubilidade , Propriedades de Superfície , Difração de Raios XRESUMO
The aim of this study was to evaluate the pharmacokinetics (PK), tissue distribution, and the specific drug targeting of cefpiramide sodium-loaded liposomes (CPMS-Lips) compared with cefpiramide sodium solution (CPMS-Sol) in mice. CPMS-Lips were prepared by reverse phase evaporation method. In the PK and biodistribution study, mice received a single intravenous (i.v.) injection of 152 mg/kg of either CPMS-Lips or CPMS-Sol. Plasma and tissues were treated using liquid-liquid extraction and determined using reversed-phase high-performance liquid chromatography (RP-HPLC). The results showed that the CPMS-Lips prepared in this study had an average diameter of 7.146 ± 0.29 µm. In the plasma, the bioavailability (F) and the mean residence times (MRT) of the CPMS-Lips were 2.8- and 4.5-fold larger, respectively, than those of CPMS-Sol. CPMS-Lips also showed a significant difference in the tissue distribution profile in mice when compared with the conventional. The value of the intake rate (r(e)) for the lung was 2.97, which was the highest among the tested tissues. Meanwhile, the ratio of targeting efficiency (Te(liposome)/Te(injection)) of lung to that of other tissues for CPMS-Lips elevated significantly. These showed that CPMS-Lips can improve the bioavailability and biodistribution of CPMS in the lung. In conclusion, the liposome was a promising sustained-release and drug-targeting system for antibiotic drugs.
Assuntos
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Sistemas de Liberação de Medicamentos , Pulmão/metabolismo , Animais , Antibacterianos/administração & dosagem , Disponibilidade Biológica , Cefalosporinas/administração & dosagem , Cromatografia Líquida de Alta Pressão , Preparações de Ação Retardada , Feminino , Injeções Intravenosas , Lipossomos , Masculino , Camundongos , Distribuição TecidualRESUMO
Local delivery of antiproliferative drugs encapsulated in biodegradable nanoparticles has shown promise as an experimental strategy for preventing vascular restenosis development. The general aim of this work was to develop polymeric nanoparticle carriers with bioadhesive properties, and to evaluate its adjuvant potential for local, intramural delivery of rapamycin for inhibition of restenosis. The bioadhesive rapamycin-loaded PLGA nanoparticles were obtained by applying carbopol 940 of different concentrations as stabilizer and bioadhesive agent. The resultant nanoparticles were characterized concerning physicochemical properties such as morphology, particle size, zeta potential, entrapment efficiency, drug loading, drug release in vitro, stability in vitro as well as the arterial uptake and retention ability in an ex-vivo model. The results revealed that carbopol could serve as a better stabilizer in the preparation of rapamycin-loaded PLGA nanoparticles compared with PVA, and the physicochemical characteristics of the obtained PLGA nanoparticles were affected by the concentration of carbopol. Furthermore, it was found that carbopol could impart the nanoparticles with bioadhesive properties, improving the rentention and uptake of nanoparticles in the arterial wall, benefiting the nanoparticles for efficient localization of therapeutic agents in restenosis site. Cell viability assay results showed that blank PLGA-carbopol nanoparticles exhibited low toxicity and excellent biocompatibility and rapamycin-loaded nanoparticles with a smaller particle size (< 200 nm) had an increased antiproliferative effect on cells in comparison to free drug. These results indicated that this research might provide a potential experimental basis for the further study of carbopol stabilized bioadhesive nanoparticles against restenosis in vivo.