RESUMEN

Bone-metastatic prostate cancer symbolizes the beginning of the later stages of the disease. We designed a cabazitaxel-loaded, poly (lactic-co-glycolic acid) (PLGA) nanoparticle using an emulsion-diffusion-evaporation technique. Bis (sulfosuccinimidyl) suberate (BS3) was non-covalently inserted into the nanoparticle as a linker for the conjugation of a bone-targeting moiety to the outside of the nanoparticle. We hypothesized that the nanoparticles would have the ability to inhibit the epithelial-to-mesenchymal transition (EMT), invasion, and migration in prostate cancer cells. Targeted, cabazitaxel-loaded nanoparticles attenuated the EMT marker, Vimentin, and led to an increased E-cadherin expression. These changes impart epithelial characteristics and inhibit invasive properties in cancer progression. Consequently, progression to distant sites is also mitigated. We observed the reduction of phosphorylated Src at tyrosine 416, along with increased expression of phosphorylated cofilin at serine 3. These changes could affect migration and invasion pathways in cancer cells. Both increased p-120 catenin and inhibition in IL-8 expression were seen in targeted, cabazitaxel-loaded nanoparticles. Overall, our data show that the targeted, cabazitaxel-loaded nanoparticles can act as a promising treatment for metastatic prostate cancer by inhibiting EMT, invasion, and migration, in prostate cancer cells.

RESUMEN

Ischemic stroke is a cerebrovascular disease normally caused by interrupted blood supply to the brain. Ischemia would initiate the cascade reaction consisted of multiple biochemical events in the damaged areas of the brain, where the ischemic cascade eventually leads to cell death and brain infarction. Extensive researches focusing on different stages of the cascade reaction have been conducted with the aim of curing ischemic stroke. However, traditional treatment methods based on antithrombotic therapy and neuroprotective therapy are greatly limited for their poor safety and treatment efficacy. Nanomedicine provides new possibilities for treating stroke as they could improve the pharmacokinetic behavior of drugs in vivo, achieve effective drug accumulation at the target site, enhance the therapeutic effect and meanwhile reduce the side effect. In this review, we comprehensively describe the pathophysiology of stroke, traditional treatment strategies and emerging nanomedicines, summarize the barriers and methods for transporting nanomedicine to the lesions, and illustrate the latest progress of nanomedicine in treating ischemic stroke, with a view to providing a new feasible path for the treatment of cerebral ischemia.

RESUMEN

Vaccine developmental strategies are utilizing antigens encapsulated in biodegradable polymeric nanoparticles. Here, we developed a Chlamydia nanovaccine (PLGA-rMOMP) by encapsulating its recombinant major outer membrane protein (rMOMP) in the extended-releasing and self-adjuvanting PLGA [poly (D, L-lactide-co-glycolide) (85:15)] nanoparticles. PLGA-rMOMP was small (nanometer size), round and smooth, thermally stable, and exhibited a sustained release of rMOMP. Stimulation of mouse primary dendritic cells (DCs) with PLGA-rMOMP augmented endosome processing, induced Th1 cytokines (IL-6 and IL-12p40), and expression of MHC-II and co-stimulatory (CD40, CD80, and CD86) molecules. BALB/c mice immunized with PLGA-rMOMP produced enhanced CD4+ T-cells-derived memory (CD44high CD62Lhigh), and effector (CD44high CD62Llow) phenotypes and functional antigen-specific serum IgG antibodies. In vivo biodistribution of PLGA-rMOMP revealed its localization within lymph nodes, suggesting migration from the injection site via DCs. Our data provide evidence that the PLGA (85:15) nanovaccine activates DCs and augments Chlamydia-specific rMOMP adaptive immune responses that are worthy of efficacy testing.

Asunto(s)

Inmunidad Adaptativa/genética , Proteínas de la Membrana Bacteriana Externa/genética , Nanopartículas/química , Vacunas/inmunología , Inmunidad Adaptativa/inmunología , Animales , Proteínas de la Membrana Bacteriana Externa/inmunología , Antígenos CD4/química , Antígenos CD4/inmunología , Chlamydia/genética , Chlamydia/inmunología , Chlamydia/patogenicidad , Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Receptores de Hialuranos/química , Receptores de Hialuranos/inmunología , Subunidad p40 de la Interleucina-12/genética , Subunidad p40 de la Interleucina-12/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Selectina L/química , Selectina L/inmunología , Ratones , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/inmunología , Linfocitos T/inmunología , Vacunas/genética

RESUMEN

PURPOSE: Amikacin, a water-soluble aminoglycoside antibiotic used to treat gram-negative bacillary infections, is a Biopharmaceutics Classification System class III drug having poor permeability and short half-life. It is given parenterally, which limits its use in patients warranting "at-home care." An oral drug delivery of amikacin is, therefore, imminent. AIM: This work focused on establishing poly d, l-lactide-co-glycolide (PLGA)-based nanoparticles of amikacin with consolidated pharmaceutical attributes capable of circumventing gastrointestinal tract membrane barriers and promoting oral administration of the drug. The partied attributes are suggestive of enhanced uptake of the drug via Peyer's patches overlaying small intestine and support successful oral delivery. MATERIALS AND METHODS: To have a robust delivery system, a statistical Box-Behnken experimental design was used and formulation parameters such as homogenization time, probe sonication time, and drug/polymer ratio of amikacin-loaded PLGA nanoparticles (A-NPs) for obtaining monodispersed nanoparticles of adequate size and high drug loading were optimized. RESULTS: The model suggested to use the optimum homogenization time, probe sonication time, and drug/polymer ratio as 30 s, 120 s, and 1:10, respectively. Under these formulation conditions, the particle size was found to be 260.3 nm and the drug loading was 3.645%. CONCLUSION: Biodegradable PLGA nanoparticulate systems with high payload, optimum size, and low polydispersity index will ensure successful uptake and ultimately leading to better bioavailability. Hence, under the aforementioned optimized conditions, the A-NPs prepared had particle size of 260.3 nm, which is appreciable for its permeability across small intestine, and drug loading of 3.645%.

RESUMEN

Liver cancer is a leading cause of death related to cancer worldwide. Poly(d-l-lactide-co-glycolide) (PLGA) nanoparticles provide prolonged blood residence time and sustained drug release, desirable for cancer treatment. To achieve this, we have developed paclitaxel-loaded PLGA nanoparticles by emulsification solvent evaporation method and evaluated by in vitro and in vivo studies. The results obtained from in vitro study showed that drug loading efficiency was 84.25% with an initial burst release followed by sustained drug release. Cellular uptake and in vitro cytotoxicity of the formulated nanoparticles using HepG2, Huh-7 cancer cells and Chang liver cells were also investigated. The formulated nanoparticles showed more cytotoxic effect at lower concentration and were internalized well by HepG2 cells compared to free-drug and marketed formulation. Prolonged half-life and higher plasma and liver drug concentrations of the formulated nanoparticles were observed as compared to free drug and marketed formulation in rats. Thus, paclitaxel-loaded polymeric nanoparticle has shown its potential for the treatment of liver cancer.

Asunto(s)

Sistemas de Liberación de Medicamentos , Ácido Láctico/química , Hígado/metabolismo , Nanopartículas/química , Paclitaxel/farmacocinética , Ácido Poliglicólico/química , Animales , Rastreo Diferencial de Calorimetría , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Células Hep G2 , Humanos , Hidrólisis , Cinética , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Nanopartículas/ultraestructura , Paclitaxel/administración & dosificación , Paclitaxel/sangre , Paclitaxel/farmacología , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ratas Sprague-Dawley , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Distribución Tisular/efectos de los fármacos

RESUMEN

Effective chemotherapy remains an important issue in the treatment of drug resistant cancer. The aim of the present study was to establish novel polymeric nanoparticles composed of the antitumor drug, doxorubicin (DOX), and an inhibitor of the drug efflux pump-associated protein, P-glycoprotein (P-gp), in order to overcome drug resistance in tumor cells. Poly(D,L-lactide-co-glycolide) (PLGA), DOX-loaded PLGA (PLGA-DOX), P-gp inhibitor (cyclosporin A; CsA)-coated PLGA (PLGA-CsA) and DOX and CsA co-loaded PLGA (PLGA-DOX-CsA) nanoparticles were prepared using solvent evaporation. The size distribution, ζ potential and electron microscopy observations of the nanoparticles were characterized. Accumulation and efflux assays were performed using confocal and fluorescence-activated cell sorting (FACS), and the pump activity of P-gp was detected through FACS. The uptake of the nanoparticles and the viability of Taxol-resistant A549 cells treated with various nanoparticles were analyzed via FACS in vitro. Furthermore, the tumor growth and survival rates of A549-Taxol-bearing mice were monitored in vivo. Prepared particles were nanosized and the efflux rates of PLGA-DOX and PLGA-DOX-CsA were significantly decreased compared with the free DOX. Drug efflux pump activity was effectively inhibited by the PLGA-CsA and PLGA-DOX-CsA groups compared with the PLGA, PLGA-DOX and free DOX groups. Cell viability results demonstrated that PLGA-DOX and PLGA-DOX-CsA induced the increased death of A549-Taxol cells. In vivo tumor models demonstrated that PLGA-DOX and PLGA-DOX-CsA markedly inhibited the tumor growth and improved the survival rate of A549-Taxol-bearing mice. Antitumor drug and drug efflux pump inhibitor co-loaded nanoparticles offer advantages to overcome the drug resistance of tumors and highlight new therapeutic strategies to control drug resistant tumors.