Oral Pharmacokinetics of a Chitosan-Based Nano- Drug Delivery System of Interferon Alpha

Abstract: Interferon alpha (IFN) is a protein drug used to treat viral infections and cancer diseases. Dueto its poor stability in the gastrointestinal tract, only parenteral administration ensures bioavailability,which is associated with severe side eects. We hypothesized that the nanoencapsulation ofIFN within nanoparticles of the mucoadhesive polysaccharide chitosan would improve theoral bioavailability of this drug. In this work, we produced IFN-loaded chitosan nanoparticlesby the ionotropic gelation method. Their hydrodynamic diameter, polydispersity index andconcentration were characterized by dynamic light scattering and nanoparticle tracking analysis.After confirming their good cell compatibility in Caco-2 and WISH cells, the permeability ofunmodified and poly(ethylene glycol) (PEG)-modified (PEGylated) nanoparticles was measured inmonoculture (Caco-2) and co-culture (Caco-2/HT29-MTX) cell monolayers. Results indicated thatthe nanoparticles cross the intestinal epithelium mainly by the paracellular route. Finally, the studyof the oral pharmacokinetics of nanoencapsulated IFN in BalbC mice revealed two maxima andarea-under-the-curve of 56.9 pg*h/mL.Fil: Imperiale, Julieta Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Schlachet, Inbar. Technion - Israel Institute of Technology; IsraelFil: Lewicki, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Sosnik, Alejandro Dario. Technion - Israel Institute of Technology; IsraelFil: Biglione, Mirna Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin

Long term bone alterations in aged rats suffering type 1 diabetes

Increasing duration of type 1 diabetes mellitus alters bone metabolism. Clinical studies and experimental studies in long bones of rats with experimentally induced diabetes have reported a decrease in bone density. Few studies have explored this diabetes related alteration in the maxillae. Given that this finding could indicate the possible development of osteopenia in the maxilla in the long term, the present study sought to analyze alterations in alveolar bone in aged rats, 12, 18, and 24 weeks after inducing diabetes, and compare alveolar bone response to that of tibial subchondral bone at the same experimental times. Thirty-six male Wistar rats, 130 g body weight, were divided into 2 groups: an experimental group (E) receiving a single i.p. 60 mg/kg dose of streptozotocin, and a control group (C). Both the control and experimental groups were divided into 3 sub-sets, according to the time of euthanasia: 12, 18 and 24 weeks. The alveolar bone and tibiae were examined histologically and histomorphometrically. The results were analyzed using Student's t-test; a value of p < 0.05 was considered statistically significant. Results: Subchondral bone volume and bone activity/remodeling, mainly bone rest, were significantly lower in diabetic animals compared to controls, at both 12 and 18 weeks. No differences in alveolar bone parameters were observed between diabetic and control animals at either of the experimental times. Animals surviving at 24 weeks showed few trabeculae at rest and severe destruction of dental and periodontal tissues. The results of the present study show that diabetic osteopenia is evident in the tibia at 12 and at 18 weeks, whereas its effects on the maxilla can be seen at 24 weeks, with substantial destruction of alveolar bone and of the remaining periodontal and dental tissues. All the above observations highlight the need for preventive oral care in diabetic patients, before irreversible damage to dental and periodontal tissues occurs.Fil: Sánchez, Luciana Marina. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: de Lucca, Romina Carmen. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Lewicki, Marianela. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ubios, Angela Matilde. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Development of a Drug Delivery System Based on Chitosan Nanoparticles for Oral Administration of Interferon‑α

Despite the good clinical efficacy of interferon-alpha (IFNα) to treat some types of cancer and viral infections, this biological drug is underused given its severe adverse effects and high dosing parenteral regimens. Aiming to achieve a breakthrough in therapy with IFNα, this work reports for the first time on the design and full characterization of a novel nanomedicine of IFNα-2b-loaded chitosan nanoparticles (IFN-CT NPs) for oral delivery. IFN-CT NPs produced by ionotropic gelation, encapsulating approximately 100% of the drug, showed a size of 36 ± 8 nm, zeta potential of +30 mV (dynamic light scattering), and spherical morphology (transmission electron microscopy). The antiviral activity of IFN-CT NPs in vitro was comparable to that of commercial IFNα. Remarkably, both treatments stimulated the expression of IFN response genes to a similar extent in both noninfected and infected cells with Human Lymphotropic-T Virus type 1. Finally, oral administration of IFN-CT NPs (0.3 MIU) to CF1 mice showed detectable levels of IFNα in plasma after 1 h, whereas no IFNα was detected with a commercial formulation. These results are encouraging and open a new avenue for the administration of this biological drug in a minimally invasive, safer, and more patient-compliant way

Development of a Drug Delivery System Based on Chitosan Nanoparticles for Oral Administration of Interferon‑α

Despite the good clinical efficacy of interferon-alpha (IFNα) to treat some types of cancer and viral infections, this biological drug is underused given its severe adverse effects and high dosing parenteral regimens. Aiming to achieve a breakthrough in therapy with IFNα, this work reports for the first time on the design and full characterization of a novel nanomedicine of IFNα-2b-loaded chitosan nanoparticles (IFN-CT NPs) for oral delivery. IFN-CT NPs produced by ionotropic gelation, encapsulating approximately 100% of the drug, showed a size of 36 ± 8 nm, zeta potential of +30 mV (dynamic light scattering), and spherical morphology (transmission electron microscopy). The antiviral activity of IFN-CT NPs in vitro was comparable to that of commercial IFNα. Remarkably, both treatments stimulated the expression of IFN response genes to a similar extent in both noninfected and infected cells with Human Lymphotropic-T Virus type 1. Finally, oral administration of IFN-CT NPs (0.3 MIU) to CF1 mice showed detectable levels of IFNα in plasma after 1 h, whereas no IFNα was detected with a commercial formulation. These results are encouraging and open a new avenue for the administration of this biological drug in a minimally invasive, safer, and more patient-compliant way

Experimental model of distraction osteogenesis in edentulous rats

Distraction osteogenesis (DO) is a surgical technique producing bone lengthening by distraction of the fracture callus. Although a large number of experimental studies on the events associated with DO of craniofacial skeleton have been reported, the few employing rat mandibular bone DO used complicated designs and produced a small volume of newly formed bone. Thus, this study aims to present an original experimental model of mandibular DO in edentulous rats that produces a sufficient quantity and quality of intramembranous bone. Eight male Wistar rats, weighing 75 g, underwent extraction of lower molars. With rats weighing 350 g, right mandibular osteotomy was performed and the distraction device was placed. The distraction device was custom made using micro-implants, expansion screws, and acrylic resin. Study protocol: latency: 6 days, distraction: ¼ turn (0.175 mm) once a day during 6 d, consolidation: 28 d after distraction phase, sacrifice. DO-treated and contralateral hemimandibles were dissected and compared macroscopically and using radiographic studies. Histological sections were obtained and stained with H&E. A distraction gap filled with newly formed and mature bone tissue was obtained. This model of mandibular DO proved useful to obtain adequate quantity and quality of bone to study bone regeneration