Nose-to-brain co-delivery of drugs for glioblastoma treatment using nanostructured system

Mutations on the epidermal growth factor receptor (EGFR), induction of angiogenesis, and reprogramming cellular energetics are all biological features acquired by tumor cells during tumor development, and also known as the hallmarks of cancer. Targeted therapies that combine drugs that are capable of acting against such concepts are of great interest, since they can potentially improve the therapeutic efficacy of treatments of complex pathologies, such as glioblastoma (GBM). However, the anatomical location and biological behavior of this neoplasm imposes great challenges for targeted therapies. A novel strategy that combines alpha-cyano-4-hydroxycinnamic acid (CHC) with the monoclonal antibody cetuximab (CTX), both carried onto a nanotechnology-based delivery system, is herein proposed for GBM treatment via nose-to-brain delivery. The biological performance of Poly (D,L-lactic-co-glycolic acid)/chitosan nanoparticles (NP), loaded with CHC, and conjugated with CTX by covalent bonds (conjugated NP) were extensively investigated. The NP platforms were able to control CHC release, indicating that drug release was driven by the Weibull model. An ex vivo study with nasal porcine mucosa demonstrated the capability of these systems to promote CHC and CTX permeation. Blot analysis confirmed that CTX, covalently associated to NP, impairs EGRF activation. The chicken chorioallantoic membrane assay demonstrated a trend of tumor reduction when conjugated NP were employed. Finally, images acquired by fluorescence tomography evidenced that the developed nanoplatform was effective in enabling nose-to-brain transport upon nasal administration. In conclusion, the developed delivery system exhibited suitability as an effective novel co-delivery approaches for GBM treatment upon intranasal administration.School of Pharmaceutical Science São Paulo State University UNESP, Rodovia Araraquara/Jaú Km 01Laboratório de Nanotecnologia Farmacêutica e Sistemas de Liberação de Fármacos FarmaTec Faculdade de Farmácia Universidade Federal de Goiás - UFG, 5ª Avenida c/Rua 240 s/n, Praça UniversitáriaLife and Health Sciences Research Institute (ICVS) School of Medicine University of MinhoICVS/3B's-PT Government Associate LaboratoryMolecular Oncology Research Center Barretos Cancer HospitalSchool of Pharmaceutical Science São Paulo State University UNESP, Rodovia Araraquara/Jaú Km 0

Antibody response in cattle after vaccination with inactivated and attenuated rabies vaccines Resposta imune humoral anti-rábica em bovinos imunizados com vacina inativada e atenuada

Despite the absence of current official reports showing the number of cattle infected by rabies, it is estimated that nearly 30,000 bovines are lost each year in Brazil. In order to minimize the important economic losses, control of the disease is achieved by eliminating bat colonies and by herd vaccination. In this study, we compare the antibody response in cattle elicited by vaccination with an attenuated ERA vaccine (AEvac) and an inactivated-adjuvanted PV (IPVvac) vaccine. The antibody titers were appraised by cell-culture neutralization test and ELISA, and the percentage of seropositivity was ascertained for a period of 180 days. IPVvac elicited complete seropositivity rates from day 30 to day 150, and even on day 180, 87% of the sera showed virus-neutralizing antibody titers (VNA) higher than 0.5IU/ml. There were no significant differences between the VNA titers and seropositivity rates obtained with IPVvac in the two methods tested. AEvac, however, elicited significantly lower titers than those observed in the group receiving inactivated vaccine. In addition, the profiles of antirabies IgG antibodies, evaluated by ELISA, and VNA, appraised by cell-culture neutralization test, were slightly different, when both vaccines were compared.<br>A raiva bovina, transmitida principalmente pelo morcego hematófago Desmodus rotundus, é endêmica em várias regiões do Brasil, com um crescente número de casos sendo registrados anualmente. O controle desta infecção em bovinos é feito pelo controle de colônias de morcegos hematófagos e pela vacinação dos rebanhos. Embora as vacinas inativadas sejam mais seguras e mais estáveis que as vacinas atenuadas, estas últimas são ainda amplamente utilizadas em muitas regiões do país, por se acreditar que confiram imunidade mais duradoura. Neste estudo, foram comparadas as respostas anticórpicas de dois grupos de bovinos imunizados com uma vacina atenuada e uma inativada disponíveis comercialmente. Os anticorpos anti-rábicos neutralizantes (AcN) foram titulados pela técnica de soroneutralização em cultura de células BHK-21, enquanto que os níveis de anticorpos anti-rábicos totais (IgG) foram avaliados pela técnica de ELISA, por um período de 180 dias. A vacina inativada induziu a soroconversão (AcN 3 0,5 UI/ml) em 100% dos animais no dia 30, mantendo-se assim até o 150o dia; no dia 180, 87% dos animais ainda mostravam-se com títulos de AcN 3 0,5 UI/ml. Neste grupo, os níveis de IgG anti-rábicas foram semelhantes aos de AcN. A vacina atenuada, no entanto, induziu títulos de AcN e de IgG significantemente menores que os encontrados com a vacina inativada, com consequente diminuição da taxa de soropositividade. Além disso, ao contrário do verificado com a vacina inativada, o perfil de AcN não teve paralelismo com o de anticorpos IgG quando soros foram testados pela técnica de soroneutralização e pelo ELISA, respectivamente

Delaying Effect of Cementite on Recrystallization Kinetics of a Ti-Nb Microalloyed High-Formability Steel

International audienceAnnealing of cold-rolled high-strength steels leads to various microstructural changes such as recrystallization, cementite precipitation, microalloying elements precipitation and austenite formation. These transformations are expected to interact with each other. Understanding how and where austenite forms in a microstructure is of prime importance to avoid formation of banded microstructures, which are detrimental to good in-use properties. In this work, a mean-field model is used to simulate concomitant recrystallization, cementite precipitation, microalloying elements precipitation and austenite formation kinetics, as well as their interactions during 1 and 10 °C/s heating. Excellent agreement with experimental data is obtained only if cementite pinning effect on recrystallized grain boundaries is considered. It is shown that cementite exhibits a much stronger delaying effect on recrystallization kinetics than microalloying elements, leading to the formation of banded microstructures. Carbon nominal content of a steel appears to be the most important parameter to acknowledge to understand recrystallization kinetics