Alpha interferon loaded chitosan nanoparticles enable the absorption of the protein by the oral route: pharmacokinetic and pharmacodynamic studies

BERINI C; IMPERIALE J; CANEPA C; BIGLIONE M; SOSNIK A

Congreso; Drug discovery for neglected diseases international congress; 2018

ALPHA INTERFERON LOADED CHITOSAN NANOPARTICLES ENABLE THE ABSORPTION OF THE PROTEIN BY THE ORAL ROUTE: PHARMACOKINETIC AND PHARMACODYNAMIC STUDIESCanepa C1, Berini C1, Sosnik A2, Biglione M1, Imperiale J31CONICET ? Universidad de Buenos Aires. Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS). Buenos Aires, Argentina, 2Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, Technion City, Haifa, Israel, 3CONICET - Universidad de Buenos Aires. Instituto de Investigaciones Farmacológicas (ININFA). Buenos Aires, Argentina. julietaimperiale@gmail.comIntroduction. Alpha interferon (αIFN) is a protein drug used to treat viral infections and cancer diseases1. It is reported that this drug is effective against Chikungunya Virus2. Due to its peptidic nature, its administration is viable only parenterally. Moreover, αIFN has a short half-life and a narrow therapeutic index3. Hence, it must be frequently applied in high doses leading to dose-dependent adverse effects that limit its use4. Pegilated αIFN is the derivative marketed because it enables a weekly administration although adverse effects persist5. The objective of this work was to produce an oral drug delivery system (DDS) that allows the drug absorption to eventually replace the parenteral route of administration to a less invasive one.Materials & Methods. αIFN loaded chitosan nanoparticles (αIFN-CT NPs) were prepared by the ionotropic gelation method. αIFN-CT NPs were characterized by dynamic light scattering. The encapsulation efficiency (%EE) of IFNα was indirectly measured using an enzyme-linked immunosorbent assay kit. The antiviral activity of αIFN-CT NPs was determined against Vesicular Stomatitis Virus (VSV) infected MDBK cells. Finally, αIFN-CT NPs were administered orally to BalbC mice (n=6, dose=0.3 MIU) in a single dose to evaluate the pharmacokinetic profile and with three doses per day to determine the pharmacodynamic profile in spleen. Results & Discussion. αIFN-CT NPs showed a size of 36 nm and a Z-Pot of +31.4 mV, which suggest the physical stability of the system. The EE was 95%. The antiviral activity of αIFN-CT NPs was comparable to commercial αIFN, suggesting that the drug conserved its antiviral activity after being loaded into nanoparticles. The in vivo study demonstrated that αIFN was absorbed after being orally administered (AUC=96.6 pg.h/mL). Regarding the pharmacodynamic study, the production of IFNγ and IL-6 was significantly higher than those obtained with the subcutaneous treatment. IL-17 was only identified in those mice treated with orally αIFN-CT NPs while TNFα and IL-12 levels were similar for both, oral αIFN-CT NPs and subcutaneous αIFN. These results suggest that the local production in spleen could provide the systemic circulation of cytokines capable of modulating the immune response.Conclusions. αIFN-CT NPs were successfully produced by gelification method. This DDS enabled the oral absorption of αIFN by the first time. The cytokines levels triggered by αIFN-CT NPs could modulate the immune response. Overall results are promising as a novel strategy to treat Chikungunya infected patients. References.1 Katze MG1, He Y, Gale M Jr. Nat Rev Immunol. 2002;2:675-87.2 Gallegos KM, Drusano GL, D Argenio DZ, Brown AN. J Infect Dis. 2016;214:1192-7.3 Shechter Y, Preciado-Patt L, Schreiber G, Fridkin M. Proc Natl Acad Sci U S A. 2001;98:1212-7.4 Sleijfer S, Bannink M, Van Gool AR, Kruit WH, Stoter G. Pharm World Sci. 2005;27:423-31.5 Matthews SJ, McCoy C. Clin Ther. 2004;26:991-1025.