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

Abstract

Alpha interferon (αIFN) is a protein drug used to treat viral infections and cancer diseases [1]. It is reported that thisdrug is effective against Chikungunya Virus [2]. Due to its peptidic nature, its administration is viable only parenterally.Moreover, αIFN has a short half-life and a narrow therapeutic index [3]. Hence, it must be frequently applied in highdoses leading to dose-dependent adverse effects that limit its use [4]. Pegylated αIFN is the derivative marketedbecause it enables a weekly administration although adverse effects persist [5]. The objective of this work was toproduce an oral drug delivery system (DDS) that allows the drug absorption to eventually replace the parenteral routeof administration to a less invasive one.αIFN loaded chitosan nanoparticles (αIFN-CT NPs) were prepared by the ionotropic gelation method. αIFN-CT NPswere characterized by dynamic light scattering. The encapsulation efficiency (%EE) of IFNα was indirectly measuredusing an enzyme-linked immunosorbent assay kit. The antiviral activity of αIFN-CT NPs was determined againstVesicular 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 thepharmacodynamic profile in spleen.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 EEwas 95%. The antiviral activity of αIFN-CT NPs was comparable to commercial αIFN, suggesting that the drug conservedits antiviral activity after being loaded into nanoparticles. The in vivo study demonstrated that αIFN was absorbedafter being orally administered (AUC = 96.6 pg.h/mL). Regarding the pharmacodynamic study, the production of IFNγand IL-6 was significantly higher than those obtained with the subcutaneous treatment. IL-17 was only identified inthose mice treated with orally αIFN-CT NPs while TNFα and IL-12 levels were similar for both, oral αIFN-CT NPs andsubcutaneous αIFN. These results suggest that the local production in spleen could provide the systemic circulation ofcytokines capable of modulating the immune response.αIFN-CT NPs were successfully produced by gelification method. This DDS enabled the oral absorption of αIFN by thefirst time. The cytokines levels triggered by αIFN-CT NPs could modulate the immune response. Overall results arepromising as a novel strategy to treat Chikungunya infected patients.