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

Abstract

Interferon alpha (IFNα) is a protein drug used to treat viral infections and cancer diseases. Due to its poor stability in the gastrointestinal tract, only parenteral administration ensures bioavailability, which is associated with severe side effects. We hypothesized that the nanoencapsulation of IFNα within nanoparticles of the mucoadhesive polysaccharide chitosan would improve the oral bioavailability of this drug. In this work, we produced IFNα-loaded chitosan nanoparticles by the ionotropic gelation method. Their hydrodynamic diameter, polydispersity index and concentration were characterized by dynamic light scattering and nanoparticle tracking analysis. After confirming their good cell compatibility in Caco-2 and WISH cells, the permeability of unmodified and poly(ethylene glycol) (PEG)-modified (PEGylated) nanoparticles was measured in monoculture (Caco-2) and co-culture (Caco-2/HT29-MTX) cell monolayers. Results indicated that the nanoparticles cross the intestinal epithelium mainly by the paracellular route. Finally, the study of the oral pharmacokinetics of nanoencapsulated IFNα in BalbC mice revealed two maxima and area-under-the-curve of 56.9 pg*h/mL.

Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems

“…Ling Tan et al [ 125 ] used chitosan-coated nanoparticles to deliver amphotericin B and found an improvement in GI retention when compared to similar uncoated nanoparticles (63.9% and 56.1%, respectively). Imperiale et al [ 126 ] used chitosan-based nanoparticles to deliver the protein drug interferon alpha, and found that the AUC (56 pg h/mL) and plasma concentration of the drug after 30 min (48.4 pg/mL) approximated that of subcutaneous injection. Murthy et al [ 127 ] used self-assembled lecithin-chitosan nanoparticles to deliver raloxifene and found a ~ 4.2-fold increase in oral bioavailability when compared to a raloxifene suspension.…”

Forms and Methods for Interferon's Encapsulation

“…encapsulated PEG-IFNα-2a in PEG-PLGA nanoparticles that released the cytokine in a sustained manner for four days in vitro[136]. In 2017, Cánepa et al synthesized chitosan nanoparticles that exhibited comparable antiviral activity to commercial IFNα in in vitro models.In the same study, preliminary in vivo assays in a CF1 mouse murine model showed that the molecule was detectable in the blood after one hour of oral administration of the formulation[109].Imperiale et al complemented this study in 2019 by demonstrating that the system provided bioavailability comparable to intravenously administered IFNα-2b in murine BALB/c mouse models[110].Kristó et al (2020) developed a nanoparticle with a core/shell structure, whose core was composed of IFNα associated with human serum albumin, and the shell was constituted by three consecutive layers of polystyrene-chitosanpolystyrene sulfonate-sulfonate, respectively. This system exhibited sustained release for ten days without reducing cytokine biological activity in a higher organism (Pannon rabbits)[111].IFNßFodor-Kardos et al in 2020 reported the first IFNß nanoencapsulation procedure.…”

The role of nanotechnology in current COVID-19 outbreak

“…It can be functionalized by digalactosyl diacyl glycerol, a natural glycolipid to selectively interact with the asialofetuin receptor of liver hepatocytes. Other examples are PegIntron® and Pegasys® as two FDA approved polymeric NPs containing PEG-interferon alfa-2b and PEG-interferon alfa-2a, respectively and chitosan NPs for the oral delivery of IFNα [ 56 , 59 ]; combination therapy of lopinavir/ritonavir/tenofovir by lipid nanoparticles composed of DSPC + MPEG + DSPE also introduced, although, a combination of Lopinavir/ritonavir has been suggested [ 60 ]. Combination therapy using nanomedicine not only increase the therapeutic effects induced by synergistic effects of drugs but also minimized the effective dose of drugs.…”

“…However, the patients are more compatible with the oral administration of the injection [ 56 ]. Some other nanoplatforms that have been applied to produce interferon are a derivate of chitosan NPs [ 25 , 56 , 59 , 83 ], Fe3O4 NPs [ 84 ], Disulfide-based PEGylatednanogels [ 85 ], CD44-targeted glutathione-sensitive hyaluronic acid-mercaptopurine prodrug (HA-GS-MP) [ 86 ],Nanoliposomes [ 87 ], Sirolimus nanocomposites [ 88 ], Sirolimus Nanocrystals [ 89 ] and Calcium phosphate (CaP) NP-based vaccine carrier functionalized with CpG and viral peptides [ 90 ]. These NPs can encapsulate biomaterials and drugs that induce interferon-α.…”