Emerging Role of the Spleen in the Pharmacokinetics of Monoclonal Antibodies, Nanoparticles and Exosomes

Abstract

After being absorbed, drugs distribute in the body in part to reach target tissues, in part to be disposed in tissues where they do not exert clinically-relevant effects. Therapeutically-relevant effects are usually terminated by drug metabolism and/or elimination. The role that has been traditionally ascribed to the spleen in these fundamental pharmacokinetic processes was definitely marginal. However, due to its high blood flow and to the characteristics of its microcirculation, this organ would be expected to be significantly exposed to large, new generation drugs that can hardly penetrate in other tissues with tight endothelial barriers. In the present review, we examine the involvement of the spleen in the disposition of monoclonal antibodies, nanoparticles and exosomes and the possible implications for their therapeutic efficacy and toxicity. The data that we will review lead to the conclusion that a new role is emerging for the spleen in the pharmacokinetics of new generation drugs, hence suggesting that this small, neglected organ will certainly deserve stronger attention by pharmacologists in the future.

Conjugate of Doxorubicin to Albumin‐Binding Peptide Outperforms Aldoxorubicin

“…No significant difference was observed between the AUC of ABD–Dox and free Dox in other tissues (Figure B). The lower AUC of ABD–Dox than free Dox in the spleen is consistent with the ability of albumin to reduce opsonization, which reduces subsequent uptake by macrophages that are present at a high level in the spleen, while also directing cellular uptake of albumin and its conjugates via FcRn receptors in the liver and spleen that then recycle albumin in these organs back into the systemic circulation. The markedly high accumulation of AlDox in lungs compared with ABD–Dox is likely, we speculate, due to the its nonspecific binding to the cysteines and lysines on blood cells such as red blood cells that have been previously reported to increase the accumulation of nanocarriers absorbed on their surface into the lungs .…”

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

“…Such a lack of rescue from FcR blockade in NSG mice xenografts may be attributed to the relatively high radiosensitivity of this strain due to a mutation in the Prkdc gene that is implicated in DNA repair (39, 40). Arguably, the highly perfused anatomy of the spleen and bone marrow combined with the acute radiosensitivity of hematopoietic cells therein might be sufficient to ablate them during the transient passage of radiolabeled antibodies through these sites despite FcR blockade in highly immunodeficient mice (41). Notably, NSG xenograft mice that were injected with imaging doses of deglycosylated or Fc-silent 89 Zr-labeled hSC16 were ultimately moribund by the end of 3 weeks post-injection of the radiotracer.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics and as a Drug Delivery Platform

“…Mostly homes to the liver and spleen, and surface engineering of exosomes can induce targeting ability …”