A predictive pharmacokinetic model for immune cell-mediated uptake and retention of nanoparticles in tumors
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2022
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Resumo
A promise of cancer nanomedicine is the “targeted” delivery of therapeutic agents to tumors
by the rational design of nanostructured materials. During the past several decades, a realization
that in vitro and in vivo preclinical data are unreliable predictors of successful clinical translation
has motivated a reexamination of this approach. Mathematical models of drug pharmacokinetics
(PK) and biodistribution (BD) are essential tools for small-molecule drugs development. A key
assumption underlying these models is that drug-target binding kinetics dominate blood clearance,
hence recognition by host innate immune cells is not explicitly included. Nanoparticles circulating in
the blood are conspicuous to phagocytes, and inevitable interactions typically trigger active biological
responses to sequester and remove them from circulation. Our recent findings suggest that, instead
of referring to nanoparticles as designed for active or passive “tumor targeting”, we ought rather to
refer to immune cells residing in the tumor microenvironment (TME) as active or passive actors in
an essentially “cell-mediated tumor retention” process that competes with active removal by other
phagocytes. Indeed, following intravenous injection, nanoparticles induce changes in the immune
compartment of the TME because of nanoparticle uptake, irrespective of the nature of tumor targeting
moieties. In this study, we propose a 6-compartment PK model as an initial mathematical framework
for modeling this tumor-associated immune cell-mediated retention. Published in vivo PK and BD
results obtained with bionized nanoferrite® (BNF®) nanoparticles were combined with results from
in vitro internalization experiments with murine macrophages to guide simulations. As a preliminary
approximation, we assumed that tumor-associated macrophages (TAMs) are solely responsible for
active retention in the TME. We model the TAM approximation by relating in vitro macrophage
uptake to an effective macrophage avidity term for the BNF® nanoparticles under consideration.
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Cancer nanomedicine, Tumor microenvironment, Targeted delivery, Tumor targeting, Immune cell interactions, Iron oxide nanoparticles, Macrophages
Citação
SOUSA-JUNIOR, Ailton; CHUN-TING, Yang; KORANGATH, Preethi; IVKOV, Robert; BAKUZIS, Andris. A predictive pharmacokinetic model for immune cell-mediated uptake and retention of nanoparticles in tumors. International Journal of Molecular Sciences, London, v. 23, n. 4, e15664, 2022. DOI: 10.3390/ijms232415664. Disponível em: https://www-ncbi-nlm-nih.ez49.periodicos.capes.gov.br/pmc/articles/PMC9779081/pdf/ijms-23-15664.pdf. Acesso em: 11 abr. 2023.