Extremely short bioavailability and fast pharmacodynamic effects of pMHC-based nanomedicines.
J Control Release
; 338: 557-570, 2021 10 10.
Article
en En
| MEDLINE
| ID: mdl-34474072
ABSTRACT
Nanoparticles (NPs) coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHCs) can blunt autoimmune diseases by re-programming cognate effector T-lymphocytes into disease-suppressing regulatory T-cells, followed by massive expansion. Here, a method to quantify the absolute amounts of the active drug product is developed, to understand the relationship between bioavailability and pharmacodynamics. Incubation with plasma results in the formation of a protein corona that stabilizes the directional pMHC coat, shielding it from proteolysis or anti-drug antibody recognition, without any appreciable loss in biological potency. A quantitative method that harnesses these features indicates that the half-life of these compounds in the circulation and organs is an order of magnitude shorter (minutes vs. hours) than that measured using commonly-used semi-quantitative methods. Extensive transmission electron microscopy-based organ scanning and flow cytometry-based enumeration of pMHCII-NP capturing cells confirmed that these compounds are rapidly captured (within 1 min) by liver sinusoidal endothelial cells, Kupffer cells, splenic phagocytes and cognate T-cells, leading to a fast decline in the circulation. Therefore, the powerful pharmacodynamic effects of these compounds are dissociated from long bioavailability, implying a hit-and-run event. Collectively, these data provide a detailed view of the life-cycle of a nanoimmunomedicine, and suggest that the real half-lives of intact nanomedicines may be much shorter than those estimated using indirect approaches.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Enfermedades Autoinmunes
/
Nanomedicina
Límite:
Humans
Idioma:
En
Revista:
J Control Release
Asunto de la revista:
FARMACOLOGIA
Año:
2021
Tipo del documento:
Article