Formulating a TMEM176B blocker in chitosan nanoparticles uncouples its paradoxical roles in innate and adaptive antitumoral immunity

Dublin Core

Title

Formulating a TMEM176B blocker in chitosan nanoparticles uncouples its paradoxical roles in innate and adaptive antitumoral immunity

Subject

NANOPARTICULAS
QUITOSANO
TMEM176B
INFLAMASOMA
INMUNIDAD TUMORAL
NANOENCAPSULACION
BIBLIOGRAFIA NACIONAL QUIMICA
2024

Abstract

The immunoregulatory cation channel TMEM176B plays a dual role in tumor immunity. On the one hand, TMEM176B promotes antigen cross-presentation to CD8+ T cells by regulating phagosomal pH in dendritic cells (DCs). On the other hand, it inhibits NLRP3 inflammasome activation through ionic mechanisms in DCs, monocytes and macrophages. We speculated that formulating BayK8644 in PEGylated chitosan nanoparticles (NP-PEG-BayK8644) should slowly release the compound and by that mean avoid cross-presentation inhibition (which happens with a fast 30 min kinetics) while still triggering inflammasome activation. Chitosan nanocarriers were successfully obtained, exhibiting a particle size within the range of 200 nm; they had a high positive surface charge and a 99 % encapsulation efficiency. In in vitro studies, NP-PEG-BayK8644 did not inhibit antigen cross-presentation by DCs, unlike the free compound. The NP-PEG-BayK8644 activated the inflammasome in a Tmem176b-dependent manner in DCs. We administered either empty (eNP-PEG) or NP-PEGBayK8644 to mice with established tumors. NP-PEG-BayK8644 significantly controlled tumor growth and improved mice survival compared to both eNP-PEG and free BayK8644 in melanoma and lymphoma models. This effect was associated with enhanced inflammasome activation by DCs in the tumor-draining lymph node and infiltration of the tumor by CD8+ T cells. Thus, encapsulation of BayK8644 in chitosan NPs improves the anti-tumoral properties of the compound by avoiding inhibition of antigen cross-presentation.

Creator

Victoria, Sabina

Castro, Analía

Pittini, Alvaro

Olivera, Daniela

Russo, Sofía

Cebrian, Ignacio

Mombru, Alvaro W.

Osinaga, Eduardo

Pardo, Helena

Segovia, Mercedes

Hill, Marcelo

Source

International Journal of Biological Macromolecules, v. 279, nº 3, 2024. -- e135327

Publisher

Elsevier

Date

2024

Rights

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Format

PDF

Extent

11 p.

Language

Inglés

Type

Artículo

Identifier

10.1016/j.ijbiomac.2024.135327

Document Item Type Metadata

Original Format

PDF
Date Added
November 28, 2024
Collection
Bibliografía Nacional Química
Item Type
Document
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Citation
Victoria, Sabina et al., “Formulating a TMEM176B blocker in chitosan nanoparticles uncouples its paradoxical roles in innate and adaptive antitumoral immunity,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed November 17, 2025, https://riquim.fq.edu.uy/items/show/6842.