ROS-responsive core-shell nano-inhibitor impedes pyruvate metabolism for reinforced photodynamic therapy and interrupted pre-metastatic niche formation.
Acta Biomater
; 182: 288-300, 2024 07 01.
Article
em En
| MEDLINE
| ID: mdl-38729547
ABSTRACT
The formation of pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor requires the communication between the tumor cells and the host environment. Pyruvate is a fundamental nutrient by which the tumor cells metabolically reshape the extracellular matrix in the lung to facilitate their own metastatic development. Here we report a combination regimen by integrating the photo-sensitizer and the mitochondrial pyruvate carrier (MPC) inhibitor in a dendritic polycarbonate core-hyaluronic acid shell nano-platform with multivalent reversible crosslinker embedded in it (DOH-NI+L) to reinforce photodynamic therapy (PDT) toward the primary tumor and interrupt PMN formation in the lung via impeding pyruvate uptake. We show that DOH-NI+L mediates tumor-specific MPC inhibitor liberation, inhibiting the aerobic respiration for facilitated PDT and restraining ATP generation for paralyzing cell invasion. Remarkably, DOH-NI+L is demonstrated to block the metabolic crosstalk of tumor cell-host environment by dampening pyruvate metabolism, provoking a series of metabolic responses and resulting in the pulmonary PMN interruption. Consequently, DOH-NI+L realizes a significant primary tumor inhibition and an efficient pulmonary metastasis prevention. Our research extends nano-based anti-metastatic strategies aiming at PMN intervention and such a dendritic core-shell nano-inhibitor provides an innovative paradigm to inhibit tumor growth and prevent metastasis efficiently. STATEMENT OF SIGNIFICANCE:
In the progression of cancer metastasis, the formation of a pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor is one of the rate-limiting stages. The current nano-based anti-metastatic modalities mainly focus on targeted killing of tumor cells and specific inhibition of tumor cell invasion, while nanomedicine-mediated interruption of PMN formation has been rarely reported. Here we report a combination regimen by integrating a photo-sensitizer and an inhibitor of mitochondrial pyruvate carrier in a dendritic core-shell nano-platform with a reversible crosslinker embedded in it to reinforce PDT toward the primary tumor and interrupt PMN formation via impeding the uptake of pyruvate that is a fundamental nutrient facilitating aerobic respiration and PMN formation. Our research proposed a nano-based anti-metastatic strategy aiming at PMN intervention.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fotoquimioterapia
/
Espécies Reativas de Oxigênio
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Ácido Pirúvico
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Acta Biomater
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China