Targeting lactate metabolism and immune interaction in breast tumor via protease-triggered delivery.
J Control Release
; 358: 706-717, 2023 06.
Article
em En
| MEDLINE
| ID: mdl-37207796
ABSTRACT
Lactate is abundant in cancer tissues due to active glycolysis (aka Warburg effect) and mediates crosstalk between tumor cells and the immune microenvironment (TIME) to promote the progression of breast cancer. Quercetin (QU) is a potent monocarboxylate transporters (MCT) inhibitor, which can reduce lactate production and secretion of tumor cells. Doxorubicin (DOX) can induce immunogenic cell death (ICD), which promotes tumor-specific immune activation. Thus, we propose a combination therapy of QU&DOX to inhibit lactate metabolism and stimulate anti-tumor immunity. To enhance tumor-targeting efficiency, we developed a legumain-activatable liposome system (KC26-Lipo) with modification of KC26 peptide for co-delivery of QU&DOX for modulation of tumor metabolism and TIME in breast cancer. The KC26 peptide is a legumain-responsive, hairpin-structured cell-penetrating peptide (polyarginine) derivative. Legumain is a protease overexpressed in breast tumors, allowing selective activation of the KC26-Lipo to subsequently facilitate intra-tumoral and intracellular penetration. The KC26-Lipo effectively inhibited 4T1 breast cancer tumor growth through chemotherapy and anti-tumor immunity. Besides, inhibition of lactate metabolism suppressed the HIF-1α/VEGF pathway and angiogenesis and repolarized the tumor-associated macrophages (TAM). This work provides a promising breast cancer therapy strategy by regulating lactate metabolism and TIME.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Neoplasias Mamárias Animais
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Control Release
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China