Inhibiting collagen I production and tumor cell colonization in the lung via miR-29a-3p loading of exosome-/liposome-based nanovesicles.
Acta Pharm Sin B
; 12(2): 939-951, 2022 Feb.
Article
em En
| MEDLINE
| ID: mdl-35256956
ABSTRACT
The lung is one of the most common sites for cancer metastasis. Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells. Therefore, down-regulating the production of collagens may contribute to the inhibition of lung metastasis. It has been suggested that miR-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens. Indeed, our clinical lung tumor data shows that miR-29a-3p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients' outcomes. However, suitable carriers need to be selected to deliver this therapeutic miRNA to the lungs. In this study, we found that the chemotherapy drug cisplatin facilitated miR-29a-3p accumulation in the exosomes of lung tumor cells, and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation. To scale up the preparation and simplify the delivery system, we designed a lung-targeting liposomal nanovesicle (by adjusting the molar ratio of DOTAP/cholesterol-miRNAs to 41) to carry miR-29a-3p and mimic the exosomes. This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo, thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.
CPT-Exo, cisplatin elicited lung tumor exosomes; CTCs, circulating tumor cells; Collagen I; DOTAP, 1,2-dioleoyl-3-trimethylammonium propane; ECM, extra cellular matrix; EVs, extracellular vesicles; Exosomes; Fibroblasts; LLC, Lewis lung carcinoma; LLC-Exo, LLC-derived exosomes; Liposomal nanovesicle; Luc-LPX, Luc-lipoplex; Lung metastasis; NC inhibitor, negative control inhibitor; NC mimic, negative control mimic; PMN, pre-metastatic niche; Pre-metastatic niche; RNA-LPX, RNA-lipoplex; cDNA, complementary DNA; miR-29a-3p; miR-29a-3p-LPX, miR-29a-3p-lipoplex
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Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article