Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer

Background 5-Fluorouracil (5-FU) has been commonly prescribed for patients with colorectal cancer (CRC), but resistance to 5-FU is one of the main reasons for failure in CRC. Recently, microRNAs (miRNAs) have been established as a means of reversing the dilemma by regulating signaling pathways invol...

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Veröffentlicht in:Journal of nanobiotechnology Jg. 18; H. 1; S. 10 - 15
Hauptverfasser: Liang, Gaofeng, Zhu, Yanliang, Ali, Doulathunnisa Jaffar, Tian, Tian, Xu, Huantian, Si, Ke, Sun, Bo, Chen, Baoan, Xiao, Zhongdang
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London BioMed Central 09.01.2020
BioMed Central Ltd
Springer Nature B.V
BMC
Schlagworte:
5-Fluorouracil
5-FU
Anticancer properties
Apoptosis
Biological products
Biotechnology
Cancer cells
Cancer patients
Cancer therapies
Care and treatment
Cell cycle
Chemistry
Chemistry and Materials Science
Chemotherapy
Colon
Colon cancer
Colorectal cancer
Colorectal carcinoma
Cytotoxicity
Delivery system
Deoxyribonucleic acid
Development and progression
DNA
DNA methylation
Drug delivery systems
Drug resistance
Drug therapy
Electroporation
ErbB-2 protein
Exosomes
Fluorouracil
Health aspects
Inhibitors
Membranes
MicroRNA
miR-21 inhibitor
miRNA
Molecular Medicine
Nanotechnology
Oligonucleotides
Proteins
PTEN protein
Ribonucleic acid
RNA
Toxicity
Tumors
China
Delivery system
miR-21 inhibitor
Exosomes
Drug resistance
5-FU
ISSN:1477-3155, 1477-3155
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Zusammenfassung:Background 5-Fluorouracil (5-FU) has been commonly prescribed for patients with colorectal cancer (CRC), but resistance to 5-FU is one of the main reasons for failure in CRC. Recently, microRNAs (miRNAs) have been established as a means of reversing the dilemma by regulating signaling pathways involved in initiation and progression of CRC. However, how to safely and effectively deliver miRNA to target cells becomes a main challenge. Results In this study, Engineered exosomes were exploited to simultaneously deliver an anticancer drug 5-FU and miR-21 inhibitor oligonucleotide (miR-21i) to Her2 expressing cancer cells. Purified engineered exosomes from the donor cells loaded with 5-FU and miR-21i via electroporation to introduce into 5-FU-resistant colorectal cancer cell line HCT-116 5FR . Furthermore, systematic administration of 5-FU and miR-21i loaded exosomes in tumor bearing mice indicated a significantly anti-tumor effect. The results showed that the engineered exosome-based 5-FU and miR-21i co-delivery system could efficiently facilitate cellular uptake and significantly down-regulate miR-21 expression in 5-FU resistant HCT-116 5FR cell lines. Consequently, the down-regulation of miR-21 induced cell cycle arrest, reduced tumor proliferation, increased apoptosis and rescued PTEN and hMSH2 expressions, regulatory targets of miR-21. Of particular importance was the significant reduction in tumor growth in a mouse model of colon cancer with systematic administration of the targeting miR-21i. More excitedly, the combinational delivery of miR-21i and 5-FU with the engineered exosomes effectively reverse drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer cells, compared with the single treatment with either miR-21i or 5-FU. Conclusion The strategy for co-delivering the functional small RNA and anticancer drug by exosomes foreshadows a potential approach to reverse the drug resistance in CRC and thus to enhance the efficacy of the cancer treatment.
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ISSN:1477-3155
1477-3155
DOI:10.1186/s12951-019-0563-2