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Polymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo
- Source :
- Journal of Controlled Release. 331:198-212
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Colorectal cancer (CRC) is a highly prevalent disease worldwide. Patient survival is hampered by tumor relapse and the appearance of drug-resistant metastases, which are sustained by the presence of cancer stem cells (CSC). Specific delivery of anti-CSC chemotherapeutic drugs to tumors by using targeted drug delivery systems that can also target CSC sub-population might substantially improve current clinical outcomes. CD44v6 is a robust biomarker for advanced CRC and CSC, due to its functional role in tumorigenesis and cancer initiation process. Here, we show that CD44v6-targeted polymeric micelles (PM) loaded with niclosamide (NCS), a drug against CSC, is a good therapeutic strategy against colorectal CSC and circulating tumor cells (CTC) in vivo. HCT116 cells were sorted according to their CD44v6 receptor expression into CD44v6+ (high) and CDv44v6- (low) subpopulations. Accordingly, CD44v6+ cells presented stemness properties, such as overexpression of defined stemness markers (ALDH1A1, CD44v3 and CXCR4) and high capacity to form colonspheres in low attachment conditions. NCS-loaded PM functionalized with an antibody fragment against CD44v6 (Fab-CD44v6) presented adequate size, charge, and encapsulation efficiency. In addition, Fab-CD44v6 significantly increased PM internalization in CD44v6+ cells. Further, encapsulation of NCS improved its effectiveness in vitro, particularly against colonspheres, and allowed to increase its intravenous dosage in vivo by increasing the amount of NCS able to be administered without causing toxicity. Remarkably, functionalized PM accumulate in tumors and significantly reduce CTC in vivo. In conclusion, CD44v6 targeted PM meet the essential conditions to become an efficient anti-CSC therapy.
- Subjects :
- Receptor expression
Pharmaceutical Science
02 engineering and technology
medicine.disease_cause
03 medical and health sciences
Circulating tumor cell
In vivo
Cancer stem cell
Cell Line, Tumor
medicine
Humans
Micelles
030304 developmental biology
0303 health sciences
Chemistry
Cancer
Neoplastic Cells, Circulating
021001 nanoscience & nanotechnology
medicine.disease
Hyaluronan Receptors
Targeted drug delivery
Neoplastic Stem Cells
Cancer research
Niclosamide
Stem cell
Colorectal Neoplasms
0210 nano-technology
Carcinogenesis
Subjects
Details
- ISSN :
- 01683659
- Volume :
- 331
- Database :
- OpenAIRE
- Journal :
- Journal of Controlled Release
- Accession number :
- edsair.doi.dedup.....b3329062259c20063305bedbd07b0ddc
- Full Text :
- https://doi.org/10.1016/j.jconrel.2021.01.022