Polymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo

被引：0

作者：

Andrade, Fernanda ^{[1
,2
,3
]}

Rafael, Diana ^{[3
,4
]}

Vilar-Hernández, Mireia ^{[3
]}

Montero, Sara ^{[3
,4
]}

Martínez-Trucharte, Francesc ^{[3
]}

Seras-Franzoso, Joaquin ^{[3
]}

Díaz-Riascos, Zamira V. ^{[3
,5
]}

Boullosa, Ana ^{[3
,5
]}

García-Aranda, Natalia ^{[3
,5
]}

Cámara-Sánchez, Patricia ^{[3
,5
]}

Arango, Diego ^{[6
]}

Nestor, Marika ^{[7
]}

Abasolo, Ibane ^{[3
,4
,5
]}

Sarmento, Bruno ^{[1
,2
,8
]}

Schwartz, Simó ^{[3
,4
]}

机构：

[1] i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, Portugal

[2] INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto,4200-180, Portugal

[3] Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain

[4] Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Zaragoza, Spain

[5] Functional Validation and Preclinical Research (FVPR), CIBBIM-Nanomedicine, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain

[6] Biomedical Research in Digestive Tract Tumors Group, CIBBIM-Nanomedicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

[7] Department of Immunology, Genetics and Pathology, Uppsala University, Sweden

[8] CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra, 1317, Gandra,4585-116, Portugal

来源：

Journal of Controlled Release | 2021年 / 331卷

基金：

欧盟地平线“2020”;

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D O I：

暂无

中图分类号：

学科分类号：

摘要：

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. © 2021 Elsevier B.V.

引用

页码：198 / 212