AKT2 siRNA delivery with amphiphilic-based polymeric micelles show efficacy against cancer stem cells

Drug Delivery

Diego Arango¹  Manuel Hidalgo²  Joaquin Seras-Franzoso³  Sara Montero³  Petra Gener⁴  Simó Schwartz⁴  Yolanda Fernández⁵  Ibane Abasolo⁵  Joan Sayós⁶  Fernanda Andrade⁷  Helena F. Florindo⁸  Mafalda Videira⁸  Diana Rafael⁹ 

[1] Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain;Division of Hematology and Oncology, Rosenberg Clinical Cancer Center Beth Israel Deaconess Medical Center, Boston, MA, USA;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;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;Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Zaragoza, Spain;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;Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Zaragoza, Spain;Functional Validation and Preclinical Research (FVPR), CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain;Immune Regulation and Immunotherapy, CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spai;Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Zaragoza, Spain;Research Institute for Medicines and Pharmaceutical Sciences, Faculdade de Farmácia, Universidade de Lisboa (iMed.ULisboa), Lisbon, Portugal;Research Institute for Medicines and Pharmaceutical Sciences, Faculdade de Farmácia, Universidade de Lisboa (iMed.ULisboa), Lisbon, Portugal;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;

关键词: Polymeric micelles;    Pluronic;    gene delivery;    AKT2;    cancer stem cells;   

DOI  :  10.1080/10717544.2018.1461276

来源: publisher

【 摘 要 】

Development of RNA interference-based therapies with appropriate therapeutic window remains a challenge for advanced cancers. Because cancer stem cells (CSC) are responsible of sustaining the metastatic spread of the disease to distal organs and the progressive gain of resistance of advanced cancers, new anticancer therapies should be validated specifically for this subpopulation of cells. A new amphihilic-based gene delivery system that combines Pluronic® F127 micelles with polyplexes spontaneously formed by electrostatic interaction between anionic siRNA and cationic polyethylenimine (PEI) 10K, was designed (PM). Resultant PM gather the requirements for an efficient and safe transport of siRNA in terms of its physicochemical characteristics, internalization capacity, toxicity profile and silencing efficacy. PM were loaded with a siRNA against AKT2, an important oncogene involved in breast cancer tumorigenesis, with a special role in CSC malignancy. Efficacy of siAKT2-PM was validated in CSC isolated from two breast cancer cell lines: MCF-7 and Triple Negative MDA-MB-231 corresponding to an aggressive subtype of breast cancer. In both cases, we observed significant reduction on cell invasion capacity and strong inhibition of mammosphere formation after treatment. These results prompt AKT2 inhibition as a powerful therapeutic target against CSC and pave the way to the appearance of more effective nanomedicine-based gene therapies aimed to prevent CSC-related tumor recurrence.

【 授权许可】

CC BY