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

Abstract

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.

Cyclin‐dependent kinase 9 promotes cervical cancer development via AKT2/p53 pathway

“…AKT2, one of the three isoforms of the AKT/PKB protein kinase family, is a major effector of the canonical PI3K pathway and plays a key role in cell survival, growth, as well as apoptosis . Our previous study has also confirmed that knockdown of AKT2 suppressed cell proliferation and induced apoptosis in cervical cancer cells .…”

Cancer stem cells (CSCs) in cancer progression and therapy

“…For example, suppression of β-catenin using inhibitors for cyclin-dependent kinase 1 (CDK1; a protein kinase important for cellular transitions of G1/S and G2/M phases) is reported to overcome the resistance of CSCs to sorafenib in HCC . A point to consider is that the β-catenin pathway is indirectly reactivated after prolong application of PI3K inhibitors for patients with cancer (evidenced in HCC), so percussion is necessary for the administration of such therapies (F. Liu, Wu, Jiang, Qian, & Gao, 2018 (Rafael et al, 2018).…”

Rational Design of a siRNA Delivery System: ALOX5 and Cancer Stem Cells as Therapeutic Targets

“…Further, the importance of nanoparticles design for gene therapy is not only related with the condensation of genetic material but also with the prevention of its potential degradation. In our case, the particles obtained using the FH method present higher storage stability (64). Oncology is certainly one of the fields that is most benefiting from the application of nanotechnology to drug and gene delivery.…”

“…Unfortunately, higher sizes and polydispersity were shown, as well as lower reproducibility and stability, suffering aggregation in the presence of serum and also under storage. To overcome these technological drawbacks, we changed to the FH technique as production method (64). This method allowed the production of micelles with better physicochemical features (lower size (<30nm) and PDI, as well as neutral zeta potential).…”