Nevertheless, the rapid degradation and poor cellular uptake of siRNA are challenges for siRNA-based therapies

Nevertheless, the rapid degradation and poor cellular uptake of siRNA are challenges for siRNA-based therapies. then highlight the mechanism of action and therapeutic efficacy of several state-of-the-art NDDSs that can be used to treat breast cancer by eliminating BCSCs. and em Eclipta prostrata /em ,174 was demonstrated to kill many cancer cellsincluding breast cancer cellsbut its disadvantages, such as poor solubility and bioavailability, restrict its PH-797804 clinical application.40,175 Das et al40 formulated wedelolactone-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (nWdl) to target BCSCs and overcome their shortcomings. nWdl was shown to sensitize BCSCs to the effects of wedelolactone by downregulating SOX2 and adenosine-triphosphate (ATP)-binding cassette super-family G member 2 (ABCG2). SAL, a polyether ionophore Rabbit Polyclonal to LRP11 antibiotic, has demonstrated great potential in eliminating BCSCs, but its clinical application is hindered by its poor aqueous solubility and severe systemic toxicity.83,139,176,177 Considering the need for an efficient drug while reducing potential damage to normal tissues, Zhao et al139 developed biocompatible gold nanoparticles coated with poly(ethylene glycol) (PEG) that were conjugated with SAL. These SAL-loaded gold nanoparticles enhanced the therapeutic efficacy of SAL against BCSCs derived from a CD24low/CD44high PH-797804 subpopulation. MET, an anti-type 2 diabetic drug, was reported to affect breast cancer at low dosages by targeting BCSCs; however, its anti-breast cancer efficacy is hindered by its low bioavailability and nonselective biodistribution. Lee et al42 demonstrated that MET-encapsulated trastuzumab-conjugated immunoliposomes (Her-LP-MET) could target BCSCs and inhibit both their proliferation and migration. The combination of Her-LP-MET with free DOX resulted in better breast tumor remission than treatment with only free DOX. It was suggested by Sun et al13 that rationally designed drug delivery systems could significantly enhance the cancer stem cell therapy of conventional chemotherapeutic drugs such as DOX by delivering these drugs into cancer stem cells. They formulated DOX-tethered gold nanoparticles (DOX-Hyd@AuNPs) and demonstrated that DOX-Hyd@AuNPs could inhibit the growth of breast cancer without increasing the BCSC subpopulation in the tumor by delivering more DOX into the BCSCs. This process overcame the intrinsic resistance of BCSCs arising from P-glycoprotein (P-gp) drug efflux. Delivery of Nucleic Acid Therapeutics to BCSCs In addition to increasing the solubilization of low-solubility drugs, NDDSs have the capacity to enhance the stability and cellular uptake of macromolecules such as siRNA, shRNA, and miRNA PH-797804 which could potentially treat cancer.130,178 AKT2, a major downstream effector of the phosphatidylinositol 3-kinase (PI3K) pathway, was reported to be associated with cancer stem cell tumorigenicity and the malignant phenotype of cancer cells.179C181 The silencing of AKT2 with siRNA has the potential to inhibit the development and recurrence of tumors. Nevertheless, the rapid degradation and poor cellular uptake of siRNA are challenges for siRNA-based therapies. Using NDDSs to deliver siRNA may be a promising strategy to increase the stability and cellular delivery of siRNA. Rafael et al152 developed an innovative nanocarrier system composed of Pluronic? F127-based micelles associated with polyethylenimine (PEI)-based polyplexes to deliver AKT2 siRNA. This AKT2-siRNA delivery system displayed strong suppressive effects on BCSCs migration and invasion in breast cancer. NF-B plays an important role in maintaining the properties of BCSCs in various types of breast cancer.182,183 Therefore, it is possible to target BCSCs PH-797804 by downregulating the expression of NF-B PH-797804 proteins using RNA interference, including siRNA and shRNA. Compared to siRNA, shRNA is more stable; it is a double-stranded RNA molecule with a tight hairpin structure.184 Ke et al38 synthesized a carbamate-mannose-modified PEI (CMP) for the targeted delivery of NF-B shRNA to BCSCs. These CMP/NF-B-targeted shRNA nanocomplexes were demonstrated to reduce the percentage of BCSCs, inhibit the formation of mammospheres and colonies, suppress the migration and invasion of breast cancer cells, and sensitize breast cancer cells to treatment with doxorubicin-loaded micellar nanoparticles. miRNAs are essential post-transcriptional regulators of.