Let-7 miRNA and CDK4 siRNA co-encapsulated in Herceptin-conjugated liposome for breast cancer stem cells

Recently,breast cancer stem cells(BCSCs)have rapidly emerged as a novel target for the therapy of breast cancer as they play critical roles in tumor growth,maintenance,metastasis,and recurrence.Let-7 miRNA is known to be downregulated in a variety of cancers,especially BCSCs,whereas CDK4 being overexpressed in human epidermal growth factor receptor 2(HER-2)overexpressing tumor cells.In this study,let-7 miRNA and CDK4-specific siRNA were chosen as therapeutic agents and co-encapsulated in Herceptinconjugated cationic liposomes for breast cancer therapy.Particle size,zeta potential,and encapsulation efficacy of mi/siRNA-loaded PEGylated liposome conjugated with Herceptin(Her-PEG-Lipo-mi/siRNA)were 176 nm,28.1 mV,and 99.7%±0.1%,respectively.Enhanced cellular uptake(86%)was observed by fluorescence microscopy when SK-BR-3 cells were treated with Her-PEG-Lipo-mi/siRNA.Also,the increased amount of let-7a mRNA and decreased amount of cellular CDK4 mRNA were observed by qRT-PCR when SK-BR-3 cells were treated with Her-PEG-Lipo-mi/siRNA,which was even more so when SK-BR-3 stem cells were used(197 vs 768 times increase for let-7a,62%vs 68%decrease for CDK4).Growth inhibition(65%)andmigration arrest(0.5%)of the cellswere achieved by the treatment of the cells with Her-PEG-Lipo-mi/siRNA,but not withmi/siRNA complex or other formulations.In conclusion,an efficient liposomal delivery system for the combination of miRNA and siRNA to target the BCSCs was developed and could be used as an efficacious therapeuticmodality for breast cancer.

Polymeric micelle nanocarriers in cancer research

Amphiphilic block copolymers （ABCs） assem- ble into a spherical nanoscopic supramolecular core/shell nanostructure termed a polymeric micelle that has been widely researched as an injectable nanocarrier for poorly water-soluble anticancer agents. The aim of this review article is to update progress in the field of drug delivery towards clinical trials, highlighting advances in polymeric micelles used for drug solubilization, reduced off-target toxicity and tumor targeting by the enhanced permeability and retention （EPR） effect. Polymeric micelles vary in stability in blood and drug release rate, and accordingly play different but key roles in drug delivery. For intravenous （IV） infusion, polymeric micelles that disas- semble in blood and rapidly release poorly water-soluble anticancer agent such as paclitaxel have been used for drug solubilization, safety and the distinct possibility of toxicity reduction relative to existing solubilizing agents, e.g., Cremophor EL. Stable polymeric micelles are long- circulating in blood and reduce distribution to non-target tissue, lowering off-target toxicity. Further, they participate in the EPR effect in murine tumor models. In summary, polymeric micelles act as injectable nanocarriers for poorly water-soluble anticancer agents, achieving reduced toxi- city and targeting tumors by the EPR effect.