PH-responsive Micelleplexes Co-loaded With SiRNA And Cisplatin Prodrug For Treatment Of Metastatic Breast Cancer

Tumor metastatic is the dominant cause of human morbidity and mortality. Acombination of RNA interference with chemotherapy is promising for treatment ofmetastatic cancer. However, the success of this treatment is impeded for lack ofsuitable vectors for siRNA and chemotherapeutic drug co-delivery. This paperreported a novel pH-responsive micelleplex platform for treatment of metastaticbreast cancer. The micelles were self-assembled from aminolated poly(ethyleneglycol)-block-poly(glycidyl methacrylate)-block-poly(2-(diisopropylamino)ethylmethacrylate)(PEG-b-PEDA-b-PDPA) triblock copolymers. At pH7.4, ahydrophobic cisplatin prodrug was loaded into the hydrophobic PDPA core, andsiRNA was complexed with the positively charged PEDA interlayer to form themicelleplexes. During blood circulation, the PEG corona can prevent proteinabsorption, minimize non-specific interaction with the RES, and prolong the systemiccirculation of the micelleplexes. When reached tumor site, the positively chargedintermediate layer can facilitate micelleplexes to penetrate tumor cells. After cellularuptake, the micelleplexes dissociated in lysosomes to release prodrug payload due toprotonation of the PDPA core. Using an orthotopic4T1breast cancer model, it wasdemonstrated that these novel micelleplexes co-loaded with cisplatin prodrug andsiRNA-p65could simultaneously inhibit both the growth of the primary tumor and thedistant metastasis of cancer cells. A mechanism study revealed that the significanttherapeutic performance of the micelleplexes might be attributed to apoptosis inducedby cisplatin and migration cease of cancer cells caused by p65knockdown.