Study On The Activities And Mechanisms Of Microrna-based Nanomedicine For Fight Against Triple Negative Breast Cancer

Breast cancer is currently the most frequent cancer and the leading cause ofcancer-related death in women worldwide. However, approximately15-20%of breastcancers are negative for the expression of estrogen and progesterone receptors as wellas HER-2receptor and diagnosed as triplenegative breast cancer (TNBC). Therefore,TNBC generally does not respond to receptor targeted treatment and is often relatedwith early recurrence, matastasis and poor survival rate, making it one of the thorniestchallenges in breast cancer treatment, which was attracted much attentions.MicroRNAs (miRNAs) are small highly conserved single-stranded non-codingRNA molecules which bind to the3’untranslated region (3’UTR) of the target mRNAto trigger mRNA degradation and/or inhibit gene translation and negatively regulategene expression. Recent studies showed that miRNAs are closely involved in cancerdevelopment and progression and regulate a number of oncogenes and tumorsuppressor genes, which are associated with the proliferation, invasion, migration anddrug resistace of tumor cells. Among them, microRNA-34a (miR-34a) is a potentendogenous tumor suppressor of breast cancer.At present, novel drugs based on small interfering RNA have attracted greatattention. However, due to its fast degradation in the physiological environment, poorcellular uptake, inefficient translocation into the cytoplasm, and lack of targetingability, delivery of synthetic small RNA remains the major obstacle for its therapeuticapplication. Development of effective delivery vectors is therefore essential formicroRNA-based therapy. To address this problem, we developed amiRNA-delivering nanocapsule technology based on hyaluronic acid(HA)/protamine sulfate (PS) interpolyelectrolyte complexes (HP-IPECs). Thenanocapsules can be successfully generated through self-assembly approach mediatedby electrostatic interaction in which miR-34a can be encapsulated with a highefficiency.In vitro and in vivo experiments illustrated that miR-34a can be efficientlydelivered into breast cancer cells or breast cancer tissues. Nanocomplex-assisteddelivery of miR-34a induced cell apoptosis and suppressed migration, proliferationand tumor growth of breast cancer cells via targeting CD44and Notch-1signaling pathway. The obtained results suggest that MHP-IPECs have a great potential asbiodegradable nanoparticle for microRNA-based therapy fight against triple negativebreast cancer.