Study On The Co-delivery Of MiR-34a And Doxorubicin With Nanoparticles For Triple Negative Breast Cancer Therapy

It has been suggested that co-delivering chemotherapy drugs and genes togetherin the same delivery system would be more effective in treatment of cancer. However,lacks of effective co-delivering carriers or systems to the tumor sites are the mainhampers in drug/gene combined therapy. Nanocarriers have been largely developed toco-deliver gene and drug. Additionally, various functional agents have attempted tointegrate into nanocarriers to improve delivery efficiency, such as targeting ability forspecific tumor sites and cells.MicroRNAs (miRNAs) are a class of small, endogenous non-coding RNAs thatpost-transcriptionally control the translation and stability of mRNAs. Dysregulation ofmiRNAs has been shown in many cancers and recognized as a hallmark of cancer.MiRNAs can function as tumor suppressors or on-miRs during tumor initiation andprogression. In our present studies, nano-complexes were prepared using hyaluronicacid and chitosan which simultaneously encapsulate positive charged Doxorubicin(DOX) and negative charged miR-34a mimics. The synergetic effects andmechanisms of DOX and miR-34a in triple negative breast cancer (TNBC) therapywere further investigated by in vitro and in vivo models.In the first part of the dissertation, we constructed HA-CS nanoparticles based onpolyionic nano-complexes (PICMs) methods. The particle size, surface zeta potential,morphology, DOX and miR-34a encapsulation efficiency, particle stability in varioussolutions and in vitro release were characterized by electronic microscope anddynamic light scattering. The obtained results showed that DOX and miR-34a can beencapsulated in nanoparticles with high efficiency, which exhibited a good stability.In the second part, the synergetic effects and mechanisms of DOX and miR-34ain breast cancer therapy were further investigated by in vitro and in vivo models. Theresults demonstrated a HA dependent targeting delivery of DOX and miR-34a. Theco-delivery of miR-34a with DOX was not only able to substantially enhanceanti-tumor activity of DOX, but also suppress breast cancer cells migration viatargeting Notch-1signaling, suggesting that co-delivery of DOX and miR-34a couldachieve synergistic effects on tumor suppression. Furthermore, nanocarrier-mediateddelivery of DOX and miR-34a can not only result in an effective reduction of drugresistance and side effects of DOX, but also enhance the therapeutic outcome of DOXby silencing Bcl-2expression. Our data potentially provided a novel strategy forTNBC therapy.