Houman Alimoradi
University of Otago, New Zealand
Title: Synergistic Anti-Cancer Effect Of Stable Nitric Oxide Releasing Nanoparticles, SMA-Tdodsno And Doxorubicin.
Biography
Biography: Houman Alimoradi
Abstract
Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutic in hypoxic regions of tumor, low cell membrane penetration and low lysosomal escape remain formidable challenges to the enhanced permeability and retention (EPR) effect based therapeutic systems. In order to overcome this limitations we have developed a stable nitric oxide (NO) releasing nanoparticles (NPs) named as SAM-tDodSNO and used it in combination with Doxorubicin (Dox) loaded NPs (SMA-Dox), and their effects on cell proliferation, induction of apoptosis, the changes of lysosomal membrane permeabilization and mitochondrial membrane potential, and tumor growth were studied. Combination of SMA-tDodSNO to Dox showed a synergistic anti-proliferative effect in 4T1 breast cancer cells, and when used in xenografted mice it resulted more than 5.5 folds reduction in tumor size compared with Dox alone. We also found, the SMA-tDodSNO could enhance the endocytosis of SMA-Dox and inhibit Dox efflux from the cells resulting higher concentration of Dox in the cells. Local administration of SMA-tDodSNO in tumor area increased the concentration of Dox in tumor when combined with free Dox or SMA-Dox. SMA-tDodSNO promoted the lysosomal membrane permeabilization and the reduction of mitochondrial membrane potential induced by doxorubicin, and resulted enhanced intracellular calcium concentration. In conclusion, the SMA-tDodSNO as novel NO releasing NPs showed significant cytotoxicity in in breast cancer cells and was able to decrease the tumor growth and potentiated the anticancer potency of Dox both in vitro and in vivo models. Due to NO release it enhanced the endocytosis of a Dox loaded NPs and increased permeability of endosomal membrane hence facilitate the escape of the NPs, and inhibited Dox efflux from the cells.