Naz Asia, Cui Yi, Collins Christopher J, Thompson David H, Irudayaraj Joseph
Bindley Bioscience Center and Purdue Center for Cancer Research, Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Department of Pharmaceutical Chemistry, University of Karachi, Karachi 75270, Pakistan.
Bindley Bioscience Center and Purdue Center for Cancer Research, Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA.
Biomed Pharmacother. 2017 Jun;90:586-597. doi: 10.1016/j.biopha.2017.03.093. Epub 2017 Apr 11.
Efficient delivery of cytidine analogues such as Azacitidine (AZA) into solid tumors constitutes a primary challenge in epigenetic therapies. We developed a di-block nano-vector based on poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) for stabilization of the conjugated AZA under physiological conditions. With equimolar drug content, our nano-conjugate could elicit a better anti-proliferative effect over free drug in breast cancer both in vitro and in vivo, through reactivation of p21 and BRCA1 to restrict cell proliferation. In addition, we applied single-molecule fluorescence tools to characterize the intracellular behavior of the AZA-PLGE-PEG nano-micelles at a finer spatiotemporal resolution. Our results suggest that the nano-micelles could effectively enrich in cancer cells and may not be limited by nucleoside transporters. Afterwards, the internalized nano-micelles exhibit pH-dependent release and resistance to active efflux. Altogether, our work describes a delivery strategy for DNA demethylating agents with nanoscale tunability, providing a cost-effective option for pharmaceutics.
