It has been risked that tumors may develop resistance to doxorubicin chemotherapeutic agents by genetic and epigenetic changes. Recently, nanotubes could change the epigenetic effect on phosphatidylserine lipid externalization from inner to outer plasma membrane leaflet and enhanced recognition of apoptotic pathway. Furthermore, due to high aspect ratios (length to width ratio) of nanotubes not only their bulk capability but also faster and high amount internalization rates as well as prolonged blood circulation time than their spherical counterparts, nanotubes could be a potential delivery system for tumor terminal disease. However, exactly penetration mechanisms of nanotubes for these process might depend on their size and the type/degree of their modification. Therefore, the object of this project is optimized cPNTs to modulate the lipid composition and enhance oral drug/gene delivery across biological system by nanotubes for anticancer/gene therapeutics. Recently, our oral biodegradable cyclopeptides nanotubes (cPNTs) delivery system with LacZ genes was detected four major stomach, duodenum, liver and kidney organs. Thus, in first approach, we will optimize the aspect ratios of cPNTs for specific tissues with phosphatidylserine externalization. The shape, aspect ratios, size, biological stability, releasing kinetics, and penetration of cPNTs will be examined. Doxorubicin or pCMV-caspase 3 plasmid will be evaluated the enhancement in vitro permeation study. Second approach, we will focus on the assessment of biodistribution of cPNTs at in vivo delivery system, the modulation of lipid composition in tissues, and doxorubicin and gene efficacy with cPNTs by multi-modality image, confocal microscopy, electron microscopy, western blotting, immunohistochemistry staining observations. Finally, we will monitor the functional and pharmacokinetic biodistribution of doxorubicin and plasmids in serum and local organs in wild type and multi drug resistance (MDR) solid tumor mice models.
|Effective start/end date||8/1/15 → 7/31/16|