In vivo Evaluation of Non-viral NICD Plasmid-Loaded PLGA Nanoparticles in Developing Zebrafish to Improve Cardiac Functions

Frontiers in Physiology

Fabrizio Bonetesta²  Edward Mager²  Amir Naderi³  Hung Cao³  Samantha Laboy-Segarra⁴  Juhyun Lee⁴  Uday Chintapula⁴  Victoria L. Messerschmidt⁴  Kytai T. Nguyen⁴ 

[1] Department of Bioengineering, University of Texas at Arlington, Arlington, TX, United States;Department of Biological Sciences, University of North Texas, Denton, TX, United States;Department of Electrical Engineering and Computer Science, University of California, Irvine, Irvine, CA, United States;University of Texas Southwestern Medical Center, Dallas, TX, United States;

关键词: PLGA nanoparticles;    toxicity;    non-viral transfection;    zebrafish;    gene delivery;    Notch signaling;   

DOI  :  10.3389/fphys.2022.819767

来源: DOAJ

【 摘 要 】

In the era of the advanced nanomaterials, use of nanoparticles has been highlighted in biomedical research. However, the demonstration of DNA plasmid delivery with nanoparticles for in vivo gene delivery experiments must be carefully tested due to many possible issues, including toxicity. The purpose of the current study was to deliver a Notch Intracellular Domain (NICD)-encoded plasmid via poly(lactic-co-glycolic acid) (PLGA) nanoparticles and to investigate the toxic environmental side effects for an in vivo experiment. In addition, we demonstrated the target delivery to the endothelium, including the endocardial layer, which is challenging to manipulate gene expression for cardiac functions due to the beating heart and rapid blood pumping. For this study, we used a zebrafish animal model and exposed it to nanoparticles at varying concentrations to observe for specific malformations over time for toxic effects of PLGA nanoparticles as a delivery vehicle. Our nanoparticles caused significantly less malformations than the positive control, ZnO nanoparticles. Additionally, the NICD plasmid was successfully delivered by PLGA nanoparticles and significantly increased Notch signaling related genes. Furthermore, our image based deep-learning analysis approach evaluated that the antibody conjugated nanoparticles were successfully bound to the endocardium to overexpress Notch related genes and improve cardiac function such as ejection fraction, fractional shortening, and cardiac output. This research demonstrates that PLGA nanoparticle-mediated target delivery to upregulate Notch related genes which can be a potential therapeutic approach with minimum toxic effects.

【 授权许可】

Unknown