For effective cancer gene therapy, systemic administration of tumor-targeting adenoviral (Ad) complexes is critical for delivery to both primary and metastatic lesions. Electrospinning was used to generate nanocomplexes of Ad, chitosan, poly(ethylene glycol) (PEG), and folic acid (FA) for effective FA receptor-expressing tumor-specific transduction. The chemical structure of the Ad/chitosan-PEG-FA nanocomplexes was characterized by NMR and FT-IR, and the diameter and surface charge were analyzed by dynamic light scattering and zeta potentiometry, respectively. The average size of Ad/chitosan-PEG-FA nanocomplexes was approximately 140. nm, and the surface charge was 2.1. mV compared to - 4.9 mV for naked Ad. Electron microscopy showed well-dispersed, individual Ad nanocomplexes without aggregation or degradation. Ad/chitosan nanocomplexes retained biological activity without impairment of the transduction efficiency of naked Ad. The transduction efficiency of Ad/chitosan-PEG-FA was increased as a function of FA ratio in FA receptor-expressing KB cells, but not in FA receptor-negative U343 cells, demonstrating FA receptor-targeted viral transduction. In addition, the transduction efficiency of Ad/chitosan-PEG-FA was 57.2% higher than chitosan-encapsulated Ad (Ad/chitosan), showing the superiority of FA receptor-mediated endocytosis for viral transduction. The production of inflammatory cytokine, IL-6 from macrophages was significantly reduced by Ad/chitosan-PEG-FA nanocomplexes, implying the potential for use in systemic administration. These results clearly demonstrate that cancer cell-targeted viral transduction by Ad/chitosan-PEG-FA nanocomplexes can be used effectively for metastatic tumor treatment with reduced immune reaction against Ad.
Bibliographical noteFunding Information:
This work was supported by grants from the Ministry of Knowledge Economy ( 10030051 , Dr. C-O Yun), the Korea Science and Engineering Foundation ( R15-2004-024-02001-0 , 2009K001644, Dr. C-O. Yun), and a faculty research grant ( 6-2010-0052 , Dr. C-O Yun) of Yonsei University College of Medicine. Yeonah Park and Oh-Joon Kwon are graduate students sponsored by NRF through National Core Research Center and Brain Korea 21 Project, respectively.
All Science Journal Classification (ASJC) codes
- Pharmaceutical Science