Ionically crosslinked Ad/chitosan nanocomplexes processed by electrospinning for targeted cancer gene therapy.
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.
Park
Yeonah
Y
Graduate Program for Nanomedical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 Project for Medical Sciences and Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Kang
Eunah
E
Brain Korea 21 Project for Medical Sciences and Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Kwon
Oh-Joon
OJ
Brain Korea 21 Project for Medical Sciences and Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hwang
Taewon
T
Department of Chemical and Biomolecular Engineering, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, Seoul, Republic of Korea.
Park
Hongkwan
H
Department of Chemical and Biomolecular Engineering, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, Seoul, Republic of Korea.
Lee
Jung Min
JM
Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, Stanford University, Stanford, CA 94305, United States; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, United States.
Kim
Jung Hyun
JH
Department of Chemical and Biomolecular Engineering, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, Seoul, Republic of Korea. Electronic address: jayhkim@yonsei.ac.kr.
Yun
Chae-Ok
CO
Graduate Program for Nanomedical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 Project for Medical Sciences and Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: chaeok@yuhs.ac.
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry*; D005492:Folic Acid / Q000737:chemistry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000628:therapy*; D011092:Polyethylene Glycols / Q000737:chemistry
D011092:Polyethylene Glycols; D048271:Chitosan; D005492:Folic Acid