Potential of atelocollagen-mediated systemic antisense therapeutics for inflammatory disease.
To study the possibility of using atelocollagen as an oligonucleotide (ODN) delivery carrier in vivo, the activity of formulated antisense ODN targeted against the intercellular adhesion molecule-1 (ICAM-1) mRNA was investigated in an allergic dermatitis model in mice. The allergic dermatitis was elicited in one ear of animals sensitized by treatment with 2,4-dinitrofluorobenzene. Antisense ODN was given to the animals as a single intravenous injection of formulation containing atelocollagen. Antisense activity was determined by measurement of ear thickness, histopathology, and immunohistochemistry 24 hr after the initiation of the dermatitis. Antisense activity was found to increase according to the concentration of atelocollagen in the formulation. The effect mediated by the ODN formulated with 0.05% atelocollagen was more than 50 times greater than that provided by ODN infusion, although the levels of ODN formulated with atelocollagen dropped below that of the 24-hr infusion group within 30 min. The formulated ODN could suppress inflammatory progression by treatment at 8 hr after the ear challenge when inflammation had already commenced at the challenged site. Moreover, antisense activity was noted even when the formulated ODN was injected 3 days before the initiation of inflammation. These data demonstrate that atelocollagen can enhance antisense activity remarkably and that the sustainable antisense activity mediated by the formulation of ODN with atelocollagen could completely change the strategy of antisense therapeutics.
Hanai
Koji
K
Formulation Research Laboratories, Sumitomo Pharmaceuticals Co., Ltd., Ibaraki-shi, Osaka 567-0878, Japan. hanai@sumitopharm.co.jp
Kurokawa
Tomoyo
T
Minakuchi
Yoshiko
Y
Maeda
Miho
M
Nagahara
Shunji
S
Miyata
Teruo
T
Ochiya
Takahiro
T
Sano
Akihiko
A
D000818:Animals; D003094:Collagen / Q000737:chemistry; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000473:pathology; D004139:Dinitrofluorobenzene / Q000633:toxicity; D004337:Drug Carriers; D007120:Immunochemistry; D008297:Male; D051379:Mice; D009838:Oligodeoxyribonucleotides; D020319:Oligodeoxyribonucleotides, Antisense / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D010032:Otitis Externa / Q000139:chemically induced / Q000473:pathology / Q000628:therapy
C120298:AS-ICAM-1 ODN; D004337:Drug Carriers; D009838:Oligodeoxyribonucleotides; D020319:Oligodeoxyribonucleotides, Antisense; C059821:atelocollagen; D003094:Collagen; D004139:Dinitrofluorobenzene