Intratracheal gene transfer of adrenomedullin using polyplex nanomicelles attenuates monocrotaline-induced pulmonary hypertension in rats.
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive PAH and right ventricular failure. Despite recent advances in therapeutic approaches using prostanoids, endothelin antagonists, and so on, PAH remains a challenging condition. To develop a novel therapeutic approach, we have established a nonviral gene delivery system of poly(ethylene glycol) (PEG)-based block catiomers, which form a polyplex nanomicelle with a nanoscaled core-shell structure in the presence of DNA. The polyplex nanomicelle from PEG-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-b-P[Asp(DET)]), having ethylenediamine units at the side chain, showed ~100-fold increase in luciferase transgene expression activity in mouse lung via intratracheal administration with a minimal toxicity compared with the polyplex from linear poly(ethylenimine) (LPEI). The transfection activity was highest on day 3 after administration and remained detectable until day 14. PEG-b-P[Asp(DET)] polyplex nanomicelles were formulated with a therapeutic plasmid bearing the human adrenomedullin (AM) gene and intratracheally administered to rats with monocrotaline-induced pulmonary hypertension. The right ventricular pressure significantly decreased 3 days after administration as confirmed by a notable increase of pulmonary human AM mRNA levels. Intratracheal administration of PEG-b-P[Asp-(DET)] polyplex nanomicelles showed remarkable therapeutic efficacy with PAH animal models without compromising biocompatibility.
Harada-Shiba
Mariko
M
Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Japan. mshiba@ri.ncvc.go.jp
Takamisawa
Itaru
I
Miyata
Kanjiro
K
Ishii
Takehiko
T
Nishiyama
Nobuhiro
N
Itaka
Keiji
K
Kangawa
Kenji
K
Yoshihara
Fumiki
F
Asada
Yujiro
Y
Hatakeyama
Kinta
K
Nagaya
Noriya
N
Kataoka
Kazunori
K