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- Title
Intratracheal Gene Transfer of Adrenomedullin Using Polyplex Nanomicelles Attenuates Monocrotaline-induced Pulmonary Hypertension in Rats.
- Authors
Harada-Shiba, Mariko; Takamisawa, Itaru; Miyata, Kanjiro; Ishii, Takehiko; Nishiyama, Nobuhiro; Itaka, Keiji; Kangawa, Kenji; Yoshihara, Fumiki; Asada, Yujiro; Hatakeyama, Kinta; Nagaya, Noriya; Kataoka, Kazunori
- Abstract
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.Molecular Therapy (2009) 17 7, 1180–1186. doi:10.1038/mt.2009.63
- Subjects
GENETIC transformation; ADRENOMEDULLIN; PULMONARY hypertension; LABORATORY rats; PROSTANOIDS; ETHYLENEDIAMINE; MESSENGER RNA; DNA
- Publication
Molecular Therapy, 2009, Vol 17, Issue 7, p1180
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1038/mt.2009.63