Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains.
The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O(6)-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O(6)-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.
Department of Neurosurgery, Nagoya University School of Medicine Nagoya, Aichi, Japan.
Takashi
T
Tsujiuchi
Department of Neurosurgery, Nagoya University School of Medicine Nagoya, Aichi, Japan.
Atsushi
A
Natsume
Department of Neurosurgery, Nagoya University School of Medicine Nagoya, Aichi, Japan.
Kazuya
K
Motomura
Department of Neurosurgery, Nagoya University School of Medicine Nagoya, Aichi, Japan.
Goro
G
Kondo
Department of Neurosurgery, Nagoya University School of Medicine Nagoya, Aichi, Japan.
Melissa
M
Ranjit
Hokkaido System Science Sapporo, Hokkaido, Japan.
Rei
R
Hachisu
New Drug Development Research Center Eniwa, Hokkaido, Japan.
Itsuro
I
Sugimura
New Drug Development Research Center Eniwa, Hokkaido, Japan.
Shinpei
S
Tomita
New Drug Development Research Center Eniwa, Hokkaido, Japan.
Isao
I
Takehara
Renishaw Advanced Materials New Mills, Wotton-under-Edge, Gloucestershire, GL 12 8JR, United Kingdom.
Max
M
Woolley
Functional Neurosurgery Research Group, University of Bristol United Kingdom.
Neil U
NU
Barua
Functional Neurosurgery Research Group, University of Bristol United Kingdom.
Steven S
SS
Gill
Department of Neurosurgery, Nagoya University School of Medicine Nagoya, Aichi, Japan.
Alison S
AS
Bienemann
Functional Neurosurgery Research Group, University of Bristol, United Kingdom.
Yoriko
Y
Yamashita
Department of Pathology and Biological Responses, Nagoya University School of Medicine, Nagoya, Japan.
Shinya
S
Toyokuni
Department of Pathology and Biological Responses, Nagoya University School of Medicine, Nagoya, Japan.
Toshihiko
T
Wakabayashi
Glioblastoma; MGMT; cationic liposome; convection-enhaced delivery; si-RNA