A cellular uptake of cis-platinum-encapsulating liposome through endocytosis by human neuroblastoma cell.
To explore the mechanisms involved in the efficient intracellular delivery of an antitumor agent, the uptake mechanism of cis-diamminedichloroplatinum (CDDP)-encapsulating liposome (phosphatidylcholine:phosphatidylserine:cholesterol = 6:2:3 in molar ratio) (CDDP-liposome) by the human neuroblastoma cell, IMR-32, was investigated. Dansylcadaverine, chloroquine and antimycin A suppressed the growth-inhibitory activity of CDDP-liposome mostly due to the interference of the energy-dependent internalization process. Colchicine and vinblastine also neutralized the DNA synthesis-inhibitory activity of CDDP-liposomes. Stimulation with CDDP-liposomes at low temperature (4 degrees C), which induces the disruption of microtubules under immunofluorescent visualization, markedly lowered the growth-inhibitory activity of CDDP-liposomes. These findings suggested that the action of CDDP-liposome was temperature-dependent and microtubules participated in the intracellular drug delivery. A23187 (0.4 ?M), further, promoted the action of CDDP-liposome, suggesting that an increase of intracellular Ca(2+) levels promotes the growth inhibitory activities of CDDP-liposomes. Taking the uptake-mechanisms and intracellular delivery processes of CDDP-liposomes into consideration, the use of CDDP-liposomes may present a promising tool for neuroblastoma chemotherapy.
Ito
J
J
Departments of Biochemistry, Bioregulation Research and Surgery, Nagoya City University Medical School, Nagoya, Japan.
Kato
T
T
Kamio
Y
Y
Kato
H
H
Kishikawa
T
T
Toda
T
T
Sasaki
S
S
Tanaka
R
R