pH-triggered release of manganese from MnAu nanoparticles that enables cellular neuronal differentiation without cellular toxicity.
At high concentrations, manganese (Mn) promotes cellular neurodevelopment but causes toxicity. Here, we report that Mn ion at high concentrations can be delivered to pheochromocytoma 12 (PC12) cells using gold nanoparticles (AuNPs) to enhance cellular neurodevelopment without toxicity. Mn(2+) release from AuNPs was designed to be pH-responsive so that low pH condition of the cell endosomes can trigger in situ release of Mn(2+) from AuNPs after cellular uptake of Mn-incorporated AuNPs (MnAuNPs). Due to the differences in reduction potentials of Mn and Au, only Mn ionized and released while Au remained intact when MnAuNPs were uptaken by cells. Compared to PC12 cells treated with a high concentration of free Mn(2+), PC12 cells treated with an equal concentration of MnAuNPs resulted in significantly enhanced cellular neurodevelopment with decreased apoptosis and necrosis. Treatment with a high concentration of free Mn(2+) led to an abrupt consumption of a large amount of ATP for the intracellular transport of Mn(2+) through the ion channel of the cell membrane and to mitochondrial damage caused by the high intracellular concentration of Mn(2+), both of which resulted in cell necrosis and apoptosis. In contrast, MnAuNP-treated cells consumed much smaller amount of ATP for the intracellular transport of MnAuNPs by endocytosis and showed pH-triggered in situ release of Mn(2+) from the MnAuNPs in the endosomes of the cells, both of which prevented the cell death caused by ATP depletion and mitochondrial damage. To our knowledge, this is the first report on the use of AuNPs as a vehicle for pH-responsive, intracellular delivery of metal ion, which may open a new window for drug delivery and clinical therapy.
School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Suk Ho
SH
Bhang
School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea.
Jin
J
Han
Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 151-744, Republic of Korea.
Hyeon-Ki
HK
Jang
School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea.
Myung-Kyung
MK
Noh
Department of Nanobiomedical Science, Dankook University, Cheonan-Si 330-714, Republic of Korea.
Wan-Geun
WG
La
Department of Chemical Engineering, College of Engineering, Kyung Hee University, Yongin 446-701, Republic of Korea.
Minyoung
M
Yi
Department of Chemical Engineering, College of Engineering, Kyung Hee University, Yongin 446-701, Republic of Korea.
Woo-Sik
WS
Kim
Department of Biology, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, Republic of Korea.
Yunhee Kim
YK
Kwon
Department of Chemical Engineering, College of Engineering, Kyung Hee University, Yongin 446-701, Republic of Korea. Electronic address: tkyu@khu.ac.kr.
Taekyung
T
Yu
School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea; Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 151-744, Republic of Korea; Bio-MAX Institute, Institute of Chemical Processes, Engineering Research Institute, Seoul National University, Seoul 151-744, Republic of Korea. Electronic address: byungskim@snu.ac.kr.
Byung-Soo
BS
Kim
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D016503:Drug Delivery Systems; D004705:Endocytosis; D006046:Gold / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007477:Ions; D019344:Lactic Acid / Q000737:chemistry; D008345:Manganese / Q000737:chemistry*; D053768:Metal Nanoparticles / Q000737:chemistry*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects; D051381:Rats
D007477:Ions; D019344:Lactic Acid; D008345:Manganese; D006046:Gold; D000255:Adenosine Triphosphate
Drug delivery; Gold nanoparticle; Manganese ion; Neuronal differentiation; Pheochromocytoma cell