Facilitated Monocyte-Macrophage Uptake and Tissue Distribution of Superparmagnetic Iron-Oxide Nanoparticles

被引:114
作者
Beduneau, Arnaud [1 ,4 ]
Ma, Zhiya [1 ,4 ]
Grotepas, Cassi B. [1 ,4 ]
Kabanov, Alexander [2 ,5 ]
Rabinow, Barrett E. [6 ]
Gong, Nan [1 ,4 ]
Mosley, R. Lee [1 ,4 ,5 ]
Dou, Huanyu [1 ,4 ,5 ]
Boska, Michael D. [3 ,4 ,5 ]
Gendelman, Howard E. [1 ,4 ,5 ]
机构
[1] Univ Nebraska, Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE 68198 USA
[2] Univ Nebraska, Med Ctr, Dept Pharm Sci, Lincoln, NE 68583 USA
[3] Univ Nebraska, Med Ctr, Dept Radiol, Lincoln, NE 68583 USA
[4] Univ Nebraska, Med Ctr, Ctr Neurovirol & Neurodegenerat Disorders, Lincoln, NE 68583 USA
[5] Univ Nebraska, Med Ctr, Ctr Drug Delivery & Nanomed, Lincoln, NE 68583 USA
[6] Baxter Healthcare Corp, Round Lake, IL USA
来源
PLOS ONE | 2009年 / 4卷 / 02期
基金
美国国家卫生研究院;
关键词
D O I
10.1371/journal.pone.0004343
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: We posit that the same mononuclear phagocytes (MP) that serve as target cells and vehicles for a host of microbial infections can be used to improve diagnostics and drug delivery. We also theorize that physical and biological processes such as particle shape, size, coating and opsonization that affect MP clearance of debris and microbes can be harnessed to facilitate uptake of nanoparticles (NP) and tissue delivery. Methods: Monocytes and monocyte-derived macrophages (MDM) were used as vehicles of superparamagnetic iron oxide (SPIO) NP and immunoglobulin (IgG) or albumin coated SPIO for studies of uptake and distribution. IgG coated SPIO was synthesized by covalent linkage and uptake into monocytes and MDM investigated related to size, time, temperature, concentration, and coatings. SPIO and IgG SPIO were infused intravenously into naive mice. T-2 measures using magnetic resonance imaging (MRI) were used to monitor tissue distribution in animals. Results: Oxidation of dextran on the SPIO surface generated reactive aldehyde groups and permitted covalent linkage to amino groups of murine and human IgG and F(ab')(2) fragments and for Alexa Fluor (R) 488 hydroxylamine to form a Schiff base. This labile intermediate was immediately reduced with sodium cyanoborohydride in order to stabilize the NP conjugate. Optical density measurements of the oxidized IgG, F(ab')(2), and/or Alexa Fluor (R) 488 SPIO demonstrated similar to 50% coupling yield. IgG-SPIO was found stable at 4 degrees C for a period of 1 month during which size and polydispersity index varied little from 175 nm and 200 nm, respectively. In vitro, NP accumulated readily within monocyte and MDM cytoplasm after IgG-SPIO exposure; whereas, the uptake of native SPIO in monocytes and MDM was 10-fold less. No changes in cell viability were noted for the SPIO-containing monocytes and MDM. Cell morphology was not changed as observed by transmission electron microscopy. Compared to unconjugated SPIO, intravenous injection of IgG-SPIO afforded enhanced and sustained lymphoid tissue distribution over 24 hours as demonstrated by MRI. Conclusions: Facilitated uptake of coated SPIO in monocytes and MDM was achieved. Uptake was linked to particle size and was time and concentration dependent. The ability of SPIO to be rapidly taken up and distributed into lymphoid tissues also demonstrates feasibility of macrophage-targeted nanoformulations for diagnostic and drug therapy.
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页数:12
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