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Surface engineering of macrophages with nanoparticles to generate a cell-nanoparticle hybrid vehicle for hypoxia-targeted drug delivery.

Holden CA, Yuan Q, Yeudall WA, Lebman DA, Yang H - Int J Nanomedicine (2010)

Bottom Line: Nanoparticles immobilized on the cell surface provide numerous new sites for anticancer drug loading, hence potentially minimizing the toxic effect of anticancer drugs on the viability and hypoxia-targeting ability of the macrophage vehicles.Further, a reducing agent, sodium cyanoborohydride, was applied to reduce Schiff bases to stable secondary amine linkages.The distribution of nanoparticles on the cell surface was confirmed by fluorescence imaging, and it was found to be dependent on the stability of the linkages coupling nanoparticles to the cell surface.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA.

ABSTRACT
Tumors frequently contain hypoxic regions that result from a shortage of oxygen due to poorly organized tumor vasculature. Cancer cells in these areas are resistant to radiation- and chemotherapy, limiting the treatment efficacy. Macrophages have inherent hypoxia-targeting ability and hold great advantages for targeted delivery of anticancer therapeutics to cancer cells in hypoxic areas. However, most anticancer drugs cannot be directly loaded into macrophages because of their toxicity. In this work, we designed a novel drug delivery vehicle by hybridizing macrophages with nanoparticles through cell surface modification. Nanoparticles immobilized on the cell surface provide numerous new sites for anticancer drug loading, hence potentially minimizing the toxic effect of anticancer drugs on the viability and hypoxia-targeting ability of the macrophage vehicles. In particular, quantum dots and 5-(aminoacetamido) fluorescein-labeled polyamidoamine dendrimer G4.5, both of which were coated with amine-derivatized polyethylene glycol, were immobilized to the sodium periodate-treated surface of RAW264.7 macrophages through a transient Schiff base linkage. Further, a reducing agent, sodium cyanoborohydride, was applied to reduce Schiff bases to stable secondary amine linkages. The distribution of nanoparticles on the cell surface was confirmed by fluorescence imaging, and it was found to be dependent on the stability of the linkages coupling nanoparticles to the cell surface.

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Related in: MedlinePlus

Confocal microscopy images of macrophage–Qdot hybrids at four hours (left panel) or 14 hours (right panel) post-treatment. A) QD525 incubated with untreated macrophages (control); B) Macrophage–T-Qdot hybrids; C) Macrophage–S-Qdot hybrids.Notes: Original magnification, ×630.Abbreviation: Qdot, quantum dot.
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f4-ijn-5-025: Confocal microscopy images of macrophage–Qdot hybrids at four hours (left panel) or 14 hours (right panel) post-treatment. A) QD525 incubated with untreated macrophages (control); B) Macrophage–T-Qdot hybrids; C) Macrophage–S-Qdot hybrids.Notes: Original magnification, ×630.Abbreviation: Qdot, quantum dot.

Mentions: Fluorescence microcopy and confocal microscopy were applied to conf irm the hybridization of nanoparticles with macrophages. As shown in Figure 3, both macrophage–T-nanoparticle hybrids and macrophage– S-nanoparticle hybrids prepared with QD525 exhibit strong fluorescence intensity at the edge of the cells, clearly outlining the cell surface. Qualitatively, more QD525 were taken up in macrophage–T-nanoparticle hybrids as opposed to macrophage–S-nanoparticle hybrids, reflecting the stability of the linkage between the nanoparticles and the cell. Confocal microscopy images in z-sections were taken to further examine the distribution of QD525 over the course of time. Without cell surface modification, QD525 were phagocytosed quickly and evenly distributed in the cytoplasm (Figure 4A – 4 h and 14 h). Although QD525 were still internalized, a significant amount of QD525 accumulated at the edge of the cells treated with sodium periodate (Figure 4B) or a combination of sodium periodate and sodium cyanoborohydride (Figure 4C). QD525 immobilized on the cell surface through a stable secondary amine bond displayed good stability overnight (Figure 4C – 14 h). In contrast, QD525 linked to the cell surface via Schiff base linkages were found to be re-distributed in the cell overnight (Figure 4B – 14 h).


Surface engineering of macrophages with nanoparticles to generate a cell-nanoparticle hybrid vehicle for hypoxia-targeted drug delivery.

Holden CA, Yuan Q, Yeudall WA, Lebman DA, Yang H - Int J Nanomedicine (2010)

Confocal microscopy images of macrophage–Qdot hybrids at four hours (left panel) or 14 hours (right panel) post-treatment. A) QD525 incubated with untreated macrophages (control); B) Macrophage–T-Qdot hybrids; C) Macrophage–S-Qdot hybrids.Notes: Original magnification, ×630.Abbreviation: Qdot, quantum dot.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2819902&req=5

f4-ijn-5-025: Confocal microscopy images of macrophage–Qdot hybrids at four hours (left panel) or 14 hours (right panel) post-treatment. A) QD525 incubated with untreated macrophages (control); B) Macrophage–T-Qdot hybrids; C) Macrophage–S-Qdot hybrids.Notes: Original magnification, ×630.Abbreviation: Qdot, quantum dot.
Mentions: Fluorescence microcopy and confocal microscopy were applied to conf irm the hybridization of nanoparticles with macrophages. As shown in Figure 3, both macrophage–T-nanoparticle hybrids and macrophage– S-nanoparticle hybrids prepared with QD525 exhibit strong fluorescence intensity at the edge of the cells, clearly outlining the cell surface. Qualitatively, more QD525 were taken up in macrophage–T-nanoparticle hybrids as opposed to macrophage–S-nanoparticle hybrids, reflecting the stability of the linkage between the nanoparticles and the cell. Confocal microscopy images in z-sections were taken to further examine the distribution of QD525 over the course of time. Without cell surface modification, QD525 were phagocytosed quickly and evenly distributed in the cytoplasm (Figure 4A – 4 h and 14 h). Although QD525 were still internalized, a significant amount of QD525 accumulated at the edge of the cells treated with sodium periodate (Figure 4B) or a combination of sodium periodate and sodium cyanoborohydride (Figure 4C). QD525 immobilized on the cell surface through a stable secondary amine bond displayed good stability overnight (Figure 4C – 14 h). In contrast, QD525 linked to the cell surface via Schiff base linkages were found to be re-distributed in the cell overnight (Figure 4B – 14 h).

Bottom Line: Nanoparticles immobilized on the cell surface provide numerous new sites for anticancer drug loading, hence potentially minimizing the toxic effect of anticancer drugs on the viability and hypoxia-targeting ability of the macrophage vehicles.Further, a reducing agent, sodium cyanoborohydride, was applied to reduce Schiff bases to stable secondary amine linkages.The distribution of nanoparticles on the cell surface was confirmed by fluorescence imaging, and it was found to be dependent on the stability of the linkages coupling nanoparticles to the cell surface.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA.

ABSTRACT
Tumors frequently contain hypoxic regions that result from a shortage of oxygen due to poorly organized tumor vasculature. Cancer cells in these areas are resistant to radiation- and chemotherapy, limiting the treatment efficacy. Macrophages have inherent hypoxia-targeting ability and hold great advantages for targeted delivery of anticancer therapeutics to cancer cells in hypoxic areas. However, most anticancer drugs cannot be directly loaded into macrophages because of their toxicity. In this work, we designed a novel drug delivery vehicle by hybridizing macrophages with nanoparticles through cell surface modification. Nanoparticles immobilized on the cell surface provide numerous new sites for anticancer drug loading, hence potentially minimizing the toxic effect of anticancer drugs on the viability and hypoxia-targeting ability of the macrophage vehicles. In particular, quantum dots and 5-(aminoacetamido) fluorescein-labeled polyamidoamine dendrimer G4.5, both of which were coated with amine-derivatized polyethylene glycol, were immobilized to the sodium periodate-treated surface of RAW264.7 macrophages through a transient Schiff base linkage. Further, a reducing agent, sodium cyanoborohydride, was applied to reduce Schiff bases to stable secondary amine linkages. The distribution of nanoparticles on the cell surface was confirmed by fluorescence imaging, and it was found to be dependent on the stability of the linkages coupling nanoparticles to the cell surface.

Show MeSH
Related in: MedlinePlus